PROFILE 1001: A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00585195
• Collaborator: (none)
• Enrollment: 590
• Locations: 29
• Arm: 1
• Actual Duration (Months): 189
• Patients Per Site: 20.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

PF-02341066 may work in cancer by blocking the cell growth, migration and invasion of tumor cells. PF-02341066 is a new class of drugs called c-Met/Hepatocyte growth factor receptor tyrosine kinase inhibitors. This compound is also an inhibitor of the anaplastic lymphoma kinase (called ALK) tyrosine kinase and ROS receptor tyrosine kinases. This research study is the first time PF-02341066 will be given to people. PF-02341066 is taken by mouth daily.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer ALK-positive; Non-Small Cell Lung Cancer c-Met Dependent; Non-Small Cell Lung Cancer ROS Marker Positive; Systemic Anaplastic Large-Cell Lymphoma; Advanced Malignancies Except Leukemia	Drug: PF-02341066; Drug: Rifampin; Drug: Itraconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 590 participants
• Allocation: N/A
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PHASE 1 SAFETY, PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF PF-02341066, A MET/HGFR SELECTIVE TYROSINE KINASE INHIBITOR, ADMINISTERED ORALLY TO PATIENTS WITH ADVANCED CANCER
• Actual Study Start Date: Apr 19, 2006
• Actual Primary Completion Date: Jul 30, 2020
• Actual Study Completion Date: Jan 19, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 1

Drug: PF-02341066; Escalating doses of PF-02341066 will be administered orally on a continuous dosing schedule. Doses to be evaluated will range from 50 mg to 2000 mg/day administered either once or twice a day. A treatment cycle is considered to be 28 days (or 21 days depending on the cohort).; Drug: Rifampin; 600 mg QD administered from Cycle 1, Day 16 to Cycle 2, Day 1 (14 days of dosing) in combination with PF-02341066.; Drug: Itraconazole; Multiple Dose Design: 200 mg QD administered from Cycle 1, Day 1 to Cycle 1, Day 16 (16 days) in combination with PF-02341066.

Outcome Measures

Primary Outcome Measures

1. Dose-Escalation Cohort: Maximum Tolerated Dose (MTD) of Crizotinib [Cycle 1 (28 days)]

   MTD: Dose level at which at most 1 of 6 participants experienced DLT within and including 28 days of treatment (during Cycle 1 [1 cycle=28 days]) with next higher dose having at least 2/3 or 2/6 participants experiencing a DLT. DLT was defined as any of following: Hematologic toxicities- 1) prolonged grade 4 neutropenia for >7 days. 2) Febrile neutropenia: grade 4 neutropenia with fever greater than (>) 38.5 degree Celsius, both sustained over a 24 hour period (3) neutropenic infection: greater than or equal to (>=) Grade 3 neutropenia with Grade >=3 infection. (4) Grade >=3 thrombocytopenia with bleeding/grade 4 lasting >=7 days. Other non-hematologic toxicity included: Grade 3/4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure [less than (<) 140/90 millimeter of mercury, and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting/diarrhea must persist at grade 3/4 despite maximal medical therapy.

2. Dose-Escalation Cohort: Recommended Phase 2 Dose (RP2D) of Crizotinib [Cycle 1 (28 days)]

   RP2D was defined as a dose below or equal to MTD, at which crizotinib was unlikely to cause a significant inhibition of CYP3A4 activity.

3. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Crizotinib on Day -7 [Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7]

   AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) extrapolated to infinite time (0-inf).

4. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Day -7 [Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7]

   Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.

5. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 1 [Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1]

   Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.

6. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 15 [Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15]

   Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.

7. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 2 Day 1 [Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1]

   Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.

8. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib Cycle 1 Day 15 [Pre-dose on Cycle 1 Day 15]

   Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.

9. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib on Cycle 2 Day 1 [Pre-dose on Cycle 2 Day 1]

   Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.

10. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Day -7 [Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7]

    Cmax is defined as the observed maximum plasma concentration post drug administration.

11. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 1 [Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1]

    Cmax is defined as the observed maximum plasma concentration post drug administration.

12. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 15 [Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15]

    Cmax is defined as the observed maximum plasma concentration post drug administration.

13. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 2 Day 1 [Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1]

    Cmax is defined as the observed maximum plasma concentration post drug administration.

14. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Day -7 [Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7]

    Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).

15. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 1 [Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1]

    Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).

16. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 15 [Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15]

    Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).

17. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib Cycle 2 Day 1 [Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1]

    Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).

18. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Plasma Decay Half-Life (t1/2) of Crizotinib on Day -7 [Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7]

    Plasma decay half-life is the time measured for the plasma concentration of Crizotinib to decrease by one half.

19. Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Number of Participants With Treatment Emergent Adverse Events (TEAES) and Serious Adverse Events (SAEs) [up to 172 Months]

    An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. AEs included both serious and all non-serious adverse events. TEAEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration.

20. Dose-Escalation Cohort: Number of Participants With Dose-limiting Toxicities (DLT) [Cycle 1 (28 days)]

    Dose-limiting toxicity (DLT) was defined as any of the following: Hematologic- prolonged grade 4 neutropenia for >7 days. Febrile neutropenia, defined as grade 4 neutropenia with fever greater than (>)38.5 degree Celsius, both sustained over a 24 hour period, neutropenic infection: greater than or equal to (>=)Grade 3 neutropenia with Grade >=3 infection. Grade >=3 thrombocytopenia with bleeding or grade 4 lasting >=7 days Lymphopenia was not considered a DLT unless accompanied by infection. Other non-hematologic toxicity: Grade 3 or 4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure [less than (<) 140/90], and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy.

21. Midazolam Interaction Cohort: Maximum Observed Plasma Concentration (Cmax) of MidaZolam When Taken Alone or Taken With Crizotinib [pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midaZolam with crizotinib arm)]

    Cmax is defined as the observed maximum plasma concentration post drug administration.

22. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of MidaZolam When Taken Alone or Taken With Crizotinib [pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midaZolam with crizotinib arm)]

    AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).

23. RP2D Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Crizotinib When Taken With Food [pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7]

    AUC0-24 of Crizotinib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.

24. RP2D Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken With Food [pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7]

    Cmax is defined as the observed maximum plasma concentration post drug administration.

25. Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib Alone and When Taken With Rifampin [pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)]

    Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau).

26. Rifampin Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib Alone and When Taken With Rifampin [pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone) and Cycle 2 Day 1 (Crizotinib with Rifampin)]

27. Rifampin Cohort: Ctrough of Crizotinib Alone and When Taken With Rifampin [pre-dose on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)]

    Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.

28. Itraconazole Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib When Taken Alone and When Taken With Itraconazole [pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)]

    Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours.

29. Itraconazole Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken Alone and When Taken With Itraconazole [pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)]

30. Itraconazole Cohort: Trough Plasma Concentration (Ctrough) of Crizotinib When Taken Alone and When Taken With Itraconazole [pre-dose on Cycle 1 Day 15 (crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)]

    Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.

31. Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Objective Response (OR) [Baseline up to 172 months]

    ORR was defined as participants with a best overall response of complete response (CR) or partial response (PR) divided by the total number of evaluable participants per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response.

32. Recommended Phase 2 Dose (RP2D) Cohort: Duration of Response (DOR) [From first documentation of response to date of PD or death due to any cause (up to 172 months)]

    Duration of response (DoR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.

33. Recommended Phase 2 Dose (RP2D) Cohort: Time to Response (TTR) [From first dose until first documented response of PR or CR (up to 172 months)]

    TTR: time between first dose until first documented response of PR or CR. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response.

34. Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 8 [Week 8]

    Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

35. Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 16 [Week 16]

    Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

36. Recommended Phase 2 Dose (RP2D) Cohort: Progression Free Survival (PFS) [From randomization until PD or death, whichever occurred first (up to 172 months)]

    Progression free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.

37. Recommended Phase 2 Dose (RP2D) Cohort: Probability of Being Event Free at Month 6 [From randomization to 6 months]

    Probability of being event free (event defined as PD or death due to any cause) at 6 months after the first dose of crizotinib was reported. PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.

38. Recommended Phase 2 Dose (RP2D) Cohort: Overall Survival (OS) [From randomization date to the date of death (up to 172 Months)]

    OS was defined as the time from randomization to death due to any cause.

39. Probability of Participant Survival at Month 6 [Month 6]

    Probability of survival was defined as the probability of being alive at Month 6.

40. Probability of Participant Survival at Month 12 [Month 12]

    Probability of survival was defined as the probability of being alive at Month 12.

41. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 1 Day 15 [Baseline, Cycle 1 Day 15]

    Geometric mean of ratio (Cycle1Day15/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.

42. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 2 Day 1 [Baseline, Cycle 2 Day 1]

    Geometric mean of ratio (Cycle 2 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.

43. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 4 Day 1 [Baseline, Cycle 4 Day 1]

    Geometric mean of ratio (Cycle 4 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.

44. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 6 Day 1 [Baseline, Cycle 6 Day 1]

    Geometric mean of ratio (Cycle 6 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.

45. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 9 Day 1 [Baseline, Cycle 9 Day 1]

    Geometric mean of ratio (Cycle 9 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

46. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 12 Day 1 [Baseline, Cycle 12 Day 1]

    Geometric mean of ratio (Cycle 12 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

47. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 15 Day 1 [Baseline, Cycle 15 Day 1]

    Geometric mean of ratio (Cycle 15 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

48. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 18 Day 1 [Baseline, Cycle 18 Day 1]

    Geometric mean of ratio (Cycle 18 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

49. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 21 Day 1 [Baseline, Cycle 21 Day 1]

    Geometric mean of ratio (Cycle 21 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

50. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 24 Day 1 [Baseline, Cycle 24 Day 1]

    Geometric mean of ratio (Cycle 24 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

51. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 27 Day 1 [Baseline, Cycle 27 Day 1]

    Geometric mean of ratio (Cycle 27 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

52. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 30 Day 1 [Baseline, Cycle 30 Day 1]

    Geometric mean of ratio (Cycle 30 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

53. Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at End of Treatment [Baseline, End of Treatment (28 days post last dose)]

    Geometric mean of ratio (End of treatment/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Advanced malignancies (except leukemias), histologically proven at diagnosis; Histologically confirmed advanced malignancies that are known to be sensitive to PF-03241066 inhibition, e.g. ALK, c-MET and ROS

• Solid tumors must have measurable disease (Recommended Phase 2 Dose Cohort patients with non-measurable disease may enter on a case-by-case basis); not required for DDI sub-studies.

• Adequate blood cell counts, kidney function, liver function and Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (for the Recommended Phase 2 Cohort, a ECOG score of 2 may be allowed on a case-by-case basis)

Exclusion Criteria:

• Major surgery, radiation therapy or anti-cancer therapy within 2 to 4 weeks of starting study treatment, depending on the patient cohort

• Prior stem cell transplant except of patients with neuroblastoma, lymphoma or myeloma

• Active or unstable cardiac disease or heart attack within 3 months of starting study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Irvine Medical Center	Orange	California	United States	92868-3201
2	University of Colorado Hospital/ Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
3	University of Colorado Hospital	Aurora	Colorado	United States	80045
4	University of Colorado	Aurora	Colorado	United States	80045
5	University of Chicago	Chicago	Illinois	United States	60637
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Ophthalmic Consultants of Boston Inc.	Boston	Massachusetts	United States	02114
8	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
9	Dana Farber Cancer Center	Boston	Massachusetts	United States	02215
10	Joslin Beetham Eye Institute	Boston	Massachusetts	United States	02215
11	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
12	Kresge Eye Institute	Detroit	Michigan	United States	48201
13	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10022
14	Memorial Sloan Kettering Cancer Center: Breast and Imaging Center	New York	New York	United States	10065
15	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
16	UNC Hospitals	Chapel Hill	North Carolina	United States	27599-7600
17	The James Cancer Hospital and Solove Research Institute	Columbus	Ohio	United States	43210
18	Ohio State Eye and Ear Institute	Columbus	Ohio	United States	43212
19	The Ohio State University Martha Morehouse Medical Plaza	Columbus	Ohio	United States	43221
20	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
21	Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
22	Vanderbilt Eye Institute	Nashville	Tennessee	United States	37232
23	The University of Vermont Medical Center	Burlington	Vermont	United States	05401
24	The University of Vermont Cancer Center	Burlington	Vermont	United States	05405
25	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
26	Aichi cancer center central hospital	Nagoya	Aichi	Japan	464-8681
27	Hyogo Cancer Center	Akashi	Hyogo	Japan	673-8558
28	Kindai University Hospital	Osakasayama	Osaka	Japan	589-8511
29	Seoul National University Hospital	Seoul		Korea, Republic of	03080

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Mar 26, 2019
• Statistical Analysis Plan - Aug 22, 2019

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00585195
• Other Study ID Numbers: A8081001; PROFILE 1001
• First Posted: Jan 3, 2008
• Last Update Posted: Feb 28, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Pfizer: Crizotinib; dose-finding; drug-drug interaction; ALK rearrangements; c-Met mutations or amplifications; c-Met dependent tumors; ROS1 rearrangements; c-Met exon 14 deletion; c-Met exon 14 skipping; c-Met exon 14 alterations
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Lymphoma, Large-Cell, Anaplastic; Itraconazole; Rifampin; Crizotinib

Study Results

Participant Flow

Pre-assignment Detail	There was a lead-in period of 7 days in which single-dose pharmacokinetics of Crizotinib or midazolam was characterized on Day-7, prior to initiation of continuous dosing in the first cycle (each cycle 28 days) of treatment in dose escalation cohorts and recommended phase 2 dose (RP2D) cohorts.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin	RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID with or without food from Day 1 Cycle 1 up to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1
Period Title: Overall Study
STARTED	3	4	9	7	9	6	7	5	3	6	11	53	85	41	48	19	154	67	21	18	14
Treated	3	4	8	7	8	6	6	5	3	6	9	53	85	41	48	18	154	66	18	18	12
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	3	4	9	7	9	6	7	5	3	6	11	53	85	41	48	19	154	67	21	18	14

Baseline Characteristics

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin	RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam	Total
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID with or without food from Day 1 Cycle 1 up to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1	Total of all reporting groups
Overall Participants	3	4	8	7	8	6	6	5	3	6	9	53	85	41	48	18	154	66	18	18	12	578
Age, Customized (participants) [Number]
less than 65 years	3 100%	4 100%	5 62.5%	5 71.4%	8 100%	6 100%	3 50%	5 100%	3 100%	6 100%	5 55.6%	23 43.4%	18 21.2%	20 48.8%	30 62.5%	12 66.7%	131 85.1%	51 77.3%	9 50%	12 66.7%	9 75%	368 63.7%
greater than or equals to 65 years	0 0%	0 0%	3 37.5%	2 28.6%	0 0%	0 0%	3 50%	0 0%	0 0%	0 0%	4 44.4%	30 56.6%	67 78.8%	21 51.2%	18 37.5%	6 33.3%	23 14.9%	15 22.7%	9 50%	6 33.3%	3 25%	210 36.3%
Sex: Female, Male (Count of Participants)
Female	3 100%	1 25%	2 25%	3 42.9%	4 50%	2 33.3%	3 50%	5 100%	0 0%	1 16.7%	3 33.3%	30 56.6%	48 56.5%	19 46.3%	24 50%	8 44.4%	80 51.9%	25 37.9%	11 61.1%	9 50%	8 66.7%	289 50%
Male	0 0%	3 75%	6 75%	4 57.1%	4 50%	4 66.7%	3 50%	0 0%	3 100%	5 83.3%	6 66.7%	23 43.4%	37 43.5%	22 53.7%	24 50%	10 55.6%	74 48.1%	41 62.1%	7 38.9%	9 50%	4 33.3%	289 50%
Race/Ethnicity, Customized (Count of Participants)
White	2 66.7%	3 75%	7 87.5%	6 85.7%	8 100%	6 100%	6 100%	4 80%	2 66.7%	5 83.3%	8 88.9%	30 56.6%	60 70.6%	38 92.7%	35 72.9%	11 61.1%	98 63.6%	49 74.2%	13 72.2%	16 88.9%	11 91.7%	418 72.3%
Black	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 20%	1 33.3%	0 0%	0 0%	2 3.8%	2 2.4%	2 4.9%	1 2.1%	3 16.7%	5 3.2%	4 6.1%	3 16.7%	2 11.1%	0 0%	27 4.7%
Asian	0 0%	0 0%	1 12.5%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 11.1%	21 39.6%	15 17.6%	1 2.4%	9 18.8%	2 11.1%	43 27.9%	9 13.6%	0 0%	0 0%	0 0%	102 17.6%
Other	0 0%	1 25%	0 0%	1 14.3%	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	0 0%	8 9.4%	0 0%	3 6.3%	2 11.1%	8 5.2%	4 6.1%	2 11.1%	0 0%	1 8.3%	31 5.4%

Outcome Measures

1. Primary Outcome

Title	Dose-Escalation Cohort: Maximum Tolerated Dose (MTD) of Crizotinib
Description	MTD: Dose level at which at most 1 of 6 participants experienced DLT within and including 28 days of treatment (during Cycle 1 [1 cycle=28 days]) with next higher dose having at least 2/3 or 2/6 participants experiencing a DLT. DLT was defined as any of following: Hematologic toxicities- 1) prolonged grade 4 neutropenia for >7 days. 2) Febrile neutropenia: grade 4 neutropenia with fever greater than (>) 38.5 degree Celsius, both sustained over a 24 hour period (3) neutropenic infection: greater than or equal to (>=) Grade 3 neutropenia with Grade >=3 infection. (4) Grade >=3 thrombocytopenia with bleeding/grade 4 lasting >=7 days. Other non-hematologic toxicity included: Grade 3/4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure [less than (<) 140/90 millimeter of mercury, and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting/diarrhea must persist at grade 3/4 despite maximal medical therapy.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description

Safety analysis (SA) set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).
Measure Participants	3	4	8	7	8	6	6	5	3	6	9
Number [milligram]	250	250	250	250	250	250	250	250	250	250	250

2. Primary Outcome

Title	Dose-Escalation Cohort: Recommended Phase 2 Dose (RP2D) of Crizotinib
Description	RP2D was defined as a dose below or equal to MTD, at which crizotinib was unlikely to cause a significant inhibition of CYP3A4 activity.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description

Safety analysis (SA) set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).
Measure Participants	3	4	8	7	8	6	6	5	3	6	9
Number [milligram]	250	250	250	250	250	250	250	250	250	250	250

3. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Crizotinib on Day -7
Description	AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) extrapolated to infinite time (0-inf).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. "Overall number of participants analyzed (N)" signifies participants evaluable for this outcome measure (OM). Data for this OM was planned to be collected for individual arms of low and high dose escalation and combined RP2D Cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" arm.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	7	2	8	1	5	5	2	6	8	29
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	274.43 (22)	1378.05 (144)	946.93 (38)	1817.35 (34)	2320.00	3457 (42)	3078 (119)	2107 (53)	3979 (39)	7547 (76)	2489.39 (53)

4. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Day -7
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be reported for individual arms of low and high dose escalation and combined RP2D Cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" arm.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	8	5	9	1	6	5	3	6	8	46
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	137.40 (8)	658.64 (136)	338.39 (50)	558.01 (33)	863.00	1731 (51)	1377 (114)	1300 (61)	1906 (39)	3423 (57)	741.50 (45)

5. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 1
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for low dose escalation cohort (excluding Crizotinib 50 mg QD, Crizotinib 200 mg QD and Crizotinib 250 mg BID arms) and combined RP2D cohort and was not planned to be collected for high dose escalation cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	4	2	5	88
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	457.55 (32)	383.98 (10)	763.71 (57)	663.39 (56)

6. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 15
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	4	8	4	5	4	6	2	3	5	3	19
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	206.13 (76)	1086.99 (34)	2047.13 (45)	1780.21 (69)	3083.93 (31)	4066.67 (53)	4375 (34)	3385 (24)	6655 (4)	6362 (37)	10480 (76)	3879.56 (45)

7. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 2 Day 1
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	3	5	3	5	2	5	3	2	4	2	16
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	425.90 (49)	1595.58 (30)	1719.30 (68)	2255.70 (14)	3054.45 (29)	3644.72 (17)	4815 (23)	3839 (65)	6330 (64)	7273 (48)	8733 (63)	4163.77 (40)

8. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib Cycle 1 Day 15
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	Pre-dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low dose escalation and combined RP2D Cohort and not planned to be collected for high dose escalation cohort".

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	4	8	3	5	4	24
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	7.29 (42)	32.61 (36)	48.18 (58)	126.76 (97)	232.59 (33)	307.83 (59)	280.43 (75)

9. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib on Cycle 2 Day 1
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	Pre-dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low dose escalation and combined RP2D Cohort and not planned to be collected for high dose escalation cohort".

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	3	5	3	5	3	18
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	12.68 (94)	31.91 (34)	54.04 (85)	157.24 (17)	232.45 (32)	329.50 (40)	312.99 (55)

10. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Day -7
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population set. "N"=participants evaluable for this outcome measure. Data for this OM was planned to be collected for dose escalation cohorts (both low and high) and combined RP2D Cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" cohort arms.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	8	5	9	1	6	5	3	6	8	46
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	24.19 (36)	67.64 (106)	55.73 (45)	87.02 (34)	130.00	184.7 (65)	115.9 (85)	146.6 (31)	154.3 (30)	270.9 (47)	108.40 (42)

11. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 1
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for low dose escalation cohort (excluding Crizotinib 50 mg QD, Crizotinib 200 mg QD and Crizotinib 250 mg BID arms) and combined RP2D cohort and was not planned to be collected for high dose escalation cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	4	2	5	98
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	54.89 (53)	64.14 (2)	114.09 (48)	98.86 (55)

12. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 15
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	4	8	4	5	4	6	3	3	5	4	24
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	24.44 (68)	85.66 (66)	149.06 (29)	188.84 (56)	326.51 (24)	420.15 (46)	315.2 (50)	215.5 (26)	395.3 (16)	379.2 (28)	671.3 (76)	411.11 (51)

13. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 2 Day 1
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	4	5	3	5	3	6	3	2	4	2	18
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	47.99 (23)	133.69 (48)	146.26 (38)	238.84 (12)	327.94 (25)	474.68 (43)	275.0 (28)	248.2 (60)	327.9 (47)	419.8 (36)	700.0 (37)	477.85 (44)

14. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Day -7
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low and high dose escalation cohorts (excluding 'Low Dose Escalation Cohort: Crizotinib 100 mg QD' arm) and combined RP2D.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	8	5	9	1	6	5	3	6	8	46
Median (Full Range) [hour]	2.00	4.09	4.00	4.00	2.02	4.00	2.15	4.00	4.00	4.99	4.00

15. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 1
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for low dose escalation cohorts (excluding Crizotinib 50 mg QD, Crizotinib 200 mg QD and Crizotinib 250 mg BID arms) and combined RP2D cohort and was not planned to be collected for high dose escalation cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	4	2	5	98
Median (Full Range) [hour]	2.52	4.00	4.00	4.05

16. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 15
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	4	8	4	5	4	6	3	3	5	4	24
Median (Full Range) [hour]	2.00	2.51	4.07	5.01	4.00	4.99	5.13	5.17	4.00	5.98	5.03	4.00

17. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib Cycle 2 Day 1
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	3	5	3	5	3	6	3	2	4	2	18
Median (Full Range) [hour]	1.02	3.98	4.00	4.00	4.00	4.05	3.00	4.00	7.59	4.30	5.00	4.00

18. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Plasma Decay Half-Life (t1/2) of Crizotinib on Day -7
Description	Plasma decay half-life is the time measured for the plasma concentration of Crizotinib to decrease by one half.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low and high dose escalation cohort and combined RP2D cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" arm.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3	7	2	8	1	5	5	2	6	8	31
Median (Full Range) [hour]	48.20	46.70	52.60	47.35	45.70	43.33	49.06	46.36	42.17	38.78	43.20

19. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Number of Participants With Treatment Emergent Adverse Events (TEAES) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. AEs included both serious and all non-serious adverse events. TEAEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration.
Time Frame	up to 172 Months

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin	RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days)	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID with or without food from Day 1 Cycle 1 up to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1
Measure Participants	3	4	8	7	8	6	6	5	3	6	9	53	85	41	48	18	154	66	18	18	12
AEs	3 100%	4 100%	8 100%	7 100%	8 100%	6 100%	6 100%	4 80%	3 100%	6 100%	9 100%	53 100%	85 100%	41 100%	47 97.9%	18 100%	154 100%	66 100%	14 77.8%	5 27.8%	12 100%
SAEs	0 0%	0 0%	1 12.5%	2 28.6%	4 50%	2 33.3%	2 33.3%	2 40%	1 33.3%	2 33.3%	4 44.4%	24 45.3%	54 63.5%	25 61%	22 45.8%	9 50%	75 48.7%	29 43.9%	7 38.9%	6 33.3%	6 50%

20. Primary Outcome

Title	Dose-Escalation Cohort: Number of Participants With Dose-limiting Toxicities (DLT)
Description	Dose-limiting toxicity (DLT) was defined as any of the following: Hematologic- prolonged grade 4 neutropenia for >7 days. Febrile neutropenia, defined as grade 4 neutropenia with fever greater than (>)38.5 degree Celsius, both sustained over a 24 hour period, neutropenic infection: greater than or equal to (>=)Grade 3 neutropenia with Grade >=3 infection. Grade >=3 thrombocytopenia with bleeding or grade 4 lasting >=7 days Lymphopenia was not considered a DLT unless accompanied by infection. Other non-hematologic toxicity: Grade 3 or 4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure [less than (<) 140/90], and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).
Measure Participants	3	4	8	7	8	6	6	5	3	6	9
Count of Participants [Participants]	0 0%	0 0%	1 12.5%	0 0%	0 0%	2 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%

21. Primary Outcome

Title	Midazolam Interaction Cohort: Maximum Observed Plasma Concentration (Cmax) of MidaZolam When Taken Alone or Taken With Crizotinib
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midaZolam with crizotinib arm)

Outcome Measure Data

Analysis Population Description

The PK concentration population of midazolam included all participants treated with midazolam (including Day -7 dose) who have at least 1 concentration of midazolam.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam	Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam	RP2D Cohort: Crizotinib 250 mg (Midazolam Alone)	RP2D Cohort: Crizotinib 250 mg + Midazolam
Arm/Group Description	Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 100 mg capsule or tablet orally QD along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet BID on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID along with 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) BID along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.
Measure Participants	4	3	5	2	14	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	14.98 (19)	19.26 (38)	13.65 (10)	32.62 (40)	12.78 (41)	25.37 (67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 50 mg QD, Low Dose Escalation Cohort: Crizotinib 100 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	131.72
	Confidence Interval	(2-Sided) 90%; 96.59 to 179.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 200 mg QD, Low Dose Escalation Cohort: Crizotinib 200 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	239.03
	Confidence Interval	(2-Sided) 90%; 172.14 to 331.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 250 mg BID, Low Dose Escalation Cohort: Crizotinib 300 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	201.56
	Confidence Interval	(2-Sided) 90%; 139.33 to 291.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Primary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of MidaZolam When Taken Alone or Taken With Crizotinib
Description	AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
Time Frame	pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midaZolam with crizotinib arm)

Outcome Measure Data

Analysis Population Description

The PK concentration population of midazolam included all participants treated with midazolam (including Day -7 dose) who have at least 1 concentration of midazolam.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam	Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam	RP2D Cohort: Crizotinib 250 mg (Midazolam Alone)	RP2D Cohort: Crizotinib 250 mg +Midazolam
Arm/Group Description	Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 100 mg capsule or tablet orally QD along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet BID on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID along with 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet on Day -7, received single 2 mg oral dose of Midazolam on Day -7	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) BID along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.
Measure Participants	4	3	5	2	14	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	41.77 (27)	90.78 (33)	37.71 (38)	151.45 (31)	32.10 (36)	112.78 (87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 50 mg QD, Low Dose Escalation Cohort: Crizotinib 100 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	216.19
	Confidence Interval	(2-Sided) 90%; 161.41 to 289.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 200 mg QD, Low Dose Escalation Cohort: Crizotinib 200 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	350.00
	Confidence Interval	(2-Sided) 90%; 141.09 to 868.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 250 mg BID, Low Dose Escalation Cohort: Crizotinib 300 mg BID
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	365.43
	Confidence Interval	(2-Sided) 90%; 263.22 to 507.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Primary Outcome

Title	RP2D Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Crizotinib When Taken With Food
Description	AUC0-24 of Crizotinib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7

Outcome Measure Data

Analysis Population Description

The food effect analysis set included all participants treated (including Day -7 dose) and in the RP2D cohort who had received a dose of crizotinib under fed conditions and for which at least 1 PK parameter of interest (Cmax or AUC) was available. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg With Food
Arm/Group Description	Participants who were enrolled in enriched RP2D cohort received single dose of Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally with food on Day -7.
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	1212.86 (46)

24. Primary Outcome

Title	RP2D Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken With Food
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7

Outcome Measure Data

Analysis Population Description

The food effect analysis set included all participants treated (including Day -7 dose) and in the RP2D cohort who had received a dose of crizotinib under fed conditions and for which at least 1 PK parameter of interest (Cmax or AUC) was available. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg With Food
Arm/Group Description	Participants who were enrolled in enriched RP2D cohort received single dose of Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally with food on Day -7.
Measure Participants	11
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	106.24 (51)

25. Primary Outcome

Title	Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib Alone and When Taken With Rifampin
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau).
Time Frame	pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)

Outcome Measure Data

Analysis Population Description

PK parameter population was defined as all participants in the Rifampin interaction cohort safety population who satisfied following criteria for Cycle 1 Day 15 or Cycle 2 Day 1: a) had at least 1 of the primary PK parameters of Crizotinib (AUCtau and Cmax). b) received adequate dosing prior to PK sampling. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) form Cycle 1Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after a meal.
Measure Participants	10	7
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	3110 (49)	509.6 (35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 50 mg QD, Low Dose Escalation Cohort: Crizotinib 100 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric mean
	Estimated Value	15.57
	Confidence Interval	(2-Sided) 90%; 10.89 to 22.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Primary Outcome

Title	Rifampin Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib Alone and When Taken With Rifampin
Time Frame	pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone) and Cycle 2 Day 1 (Crizotinib with Rifampin)

Outcome Measure Data

Analysis Population Description

PK parameter population was defined as all participants in the Rifampin interaction cohort safety population who satisfied following criteria for Cycle 1 Day 15 or Cycle 2 Day 1: a) had at least 1 of the primary PK parameters of Crizotinib (AUCtau and Cmax). b) Received adequate dosing prior to PK sampling. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) form Cycle 1Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after a meal.
Measure Participants	10	7
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	326.4 (48)	71.53 (49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 50 mg QD, Low Dose Escalation Cohort: Crizotinib 100 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric mean
	Estimated Value	20.64
	Confidence Interval	(2-Sided) 90%; 14.59 to 29.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Primary Outcome

Title	Rifampin Cohort: Ctrough of Crizotinib Alone and When Taken With Rifampin
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	pre-dose on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)

Outcome Measure Data

Analysis Population Description

PK parameter population was defined as all participants in the Rifampin interaction cohort safety population who satisfied following criteria for Cycle 1 Day 15 or Cycle 2 Day 1: a) had at least 1 of the primary PK parameters of Crizotinib (AUCtau and Cmax). b) Received adequate dosing prior to PK sampling. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) form Cycle 1Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after a meal.
Measure Participants	9	7
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	251.7 (46)	26.67 (50)

28. Primary Outcome

Title	Itraconazole Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib When Taken Alone and When Taken With Itraconazole
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours.
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)

Outcome Measure Data

Analysis Population Description

PK parameter evaluable population included participants who had at least 1 of the PK parameters of Crizotinib (AUCtau or Cmax) and had received 10 consecutive doses of both Crizotinib 250 mg QD and itraconazole 200 mg QD immediately prior to end of Crizotinib 250 mg + Itraconazole treatment as well as 10 consecutive doses of Crizotinib 250 mg QD prior to end of Crizotinib 250 mg + Itraconazole treatment. Overall number of participants analyzed =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone	Itraconazole Interaction Cohort: Crizotinib 250 mg + Itraconazole
Arm/Group Description	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16. (each cycle 28 days).
Measure Participants	10	10
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter]	4102 (31)	6665 (16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 50 mg QD, Low Dose Escalation Cohort: Crizotinib 100 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	157.40
	Confidence Interval	(2-Sided) 90%; 136.89 to 180.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Primary Outcome

Title	Itraconazole Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken Alone and When Taken With Itraconazole
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)

Outcome Measure Data

Analysis Population Description

PK parameter evaluable population included participants who had at least 1 of the PK parameters of Crizotinib (AUCtau or Cmax) and had received 10 consecutive doses of both Crizotinib 250 mg QD and itraconazole 200 mg QD immediately prior to end of Crizotinib 250 mg + Itraconazole treatment as well as 10 consecutive doses of Crizotinib 250 mg QD prior to end of Crizotinib 250 mg + Itraconazole treatment. Overall number of participants analyzed =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole
Arm/Group Description	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16. (each cycle 28 days).
Measure Participants	10	10
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	259.9 (23)	353.2 (14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 50 mg QD, Low Dose Escalation Cohort: Crizotinib 100 mg QD
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	132.81
	Confidence Interval	(2-Sided) 90%; 119.10 to 148.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Primary Outcome

Title	Itraconazole Cohort: Trough Plasma Concentration (Ctrough) of Crizotinib When Taken Alone and When Taken With Itraconazole
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	pre-dose on Cycle 1 Day 15 (crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)

Outcome Measure Data

Analysis Population Description

PK parameter evaluable population included participants who had at least 1 of the PK parameters of Crizotinib (AUCtau or Cmax) and had received 10 consecutive doses of both Crizotinib 250 mg QD and itraconazole 200 mg QD immediately prior to end of Crizotinib 250 mg + Itraconazole treatment as well as 10 consecutive doses of Crizotinib 250 mg QD prior to end of Crizotinib 250 mg + Itraconazole treatment. Overall number of participants analyzed =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole
Arm/Group Description	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16. (each cycle 28 days).
Measure Participants	7	9
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter]	136.0 (36)	214.0 (30)

31. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Objective Response (OR)
Description	ORR was defined as participants with a best overall response of complete response (CR) or partial response (PR) divided by the total number of evaluable participants per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response.
Time Frame	Baseline up to 172 months

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants Analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).
Measure Participants	53	65	38	18	116	66
Number (95% Confidence Interval) [percentage of participants]	71.7 2390%	32.3 807.5%	31.6 395%	19.0 271.4%	61.2 765%	8.3 138.3%

32. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Duration of Response (DOR)
Description	Duration of response (DoR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	From first documentation of response to date of PD or death due to any cause (up to 172 months)

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants who were objective responders. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	38	33	12	71
Median (Full Range) [Weeks]	14.5	6.8	5.2	26.2

33. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Time to Response (TTR)
Description	TTR: time between first dose until first documented response of PR or CR. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response.
Time Frame	From first dose until first documented response of PR or CR (up to 172 months)

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants who were objective responders. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	38	33	12	71
Median (Full Range) [Weeks]	7.9	7.6	8.0	7.7

34. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 8
Description	Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).
Measure Participants	53	85	116	18
Number (95% Confidence Interval) [percentage of participants]	86.8 2893.3%	71.8 1795%	79.3 991.3%	47.6 680%

35. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 16
Description	Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).
Measure Participants	53	85	116	18
Number (95% Confidence Interval) [percentage of participants]	79.2 2640%	51.8 1295%	67.2 840%	42.9 612.9%

36. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Progression Free Survival (PFS)
Description	Progression free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	From randomization until PD or death, whichever occurred first (up to 172 months)

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	53	85	41	119
Median (95% Confidence Interval) [Months]	19.3	7.6	4.0	10.0

37. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Probability of Being Event Free at Month 6
Description	Probability of being event free (event defined as PD or death due to any cause) at 6 months after the first dose of crizotinib was reported. PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	From randomization to 6 months

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall Number of Participants Analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	53	85	41	119
Number (95% Confidence Interval) [Probability of being event-free]	76.9	57.5	39.0	71.9

38. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	From randomization date to the date of death (up to 172 Months)

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	53	85	41	119
Median (95% Confidence Interval) [Months]	51.4	20.0	10.1	NA

39. Primary Outcome

Title	Probability of Participant Survival at Month 6
Description	Probability of survival was defined as the probability of being alive at Month 6.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	53	85	41	119
Number (95% Confidence Interval) [Probability of participants survival]	90.5 3016.7%	86.7 2167.5%	67.8 847.5%	90.0 1285.7%

40. Primary Outcome

Title	Probability of Participant Survival at Month 12
Description	Probability of survival was defined as the probability of being alive at Month 12.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall Number of Participants Analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Measure Participants	53	85	41	119
Number (95% Confidence Interval) [probability of participants survival]	78.8 2626.7%	66.0 1650%	37.1 463.8%	80.5 1150%

41. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 1 Day 15
Description	Geometric mean of ratio (Cycle1Day15/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	28
Testosterone	0.46
Estradiol	0.53
Prolactin	1.19
Luteinizing Hormone (LH) Serum	0.58
Follicle Stimulating Hormone	0.77
Free Testosterone	0.96
Sex Hormone Binding Globulin	0.36
Dihydroepiandrosterone Sulfate	0.97

42. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 2 Day 1
Description	Geometric mean of ratio (Cycle 2 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	25
Testosterone	0.47
Estradiol	0.72
Prolactin	0.89
LH Serum	0.42
Follicle Stimulating Hormone	0.69
Free Testosterone	1.31
Sex Hormone Binding Globulin	0.24
Dihydroepiandrosterone Sulfate	0.85

43. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 4 Day 1
Description	Geometric mean of ratio (Cycle 4 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 4 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	10
Testosterone	0.48
Estradiol	0.66
Prolactin	0.84
LH Serum	0.75
Follicle Stimulating Hormone	0.88
Free Testosterone	1.63
Sex Hormone Binding Globulin	0.22
Dihydroepiandrosterone Sulfate	0.81

44. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 6 Day 1
Description	Geometric mean of ratio (Cycle 6 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 6 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	10
Testosterone	0.49
Estradiol	0.75
Prolactin	0.69
LH Serum	0.78
Follicle Stimulating Hormone	1.07
Free Testosterone	1.71
Sex Hormone Binding Globulin	0.25
Dihydroepiandrosterone Sulfate	0.87

45. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 9 Day 1
Description	Geometric mean of ratio (Cycle 9 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 9 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	6
Testosterone	0.38
Estradiol	0.56
Prolactin	1.19
LH Serum	0.72
Follicle Stimulating Hormone	0.83
Free Testosterone	1.23
Sex Hormone Binding Globulin	0.19
Dihydroepiandrosterone Sulfate	0.72

46. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 12 Day 1
Description	Geometric mean of ratio (Cycle 12 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 12 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	6
Testosterone	0.38
Estradiol	0.66
Prolactin	1.06
LH Serum	0.88
Follicle Stimulating Hormone	1.02
Free Testosterone	1.39
Sex Hormone Binding Globulin	0.23
Dihydroepiandrosterone Sulfate	0.75

47. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 15 Day 1
Description	Geometric mean of ratio (Cycle 15 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 15 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	4
Testosterone	0.49
Estradiol	1.03
Prolactin	1.32
LH Serum	0.90
Follicle Stimulating Hormone	0.81
Free Testosterone	1.71
Sex Hormone Binding Globulin	0.24
Dihydroepiandrosterone Sulfate	0.76

48. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 18 Day 1
Description	Geometric mean of ratio (Cycle 18 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 18 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	3
Testosterone	0.32
Estradiol	0.55
Prolactin	1.64
LH Serum	0.69
Follicle Stimulating Hormone	0.89
Free Testosterone	1.10
Sex Hormone Binding Globulin	0.18
Dihydroepiandrosterone Sulfate	0.69

49. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 21 Day 1
Description	Geometric mean of ratio (Cycle 21 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 21 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	2
Testosterone	0.23
Estradiol	0.48
Prolactin	1.46
LH Serum	0.53
Follicle Stimulating Hormone	0.77
Free Testosterone	1.23
Sex Hormone Binding Globulin	0.15
Dihydroepiandrosterone Sulfate	0.72

50. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 24 Day 1
Description	Geometric mean of ratio (Cycle 24 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 24 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	2
Testosterone	0.39
Estradiol	0.70
Prolactin	1.13
LH Serum	0.69
Follicle Stimulating Hormone	0.53
Free Testosterone	2.35
Sex Hormone Binding Globulin	0.20
Dihydroepiandrosterone Sulfate	0.90

51. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 27 Day 1
Description	Geometric mean of ratio (Cycle 27 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 27 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	2
Testosterone	0.46
Estradiol	0.97
Prolactin	1.48
LH Serum	0.70
Follicle Stimulating Hormone	0.66
Free Testosterone	1.86
Sex Hormone Binding Globulin	0.24
Dihydroepiandrosterone Sulfate	0.95

52. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 30 Day 1
Description	Geometric mean of ratio (Cycle 30 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 30 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	1
Testosterone	0.16
Estradiol	0.38
Prolactin	1.14
LH Serum	0.85
Follicle Stimulating Hormone	0.80
Free Testosterone	1.25
Sex Hormone Binding Globulin	0.09
Dihydroepiandrosterone Sulfate	0.71

53. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at End of Treatment
Description	Geometric mean of ratio (End of treatment/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, End of Treatment (28 days post last dose)

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Measure Participants	5
Testosterone	0.40
Estradiol	0.66
Prolactin	1.48
LH Serum	0.52
Follicle Stimulating Hormone	0.85
Free Testosterone	0.62
Sex Hormone Binding Globulin	0.64
Dihydroepiandrosterone Sulfate	0.41

Adverse Events

Time Frame	Until 28 days after the last dose day of study drug (up to 172 months)
Adverse Event Reporting Description	Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis performed on safety analysis set.
Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD		Low Dose Escalation Cohort: Crizotinib 100 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg BID		Low Dose Escalation Cohort: Crizotinib 250 mg BID		Low Dose Escalation Cohort: Crizotinib 300 mg BID		High Dose Escalation Cohort: Crizotinib 300 mg QD		High Dose Escalation Cohort: Crizotinib 400 mg QD		High Dose Escalation Cohort: Crizotinib 500 mg QD		High Dose Escalation Cohort: Crizotinib 650 mg QD		High Dose Escalation Cohort: Crizotinib 800 mg QD		RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg		RP2D Cohort: Enriched Other: Crizotinib 250 mg		Itraconazole Interaction Sub-study: Crizotinib 250 mg		RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin		Midazolam Interaction Cohort: Crizotinib 250
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).		Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.		Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).		Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).		Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.		Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).		Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).		Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).		Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).		Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.		Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID from Day 1Cycle 1 up to p to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1.
All Cause Mortality
	Low Dose Escalation Cohort: Crizotinib 50 mg QD		Low Dose Escalation Cohort: Crizotinib 100 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg BID		Low Dose Escalation Cohort: Crizotinib 250 mg BID		Low Dose Escalation Cohort: Crizotinib 300 mg BID		High Dose Escalation Cohort: Crizotinib 300 mg QD		High Dose Escalation Cohort: Crizotinib 400 mg QD		High Dose Escalation Cohort: Crizotinib 500 mg QD		High Dose Escalation Cohort: Crizotinib 650 mg QD		High Dose Escalation Cohort: Crizotinib 800 mg QD		RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg		RP2D Cohort: Enriched Other: Crizotinib 250 mg		Itraconazole Interaction Sub-study: Crizotinib 250 mg		RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin		Midazolam Interaction Cohort: Crizotinib 250
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		1/3 (33.3%)		1/6 (16.7%)		1/9 (11.1%)		10/53 (18.9%)		15/85 (17.6%)		8/41 (19.5%)		13/48 (27.1%)		9/18 (50%)		25/154 (16.2%)		15/66 (22.7%)		0/18 (0%)		1/18 (5.6%)		4/12 (33.3%)
Serious Adverse Events
	Low Dose Escalation Cohort: Crizotinib 50 mg QD		Low Dose Escalation Cohort: Crizotinib 100 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg BID		Low Dose Escalation Cohort: Crizotinib 250 mg BID		Low Dose Escalation Cohort: Crizotinib 300 mg BID		High Dose Escalation Cohort: Crizotinib 300 mg QD		High Dose Escalation Cohort: Crizotinib 400 mg QD		High Dose Escalation Cohort: Crizotinib 500 mg QD		High Dose Escalation Cohort: Crizotinib 650 mg QD		High Dose Escalation Cohort: Crizotinib 800 mg QD		RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg		RP2D Cohort: Enriched Other: Crizotinib 250 mg		Itraconazole Interaction Sub-study: Crizotinib 250 mg		RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin		Midazolam Interaction Cohort: Crizotinib 250
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		2/7 (28.6%)		4/8 (50%)		2/6 (33.3%)		2/6 (33.3%)		2/5 (40%)		1/3 (33.3%)		2/6 (33.3%)		4/9 (44.4%)		24/53 (45.3%)		54/85 (63.5%)		25/41 (61%)		22/48 (45.8%)		9/18 (50%)		75/154 (48.7%)		29/66 (43.9%)		7/18 (38.9%)		6/18 (33.3%)		6/12 (50%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Disseminated intravascular coagulation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Febrile neutropenia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Thrombocytopenia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Cardiac disorders
Bradycardia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pericardial effusion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Arrhythmia supraventricular	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Atrial fibrillation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		3/154 (1.9%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Atrial thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardiac arrest	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardiac failure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardiac tamponade	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardio-respiratory arrest	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Left ventricular dysfunction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Myocardial infarction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Sinus bradycardia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Syncope	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		4/154 (2.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Endocrine disorders
Adrenal insufficiency	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Autoimmune thyroiditis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Eye disorders
Papilloedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastrointestinal amyloidosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Large intestine perforation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nausea	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Vomiting	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		1/66 (1.5%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Abdominal pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Ascites	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Constipation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Diarrhoea	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Dysphagia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastric haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Gastrointestinal haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastrointestinal necrosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastrointestinal perforation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastrooesophageal reflux disease	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Intestinal obstruction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Large intestinal obstruction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Megacolon	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oesophageal ulcer	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Small intestinal obstruction	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Small intestinal perforation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
General disorders
Chest discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Disease progression	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		2/8 (25%)		1/6 (16.7%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		1/9 (11.1%)		10/53 (18.9%)		8/85 (9.4%)		6/41 (14.6%)		8/48 (16.7%)		1/18 (5.6%)		19/154 (12.3%)		12/66 (18.2%)		0/18 (0%)		0/18 (0%)		4/12 (33.3%)
Asthenia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chest pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Death	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Fatigue	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gait disturbance	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Impaired healing	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Localised oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oedema peripheral	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Physical deconditioning	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pyrexia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		4/85 (4.7%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Fat necrosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Hepatobiliary disorders
Cholangitis acute	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Drug-induced liver injury	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cholangitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hyperbilirubinaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Immune system disorders
Anaphylactic reaction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Infections and infestations
Bronchitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastroenteritis viral	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Influenza	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oesophageal candidiasis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pneumocystis jirovecii pneumonia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pneumonia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		3/53 (5.7%)		11/85 (12.9%)		3/41 (7.3%)		2/48 (4.2%)		0/18 (0%)		15/154 (9.7%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Scrub typhus	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Skin infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Appendicitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Aspergillus infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bacteraemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Candida infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cellulitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		3/154 (1.9%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chest wall abscess	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Diverticulitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Enterocolitis infectious	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Fungal infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastroenteritis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastrointestinal infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Graft infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
H1N1 influenza	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Herpes zoster	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Lower respiratory tract infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Meningitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Mesenteric abscess	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Nasal abscess	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Parainfluenzae virus infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pleural infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pneumonia pneumococcal	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Respiratory syncytial virus bronchitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Sepsis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Septic arthritis streptococcal	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Septic shock	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Subcutaneous abscess	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Upper respiratory tract infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urinary tract infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urosepsis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Clavicle fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Compression fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Fall	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Femoral neck fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Foetal exposure during pregnancy	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hip fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pelvic fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Post-traumatic pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Spinal compression fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Subcutaneous haematoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Subdural haematoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Tendon rupture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Wrist fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Aspartate aminotransferase increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Blood creatinine increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Electrocardiogram QT prolonged	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Liver function test increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Metabolism and nutrition disorders
Adult failure to thrive	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Decreased appetite	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Dehydration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Failure to thrive	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hypercalcaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hypokalaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hyponatraemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Arthralgia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bone pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Fracture pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haemarthrosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Muscular weakness	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Musculoskeletal pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Osteonecrosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pain in extremity	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pathological fracture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Rhabdomyolysis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Soft tissue disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer recurrent	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chronic lymphocytic leukaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Malignant melanoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Prostate cancer	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Small cell lung cancer	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Squamous cell carcinoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nervous system disorders
Aphasia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haemorrhage intracranial	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Headache	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Brain oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Central nervous system haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cerebral haematoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cerebral haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Cerebrovascular accident	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Encephalopathy	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hypoxic-ischaemic encephalopathy	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Intracranial pressure increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Seizure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		5/154 (3.2%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Spinal cord compression	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Transient ischaemic attack	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		2/18 (11.1%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Psychiatric disorders
Mental status changes	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Anxiety	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Confusional state	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Drug abuse	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Suicidal ideation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Renal and urinary disorders
Renal cyst	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urinary retention	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Acute kidney injury	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		4/41 (9.8%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Haematuria	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nephrolithiasis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vaginal haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		6/85 (7.1%)		2/41 (4.9%)		4/48 (8.3%)		0/18 (0%)		7/154 (4.5%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hypoxia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Pneumothorax	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		2/48 (4.2%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pulmonary embolism	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		2/85 (2.4%)		4/41 (9.8%)		1/48 (2.1%)		1/18 (5.6%)		10/154 (6.5%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Acute respiratory failure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bronchial obstruction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bronchospasm	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chronic obstructive pulmonary disease	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cough	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haemoptysis	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pleural effusion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		5/85 (5.9%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Pneumonia aspiration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pneumonitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		6/85 (7.1%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Pulmonary haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Respiratory arrest	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Respiratory failure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Skin and subcutaneous tissue disorders
Stasis dermatitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Subcutaneous emphysema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)	0
Vascular disorders
Deep vein thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		6/154 (3.9%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Aortic stenosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Embolism	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haematoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hypotension	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Jugular vein thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Peripheral embolism	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Shock	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vena cava thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Low Dose Escalation Cohort: Crizotinib 50 mg QD		Low Dose Escalation Cohort: Crizotinib 100 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg QD		Low Dose Escalation Cohort: Crizotinib 200 mg BID		Low Dose Escalation Cohort: Crizotinib 250 mg BID		Low Dose Escalation Cohort: Crizotinib 300 mg BID		High Dose Escalation Cohort: Crizotinib 300 mg QD		High Dose Escalation Cohort: Crizotinib 400 mg QD		High Dose Escalation Cohort: Crizotinib 500 mg QD		High Dose Escalation Cohort: Crizotinib 650 mg QD		High Dose Escalation Cohort: Crizotinib 800 mg QD		RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg		RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg		RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg		RP2D Cohort: Enriched Other: Crizotinib 250 mg		Itraconazole Interaction Sub-study: Crizotinib 250 mg		RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin		Midazolam Interaction Cohort: Crizotinib 250
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		4/4 (100%)		8/8 (100%)		7/7 (100%)		8/8 (100%)		6/6 (100%)		6/6 (100%)		4/5 (80%)		3/3 (100%)		6/6 (100%)		9/9 (100%)		53/53 (100%)		85/85 (100%)		41/41 (100%)		46/48 (95.8%)		18/18 (100%)		154/154 (100%)		66/66 (100%)		18/18 (100%)		18/18 (100%)		12/12 (100%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)		0/4 (0%)		2/8 (25%)		1/7 (14.3%)		0/8 (0%)		1/6 (16.7%)		2/6 (33.3%)		1/5 (20%)		0/3 (0%)		1/6 (16.7%)		3/9 (33.3%)		8/53 (15.1%)		14/85 (16.5%)		8/41 (19.5%)		2/48 (4.2%)		2/18 (11.1%)		17/154 (11%)		15/66 (22.7%)		4/18 (22.2%)		4/18 (22.2%)		1/12 (8.3%)
Leukopenia	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		1/85 (1.2%)		1/41 (2.4%)		3/48 (6.3%)		1/18 (5.6%)		14/154 (9.1%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Neutropenia	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		1/9 (11.1%)		9/53 (17%)		2/85 (2.4%)		2/41 (4.9%)		5/48 (10.4%)		2/18 (11.1%)		26/154 (16.9%)		5/66 (7.6%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Thrombocytopenia	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		6/154 (3.9%)		3/66 (4.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Leukocytosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		0/41 (0%)		3/48 (6.3%)		0/18 (0%)		3/154 (1.9%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Lymphopenia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		2/41 (4.9%)		1/48 (2.1%)		1/18 (5.6%)		11/154 (7.1%)		7/66 (10.6%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardiac disorders
Bradycardia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		7/53 (13.2%)		13/85 (15.3%)		2/41 (4.9%)		2/48 (4.2%)		1/18 (5.6%)		13/154 (8.4%)		2/66 (3%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Sinus bradycardia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		1/9 (11.1%)		5/53 (9.4%)		11/85 (12.9%)		4/41 (9.8%)		5/48 (10.4%)		0/18 (0%)		9/154 (5.8%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/0 (NaN)
Syncope	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		3/53 (5.7%)		3/85 (3.5%)		1/41 (2.4%)		2/48 (4.2%)		0/18 (0%)		9/154 (5.8%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Arrhythmia supraventricular	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Atrial fibrillation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		3/41 (7.3%)		2/48 (4.2%)		0/18 (0%)		5/154 (3.2%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Atrioventricular block first degree	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardiac arrest	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Palpitations	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		4/85 (4.7%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Pericardial effusion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Supraventricular tachycardia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Tachycardia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		2/48 (4.2%)		0/18 (0%)		6/154 (3.9%)		3/66 (4.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Ear and labyrinth disorders
Tinnitus	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		5/53 (9.4%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		3/154 (1.9%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Ear discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Excessive cerumen production	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hypoacusis	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Eye disorders
Cataract	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		5/53 (9.4%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		4/154 (2.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/0 (NaN)
Vision blurred	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		7/53 (13.2%)		8/85 (9.4%)		5/41 (12.2%)		3/48 (6.3%)		0/18 (0%)		8/154 (5.2%)		3/66 (4.5%)		1/18 (5.6%)		2/18 (11.1%)		1/12 (8.3%)
Visual impairment	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		2/5 (40%)		0/3 (0%)		4/6 (66.7%)		3/9 (33.3%)		43/53 (81.1%)		11/85 (12.9%)		6/41 (14.6%)		26/48 (54.2%)		9/18 (50%)		92/154 (59.7%)		22/66 (33.3%)		3/18 (16.7%)		10/18 (55.6%)		1/12 (8.3%)
Vitreous detachment	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Conjunctival haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Diplopia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		2/41 (4.9%)		0/48 (0%)		1/18 (5.6%)		3/154 (1.9%)		3/66 (4.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Dry eye	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		2/48 (4.2%)		1/18 (5.6%)		3/154 (1.9%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Eye pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		1/48 (2.1%)		1/18 (5.6%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Eyelid oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Glaucoma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Lacrimation increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		3/85 (3.5%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Periorbital oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		10/154 (6.5%)		1/66 (1.5%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Photophobia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Photopsia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		2/53 (3.8%)		8/85 (9.4%)		1/41 (2.4%)		1/48 (2.1%)		1/18 (5.6%)		13/154 (8.4%)		2/66 (3%)		2/18 (11.1%)		2/18 (11.1%)		1/12 (8.3%)
Retinal degeneration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Retinal drusen	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Swelling of eyelid	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Visual acuity reduced	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Visual brightness	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vitreous degeneration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vitreous floaters	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		19/85 (22.4%)		3/41 (7.3%)		0/48 (0%)		0/18 (0%)		4/154 (2.6%)		4/66 (6.1%)		3/18 (16.7%)		1/18 (5.6%)		0/12 (0%)
Eyelid ptosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		3/53 (5.7%)		3/85 (3.5%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		12/154 (7.8%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Abdominal distension	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		1/8 (12.5%)		1/6 (16.7%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		2/6 (33.3%)		0/9 (0%)		3/53 (5.7%)		7/85 (8.2%)		0/41 (0%)		1/48 (2.1%)		1/18 (5.6%)		10/154 (6.5%)		3/66 (4.5%)		3/18 (16.7%)		0/18 (0%)		0/12 (0%)
Abdominal pain	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		2/7 (28.6%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		1/3 (33.3%)		1/6 (16.7%)		0/9 (0%)		8/53 (15.1%)		11/85 (12.9%)		7/41 (17.1%)		2/48 (4.2%)		2/18 (11.1%)		8/154 (5.2%)		7/66 (10.6%)		2/18 (11.1%)		1/18 (5.6%)		2/12 (16.7%)
Abdominal pain upper	0/3 (0%)		0/4 (0%)		2/8 (25%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		4/85 (4.7%)		3/41 (7.3%)		4/48 (8.3%)		1/18 (5.6%)		19/154 (12.3%)		2/66 (3%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Constipation	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		2/7 (28.6%)		3/8 (37.5%)		2/6 (33.3%)		3/6 (50%)		3/5 (60%)		2/3 (66.7%)		4/6 (66.7%)		4/9 (44.4%)		24/53 (45.3%)		45/85 (52.9%)		10/41 (24.4%)		21/48 (43.8%)		11/18 (61.1%)		68/154 (44.2%)		15/66 (22.7%)		11/18 (61.1%)		7/18 (38.9%)		1/12 (8.3%)
Diarrhoea	2/3 (66.7%)		0/4 (0%)		2/8 (25%)		1/7 (14.3%)		1/8 (12.5%)		1/6 (16.7%)		1/6 (16.7%)		1/5 (20%)		0/3 (0%)		3/6 (50%)		2/9 (22.2%)		25/53 (47.2%)		50/85 (58.8%)		17/41 (41.5%)		17/48 (35.4%)		5/18 (27.8%)		93/154 (60.4%)		32/66 (48.5%)		7/18 (38.9%)		7/18 (38.9%)		4/12 (33.3%)
Dyspepsia	0/3 (0%)		1/4 (25%)		2/8 (25%)		1/7 (14.3%)		0/8 (0%)		3/6 (50%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		6/53 (11.3%)		5/85 (5.9%)		2/41 (4.9%)		3/48 (6.3%)		1/18 (5.6%)		19/154 (12.3%)		4/66 (6.1%)		4/18 (22.2%)		0/18 (0%)		3/12 (25%)
Dysphagia	0/3 (0%)		1/4 (25%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		10/85 (11.8%)		5/41 (12.2%)		1/48 (2.1%)		0/18 (0%)		12/154 (7.8%)		1/66 (1.5%)		2/18 (11.1%)		1/18 (5.6%)		0/12 (0%)
Flatulence	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		5/85 (5.9%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		2/154 (1.3%)		1/66 (1.5%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Gastrooesophageal reflux disease	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		2/9 (22.2%)		3/53 (5.7%)		7/85 (8.2%)		1/41 (2.4%)		3/48 (6.3%)		0/18 (0%)		17/154 (11%)		5/66 (7.6%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Nausea	1/3 (33.3%)		3/4 (75%)		6/8 (75%)		3/7 (42.9%)		3/8 (37.5%)		3/6 (50%)		2/6 (33.3%)		1/5 (20%)		3/3 (100%)		3/6 (50%)		5/9 (55.6%)		33/53 (62.3%)		49/85 (57.6%)		14/41 (34.1%)		20/48 (41.7%)		10/18 (55.6%)		97/154 (63%)		41/66 (62.1%)		10/18 (55.6%)		12/18 (66.7%)		7/12 (58.3%)
Vomiting	2/3 (66.7%)		2/4 (50%)		5/8 (62.5%)		4/7 (57.1%)		4/8 (50%)		1/6 (16.7%)		3/6 (50%)		2/5 (40%)		1/3 (33.3%)		2/6 (33.3%)		5/9 (55.6%)		28/53 (52.8%)		35/85 (41.2%)		15/41 (36.6%)		26/48 (54.2%)		9/18 (50%)		81/154 (52.6%)		34/66 (51.5%)		8/18 (44.4%)		10/18 (55.6%)		8/12 (66.7%)
Abdominal mass	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Abdominal pain lower	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		2/66 (3%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Ascites	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		3/66 (4.5%)		5/18 (27.8%)		2/18 (11.1%)		0/12 (0%)
Diarrhoea haemorrhagic	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Dry mouth	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		3/41 (7.3%)		2/48 (4.2%)		0/18 (0%)		4/154 (2.6%)		0/66 (0%)		3/18 (16.7%)		2/18 (11.1%)		0/12 (0%)
Duodenogastric reflux	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Eructation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		2/6 (33.3%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gastritis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Gastrointestinal sounds abnormal	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Gingival discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Haemorrhoids	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Intestinal obstruction	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Lip oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oral blood blister	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Oral disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Pancreatitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		1/12 (8.3%)
Paraesthesia oral	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Rectal haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Retching	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Salivary gland disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Stomatitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Swollen tongue	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Tongue disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Tongue oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Umbilical hernia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Epigastric discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Nausea	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		7/12 (58.3%)
General disorders
Asthenia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		6/53 (11.3%)		3/85 (3.5%)		3/41 (7.3%)		3/48 (6.3%)		1/18 (5.6%)		14/154 (9.1%)		4/66 (6.1%)		0/18 (0%)		0/18 (0%)		6/12 (50%)
Chest pain	1/3 (33.3%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		5/53 (9.4%)		5/85 (5.9%)		4/41 (9.8%)		3/48 (6.3%)		0/18 (0%)		16/154 (10.4%)		5/66 (7.6%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chills	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		4/53 (7.5%)		12/85 (14.1%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		7/154 (4.5%)		5/66 (7.6%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Face oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		6/154 (3.9%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Fatigue	2/3 (66.7%)		2/4 (50%)		3/8 (37.5%)		3/7 (42.9%)		4/8 (50%)		3/6 (50%)		3/6 (50%)		1/5 (20%)		2/3 (66.7%)		2/6 (33.3%)		3/9 (33.3%)		20/53 (37.7%)		35/85 (41.2%)		11/41 (26.8%)		23/48 (47.9%)		8/18 (44.4%)		59/154 (38.3%)		26/66 (39.4%)		8/18 (44.4%)		6/18 (33.3%)		5/12 (41.7%)
Malaise	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		3/85 (3.5%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		8/53 (15.1%)		4/85 (4.7%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		14/154 (9.1%)		3/66 (4.5%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Oedema peripheral	0/3 (0%)		0/4 (0%)		0/8 (0%)		2/7 (28.6%)		1/8 (12.5%)		0/6 (0%)		2/6 (33.3%)		1/5 (20%)		0/3 (0%)		2/6 (33.3%)		0/9 (0%)		27/53 (50.9%)		49/85 (57.6%)		14/41 (34.1%)		15/48 (31.3%)		4/18 (22.2%)		69/154 (44.8%)		18/66 (27.3%)		3/18 (16.7%)		5/18 (27.8%)		1/12 (8.3%)
Pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		5/53 (9.4%)		3/85 (3.5%)		3/41 (7.3%)		6/48 (12.5%)		1/18 (5.6%)		12/154 (7.8%)		5/66 (7.6%)		2/18 (11.1%)		2/18 (11.1%)		0/12 (0%)
Pyrexia	1/3 (33.3%)		3/4 (75%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		2/6 (33.3%)		2/9 (22.2%)		15/53 (28.3%)		12/85 (14.1%)		2/41 (4.9%)		6/48 (12.5%)		2/18 (11.1%)		34/154 (22.1%)		3/66 (4.5%)		3/18 (16.7%)		3/18 (16.7%)		1/12 (8.3%)
Breakthrough pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chest discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		4/85 (4.7%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		13/154 (8.4%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Early satiety	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Facial pain	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Gait disturbance	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		6/85 (7.1%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		8/154 (5.2%)		0/66 (0%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Influenza like illness	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		9/154 (5.8%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Infusion site erythema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Localised oedema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Mucosal inflammation	0/3 (0%)		1/4 (25%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Peripheral swelling	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		2/48 (4.2%)		1/18 (5.6%)		17/154 (11%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Swelling	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Systemic inflammatory response syndrome	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hepatobiliary disorders
Bile duct stenosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hyperbilirubinaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		2/66 (3%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Jaundice	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Immune system disorders
Multiple allergies	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Seasonal allergy	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		1/85 (1.2%)		1/41 (2.4%)		2/48 (4.2%)		0/18 (0%)		5/154 (3.2%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Infections and infestations
Herpes zoster	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		0/85 (0%)		1/41 (2.4%)		2/48 (4.2%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Influenza	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		1/85 (1.2%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		8/154 (5.2%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nasopharyngitis	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		13/53 (24.5%)		3/85 (3.5%)		1/41 (2.4%)		7/48 (14.6%)		0/18 (0%)		26/154 (16.9%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pneumonia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		7/53 (13.2%)		8/85 (9.4%)		5/41 (12.2%)		3/48 (6.3%)		2/18 (11.1%)		12/154 (7.8%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Sinusitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		4/85 (4.7%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		7/154 (4.5%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Upper respiratory tract infection	1/3 (33.3%)		0/4 (0%)		2/8 (25%)		1/7 (14.3%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		11/53 (20.8%)		15/85 (17.6%)		1/41 (2.4%)		5/48 (10.4%)		4/18 (22.2%)		39/154 (25.3%)		1/66 (1.5%)		3/18 (16.7%)		0/18 (0%)		0/12 (0%)
Urinary tract infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		6/53 (11.3%)		11/85 (12.9%)		5/41 (12.2%)		1/48 (2.1%)		1/18 (5.6%)		13/154 (8.4%)		5/66 (7.6%)		1/18 (5.6%)		1/18 (5.6%)		1/12 (8.3%)
Viral infection	1/3 (33.3%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Viral upper respiratory tract infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		2/85 (2.4%)		0/41 (0%)		2/48 (4.2%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bronchitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		2/7 (28.6%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		4/85 (4.7%)		2/41 (4.9%)		2/48 (4.2%)		0/18 (0%)		4/154 (2.6%)		0/66 (0%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Candida infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		3/85 (3.5%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		5/154 (3.2%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Epididymitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Fungal infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oral candidiasis	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		4/154 (2.6%)		2/66 (3%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Rhinitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		5/154 (3.2%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Skin infection	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		5/85 (5.9%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Tinea pedis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urosepsis	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bacteraemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Fall	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		6/53 (11.3%)		14/85 (16.5%)		5/41 (12.2%)		3/48 (6.3%)		1/18 (5.6%)		19/154 (12.3%)		6/66 (9.1%)		2/18 (11.1%)		1/18 (5.6%)		1/12 (8.3%)
Bone contusion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Contusion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		2/85 (2.4%)		2/41 (4.9%)		1/48 (2.1%)		1/18 (5.6%)		4/154 (2.6%)		1/66 (1.5%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Infusion related reaction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Ligament rupture	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Limb injury	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		2/41 (4.9%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Muscle strain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Optic nerve injury	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Postoperative ileus	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Road traffic accident	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Stoma site rash	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Skin laceration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		2/9 (22.2%)		17/53 (32.1%)		19/85 (22.4%)		9/41 (22%)		4/48 (8.3%)		0/18 (0%)		35/154 (22.7%)		11/66 (16.7%)		3/18 (16.7%)		4/18 (22.2%)		0/12 (0%)
Aspartate aminotransferase increased	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		2/9 (22.2%)		16/53 (30.2%)		15/85 (17.6%)		10/41 (24.4%)		8/48 (16.7%)		2/18 (11.1%)		30/154 (19.5%)		10/66 (15.2%)		3/18 (16.7%)		4/18 (22.2%)		0/12 (0%)
Blood creatinine increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		2/9 (22.2%)		6/53 (11.3%)		11/85 (12.9%)		6/41 (14.6%)		4/48 (8.3%)		1/18 (5.6%)		5/154 (3.2%)		9/66 (13.6%)		3/18 (16.7%)		3/18 (16.7%)		1/12 (8.3%)
Blood testosterone decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		5/53 (9.4%)		2/85 (2.4%)		1/41 (2.4%)		1/48 (2.1%)		1/18 (5.6%)		12/154 (7.8%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Weight decreased	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		2/5 (40%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		5/53 (9.4%)		11/85 (12.9%)		9/41 (22%)		2/48 (4.2%)		2/18 (11.1%)		28/154 (18.2%)		5/66 (7.6%)		1/18 (5.6%)		2/18 (11.1%)		2/12 (16.7%)
Weight increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		6/53 (11.3%)		6/85 (7.1%)		5/41 (12.2%)		2/48 (4.2%)		1/18 (5.6%)		33/154 (21.4%)		2/66 (3%)		2/18 (11.1%)		1/18 (5.6%)		0/12 (0%)
Activated partial thromboplastin time prolonged	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		4/41 (9.8%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Bacterial test positive	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Bilirubin conjugated increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Blood albumin decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		5/154 (3.2%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Blood alkaline phosphatase	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Blood alkaline phosphatase increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		1/8 (12.5%)		2/6 (33.3%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		7/85 (8.2%)		4/41 (9.8%)		4/48 (8.3%)		3/18 (16.7%)		13/154 (8.4%)		4/66 (6.1%)		2/18 (11.1%)		2/18 (11.1%)		1/12 (8.3%)
Blood bilirubin increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Blood iron decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Blood lactate dehydrogenase increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		2/66 (3%)		1/18 (5.6%)		2/18 (11.1%)		0/12 (0%)
Blood phosphorus decreased	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Blood potassium decreased	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Blood pressure systolic increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Blood urea increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		1/66 (1.5%)		1/18 (5.6%)		2/18 (11.1%)		0/12 (0%)
Blood uric acid increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Blood urine	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Blood urine present	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Brain natriuretic peptide increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Electrocardiogram QT prolonged	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		3/85 (3.5%)		2/41 (4.9%)		3/48 (6.3%)		0/18 (0%)		2/154 (1.3%)		4/66 (6.1%)		1/18 (5.6%)		2/18 (11.1%)		0/12 (0%)
Electrocardiogram abnormal	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Glucose urine present	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haematocrit decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Haemoglobin decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		3/41 (7.3%)		1/48 (2.1%)		0/18 (0%)		4/154 (2.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Heart rate increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
International normalised ratio increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		3/41 (7.3%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Iron binding capacity total decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Liver function test increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Lymphocyte count decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		4/41 (9.8%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Mean cell haemoglobin concentration decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Monocyte count increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Neutrophil count decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		2/53 (3.8%)		3/85 (3.5%)		4/41 (9.8%)		0/48 (0%)		1/18 (5.6%)		2/154 (1.3%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nitrite urine present	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Oxygen saturation decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Platelet count decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		3/41 (7.3%)		0/48 (0%)		0/18 (0%)		4/154 (2.6%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Protein total decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Protein urine present	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Prothrombin time prolonged	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Red blood cells urine positive	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Red cell distribution width increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Serum ferritin increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Transferrin saturation decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Urine ketone body present	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urine leukocyte esterase positive	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Urine output decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vital dye staining cornea present	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Waist circumference increased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
White blood cell count decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		5/85 (5.9%)		4/41 (9.8%)		0/48 (0%)		0/18 (0%)		7/154 (4.5%)		6/66 (9.1%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cardiac murmur	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Metabolism and nutrition disorders
Decreased appetite	1/3 (33.3%)		2/4 (50%)		4/8 (50%)		2/7 (28.6%)		2/8 (25%)		4/6 (66.7%)		1/6 (16.7%)		1/5 (20%)		2/3 (66.7%)		1/6 (16.7%)		3/9 (33.3%)		16/53 (30.2%)		24/85 (28.2%)		7/41 (17.1%)		9/48 (18.8%)		3/18 (16.7%)		50/154 (32.5%)		20/66 (30.3%)		5/18 (27.8%)		6/18 (33.3%)		3/12 (25%)
Dehydration	0/3 (0%)		2/4 (50%)		1/8 (12.5%)		1/7 (14.3%)		2/8 (25%)		1/6 (16.7%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		1/6 (16.7%)		2/9 (22.2%)		5/53 (9.4%)		3/85 (3.5%)		6/41 (14.6%)		6/48 (12.5%)		2/18 (11.1%)		13/154 (8.4%)		6/66 (9.1%)		4/18 (22.2%)		1/18 (5.6%)		3/12 (25%)
Hyperglycaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		3/53 (5.7%)		2/85 (2.4%)		8/41 (19.5%)		3/48 (6.3%)		1/18 (5.6%)		7/154 (4.5%)		1/66 (1.5%)		1/18 (5.6%)		2/18 (11.1%)		0/12 (0%)
Hypoalbuminaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		2/6 (33.3%)		1/9 (11.1%)		4/53 (7.5%)		8/85 (9.4%)		12/41 (29.3%)		3/48 (6.3%)		2/18 (11.1%)		8/154 (5.2%)		10/66 (15.2%)		3/18 (16.7%)		3/18 (16.7%)		0/12 (0%)
Hypocalcaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		3/53 (5.7%)		0/85 (0%)		5/41 (12.2%)		2/48 (4.2%)		2/18 (11.1%)		8/154 (5.2%)		4/66 (6.1%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Hyponatraemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		2/9 (22.2%)		3/53 (5.7%)		11/85 (12.9%)		12/41 (29.3%)		3/48 (6.3%)		1/18 (5.6%)		10/154 (6.5%)		11/66 (16.7%)		2/18 (11.1%)		2/18 (11.1%)		2/12 (16.7%)
Hypophosphataemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		10/53 (18.9%)		7/85 (8.2%)		6/41 (14.6%)		5/48 (10.4%)		2/18 (11.1%)		29/154 (18.8%)		10/66 (15.2%)		0/18 (0%)		2/18 (11.1%)		1/12 (8.3%)
Vitamin D deficiency	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hyperkalaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		8/85 (9.4%)		5/41 (12.2%)		0/48 (0%)		1/18 (5.6%)		4/154 (2.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hyperuricaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		3/85 (3.5%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		4/66 (6.1%)		2/18 (11.1%)		1/18 (5.6%)		0/12 (0%)
Hypoglycaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Hypokalaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		3/41 (7.3%)		1/48 (2.1%)		0/18 (0%)		8/154 (5.2%)		4/66 (6.1%)		1/18 (5.6%)		4/18 (22.2%)		0/12 (0%)
Hypomagnesaemia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Hypophagia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Malnutrition	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Metabolic acidosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)		1/4 (25%)		1/8 (12.5%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		9/53 (17%)		16/85 (18.8%)		4/41 (9.8%)		4/48 (8.3%)		4/18 (22.2%)		22/154 (14.3%)		7/66 (10.6%)		2/18 (11.1%)		1/18 (5.6%)		0/12 (0%)
Back pain	1/3 (33.3%)		0/4 (0%)		3/8 (37.5%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		9/53 (17%)		13/85 (15.3%)		12/41 (29.3%)		4/48 (8.3%)		5/18 (27.8%)		32/154 (20.8%)		9/66 (13.6%)		1/18 (5.6%)		2/18 (11.1%)		1/12 (8.3%)
Flank pain	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		3/18 (16.7%)		6/154 (3.9%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Joint swelling	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		1/85 (1.2%)		2/41 (4.9%)		5/48 (10.4%)		0/18 (0%)		20/154 (13%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Muscle spasms	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		6/85 (7.1%)		1/41 (2.4%)		6/48 (12.5%)		1/18 (5.6%)		27/154 (17.5%)		3/66 (4.5%)		1/18 (5.6%)		0/18 (0%)		1/12 (8.3%)
Muscular weakness	1/3 (33.3%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		8/53 (15.1%)		16/85 (18.8%)		7/41 (17.1%)		5/48 (10.4%)		0/18 (0%)		12/154 (7.8%)		4/66 (6.1%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Musculoskeletal chest pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		6/85 (7.1%)		1/41 (2.4%)		1/48 (2.1%)		1/18 (5.6%)		8/154 (5.2%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Musculoskeletal pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		6/85 (7.1%)		3/41 (7.3%)		5/48 (10.4%)		0/18 (0%)		15/154 (9.7%)		4/66 (6.1%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Myalgia	0/3 (0%)		1/4 (25%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		5/53 (9.4%)		12/85 (14.1%)		2/41 (4.9%)		1/48 (2.1%)		2/18 (11.1%)		11/154 (7.1%)		3/66 (4.5%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Pain in extremity	0/3 (0%)		0/4 (0%)		0/8 (0%)		2/7 (28.6%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		7/53 (13.2%)		11/85 (12.9%)		2/41 (4.9%)		2/48 (4.2%)		1/18 (5.6%)		18/154 (11.7%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Groin pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Limb discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		4/48 (8.3%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Limb mass	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Muscle twitching	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Musculoskeletal discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		0/85 (0%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		6/154 (3.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Neck pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		3/85 (3.5%)		2/41 (4.9%)		0/48 (0%)		1/18 (5.6%)		10/154 (6.5%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Spinal stenosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Tendonitis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Oncologic complication	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nervous system disorders
Dizziness	0/3 (0%)		0/4 (0%)		2/8 (25%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		21/53 (39.6%)		25/85 (29.4%)		9/41 (22%)		12/48 (25%)		3/18 (16.7%)		65/154 (42.2%)		15/66 (22.7%)		5/18 (27.8%)		3/18 (16.7%)		1/12 (8.3%)
Dysgeusia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		1/9 (11.1%)		5/53 (9.4%)		19/85 (22.4%)		4/41 (9.8%)		2/48 (4.2%)		0/18 (0%)		7/154 (4.5%)		4/66 (6.1%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Headache	1/3 (33.3%)		1/4 (25%)		1/8 (12.5%)		1/7 (14.3%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		1/9 (11.1%)		15/53 (28.3%)		16/85 (18.8%)		3/41 (7.3%)		7/48 (14.6%)		2/18 (11.1%)		34/154 (22.1%)		8/66 (12.1%)		3/18 (16.7%)		1/18 (5.6%)		0/12 (0%)
Hypoaesthesia	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		0/85 (0%)		1/41 (2.4%)		3/48 (6.3%)		2/18 (11.1%)		13/154 (8.4%)		2/66 (3%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Memory impairment	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		1/85 (1.2%)		1/41 (2.4%)		2/48 (4.2%)		1/18 (5.6%)		6/154 (3.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Neuropathy peripheral	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		2/85 (2.4%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		13/154 (8.4%)		4/66 (6.1%)		1/18 (5.6%)		1/18 (5.6%)		2/12 (16.7%)
Paraesthesia	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		8/53 (15.1%)		8/85 (9.4%)		2/41 (4.9%)		6/48 (12.5%)		0/18 (0%)		21/154 (13.6%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Taste disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		7/53 (13.2%)		3/85 (3.5%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		18/154 (11.7%)		4/66 (6.1%)		1/18 (5.6%)		3/18 (16.7%)		0/12 (0%)
Ageusia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Amnesia	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		5/154 (3.2%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Aphasia	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		8/154 (5.2%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Ataxia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Coma	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Coordination abnormal	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Disturbance in attention	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Dizziness postural	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Dysarthria	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		1/18 (5.6%)		4/154 (2.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Facial nerve disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haemorrhage intracranial	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Hydrocephalus	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Hypoxic-ischaemic encephalopathy	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Loss of consciousness	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Migraine	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Migraine with aura	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Myoclonus	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Neuralgia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		4/154 (2.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Parosmia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		5/154 (3.2%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Peripheral sensory neuropathy	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		6/85 (7.1%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Seizure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		4/85 (4.7%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		7/154 (4.5%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Sinus headache	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Tremor	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		1/18 (5.6%)		8/154 (5.2%)		3/66 (4.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Visual field defect	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Visual perseveration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Psychiatric disorders
Anxiety	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		3/85 (3.5%)		3/41 (7.3%)		3/48 (6.3%)		1/18 (5.6%)		15/154 (9.7%)		4/66 (6.1%)		0/18 (0%)		2/18 (11.1%)		0/12 (0%)
Depression	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		3/85 (3.5%)		0/41 (0%)		3/48 (6.3%)		0/18 (0%)		12/154 (7.8%)		3/66 (4.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Insomnia	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		7/53 (13.2%)		11/85 (12.9%)		6/41 (14.6%)		2/48 (4.2%)		0/18 (0%)		26/154 (16.9%)		7/66 (10.6%)		1/18 (5.6%)		0/18 (0%)		1/12 (8.3%)
Abnormal dreams	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Confusional state	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		8/85 (9.4%)		5/41 (12.2%)		1/48 (2.1%)		1/18 (5.6%)		8/154 (5.2%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		1/12 (8.3%)
Delirium	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		3/41 (7.3%)		1/48 (2.1%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hallucination, visual	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Psychotic disorder	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Renal and urinary disorders
Dysuria	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		4/53 (7.5%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		9/154 (5.8%)		1/66 (1.5%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Renal cyst	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Acute kidney injury	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		2/9 (22.2%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Chromaturia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haematuria	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		2/41 (4.9%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Incontinence	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/5 (20%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nocturia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pollakiuria	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		2/48 (4.2%)		2/18 (11.1%)		5/154 (3.2%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Proteinuria	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Renal failure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Renal pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urinary incontinence	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		8/85 (9.4%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urinary retention	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		1/6 (16.7%)		2/9 (22.2%)		1/53 (1.9%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		4/154 (2.6%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Urinary tract obstruction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urine abnormality	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Urine flow decreased	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Erectile dysfunction	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		1/41 (2.4%)		0/48 (0%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Genital haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Testicular pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vaginal haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vulvovaginal pruritus	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		13/53 (24.5%)		24/85 (28.2%)		7/41 (17.1%)		7/48 (14.6%)		4/18 (22.2%)		24/154 (15.6%)		3/66 (4.5%)		5/18 (27.8%)		1/18 (5.6%)		1/12 (8.3%)
Dysphonia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		9/85 (10.6%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		10/154 (6.5%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Dyspnoea	2/3 (66.7%)		0/4 (0%)		0/8 (0%)		2/7 (28.6%)		0/8 (0%)		3/6 (50%)		2/6 (33.3%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		12/53 (22.6%)		27/85 (31.8%)		10/41 (24.4%)		11/48 (22.9%)		4/18 (22.2%)		34/154 (22.1%)		14/66 (21.2%)		8/18 (44.4%)		1/18 (5.6%)		1/12 (8.3%)
Dyspnoea exertional	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		7/53 (13.2%)		0/85 (0%)		1/41 (2.4%)		3/48 (6.3%)		1/18 (5.6%)		10/154 (6.5%)		1/66 (1.5%)		2/18 (11.1%)		1/18 (5.6%)		0/12 (0%)
Hypoxia	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		6/53 (11.3%)		8/85 (9.4%)		3/41 (7.3%)		1/48 (2.1%)		1/18 (5.6%)		4/154 (2.6%)		0/66 (0%)		2/18 (11.1%)		2/18 (11.1%)		2/12 (16.7%)
Oropharyngeal pain	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		4/53 (7.5%)		3/85 (3.5%)		2/41 (4.9%)		6/48 (12.5%)		0/18 (0%)		11/154 (7.1%)		2/66 (3%)		1/18 (5.6%)		0/18 (0%)		1/12 (8.3%)
Pleural effusion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		11/85 (12.9%)		4/41 (9.8%)		2/48 (4.2%)		3/18 (16.7%)		8/154 (5.2%)		1/66 (1.5%)		2/18 (11.1%)		1/18 (5.6%)		2/12 (16.7%)
Productive cough	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		0/85 (0%)		0/41 (0%)		3/48 (6.3%)		0/18 (0%)		9/154 (5.8%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Pulmonary embolism	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		9/53 (17%)		6/85 (7.1%)		1/41 (2.4%)		2/48 (4.2%)		2/18 (11.1%)		5/154 (3.2%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Rhinorrhoea	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		4/53 (7.5%)		6/85 (7.1%)		2/41 (4.9%)		3/48 (6.3%)		1/18 (5.6%)		2/154 (1.3%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Wheezing	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		2/9 (22.2%)		7/53 (13.2%)		5/85 (5.9%)		0/41 (0%)		2/48 (4.2%)		1/18 (5.6%)		12/154 (7.8%)		2/66 (3%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Acute respiratory failure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Aspiration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Bronchial secretion retention	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Epistaxis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		0/48 (0%)		0/18 (0%)		5/154 (3.2%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Haemoptysis	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		1/41 (2.4%)		1/48 (2.1%)		1/18 (5.6%)		10/154 (6.5%)		4/66 (6.1%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Hiccups	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		6/154 (3.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Nasal congestion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		12/85 (14.1%)		0/41 (0%)		1/48 (2.1%)		1/18 (5.6%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Paranasal sinus discomfort	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		2/48 (4.2%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Paranasal sinus hypersecretion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Pneumonia aspiration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Pulmonary haemorrhage	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		5/85 (5.9%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Respiratory failure	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Rhinitis allergic	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		3/85 (3.5%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		1/66 (1.5%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Sinus congestion	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		1/18 (5.6%)		2/154 (1.3%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Tonsillar hypertrophy	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Upper-airway cough syndrome	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		3/85 (3.5%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Atelectasis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		1/12 (8.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/9 (0%)		4/53 (7.5%)		5/85 (5.9%)		1/41 (2.4%)		2/48 (4.2%)		0/18 (0%)		19/154 (12.3%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Erythema	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		3/53 (5.7%)		3/85 (3.5%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		9/154 (5.8%)		4/66 (6.1%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Pruritus	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		8/53 (15.1%)		8/85 (9.4%)		0/41 (0%)		2/48 (4.2%)		0/18 (0%)		17/154 (11%)		3/66 (4.5%)		4/18 (22.2%)		0/18 (0%)		0/12 (0%)
Rash	0/3 (0%)		1/4 (25%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		2/6 (33.3%)		0/9 (0%)		15/53 (28.3%)		6/85 (7.1%)		2/41 (4.9%)		2/48 (4.2%)		2/18 (11.1%)		41/154 (26.6%)		5/66 (7.6%)		3/18 (16.7%)		2/18 (11.1%)		0/12 (0%)
Blister	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Cold sweat	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Decubitus ulcer	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		2/85 (2.4%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Dermatitis acneiform	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		2/53 (3.8%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		3/154 (1.9%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Dry skin	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		8/85 (9.4%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		10/154 (6.5%)		2/66 (3%)		3/18 (16.7%)		0/18 (0%)		0/12 (0%)
Ecchymosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		2/48 (4.2%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Hyperhidrosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		2/53 (3.8%)		1/85 (1.2%)		0/41 (0%)		3/48 (6.3%)		0/18 (0%)		5/154 (3.2%)		3/66 (4.5%)		0/18 (0%)		1/18 (5.6%)		1/12 (8.3%)
Night sweats	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		2/85 (2.4%)		2/41 (4.9%)		2/48 (4.2%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		1/18 (5.6%)		0/12 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Petechiae	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Photosensitivity reaction	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		1/18 (5.6%)		0/12 (0%)
Rash macular	0/3 (0%)		1/4 (25%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		1/48 (2.1%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Rash maculo-papular	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		1/6 (16.7%)		0/9 (0%)		1/53 (1.9%)		9/85 (10.6%)		2/41 (4.9%)		1/48 (2.1%)		0/18 (0%)		1/154 (0.6%)		1/66 (1.5%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Skin discolouration	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		2/66 (3%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Skin fissures	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Skin hyperpigmentation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Skin mass	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Surgical and medical procedures
Sinus operation	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		1/154 (0.6%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Vascular disorders
Deep vein thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		3/53 (5.7%)		3/85 (3.5%)		6/41 (14.6%)		4/48 (8.3%)		2/18 (11.1%)		9/154 (5.8%)		1/66 (1.5%)		1/18 (5.6%)		0/18 (0%)		0/12 (0%)
Hypotension	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		5/53 (9.4%)		19/85 (22.4%)		7/41 (17.1%)		2/48 (4.2%)		0/18 (0%)		15/154 (9.7%)		5/66 (7.6%)		0/18 (0%)		2/18 (11.1%)		1/12 (8.3%)
Flushing	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		1/53 (1.9%)		1/85 (1.2%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		2/154 (1.3%)		0/66 (0%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Hot flush	0/3 (0%)		0/4 (0%)		1/8 (12.5%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		1/85 (1.2%)		1/41 (2.4%)		1/48 (2.1%)		0/18 (0%)		4/154 (2.6%)		0/66 (0%)		2/18 (11.1%)		0/18 (0%)		0/12 (0%)
Hypertension	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		1/9 (11.1%)		1/53 (1.9%)		8/85 (9.4%)		2/41 (4.9%)		2/48 (4.2%)		0/18 (0%)		7/154 (4.5%)		1/66 (1.5%)		0/18 (0%)		1/18 (5.6%)		1/12 (8.3%)
Jugular vein thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		0/7 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		1/18 (5.6%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Thrombophlebitis superficial	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)
Thrombosis	0/3 (0%)		0/4 (0%)		0/8 (0%)		1/7 (14.3%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)		0/9 (0%)		0/53 (0%)		0/85 (0%)		0/41 (0%)		0/48 (0%)		0/18 (0%)		0/154 (0%)		0/66 (0%)		0/18 (0%)		0/18 (0%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.