Safety Study of PLX4032 in Patients With Solid Tumors

• Sponsor: Plexxikon (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00405587
• Collaborator: Roche Pharma AG (Industry)
• Enrollment: 109
• Locations: 7
• Arm: 1
• Duration (Months): 111
• Patients Per Site: 15.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma; Colorectal Carcinoma	Drug: PLX4032	Phase 1

Detailed Description

Activating mutations of the BRAF gene have been observed in a variety of cancers, including 55-68% of malignant melanomas. In general, oncogenic mutations of BRAF correlate with a poor outcome. PLX4032 is a compound that selectively inhibits oncogenic B-Raf kinase.

Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX4032 in Patients With Solid Tumors
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PLX4032 Open-label, sequential dose escalation	Drug: PLX4032; Oral capsules administered BID

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

   AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

2. Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

   AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

3. Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation [Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8]

4. Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation [Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16]

5. Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8]

6. Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16]

7. AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

   AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

8. AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

   AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

9. Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation [Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose]

   Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

10. Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC [Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose]

    Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

11. Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8]

12. Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16]

13. Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8]

14. Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16]

15. AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

    AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

16. AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

    AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

17. Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8]

18. Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16]

19. Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8]

20. Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16]

21. Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma [Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)]

    BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

22. Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC [Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)]

    BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

23. Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation [Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)]

    BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

24. Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation [Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)]

    BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Secondary Outcome Measures

1. Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma [Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)]

   Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.

2. Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort [Month 1, 3, 4, 6, 9, and Last event (350) days]

   PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.

3. PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma [Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)]

   PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.

4. Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma [Screening, BL, until PD, or end of efficacy follow-up, up to 444 days]

5. Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma [Screening, BL, until PD, or end of efficacy follow-up, up to 444 days]

   OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.

6. Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma [Screening, BL, and up to 168 days]

   Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.

7. Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma [Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose]

   AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

8. Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16]

9. Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG) [BL and Day 15]

   Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)

10. Cmax of RO5185426 - Food Effect [Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16]

11. Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67 [BL and Day 15]

    The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Solid tumors confirmed histologically whose tumors are refractory to standard therapy, or for whom standard or curative therapy does not exist

• Patients from whom paired melanoma biopsies are planned must have a V600E+ BRAF mutation confirmed prior to the administration of PLX4032

• Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 2 weeks prior to starting PLX4032 therapy, and all associated toxicity must be resolved prior to administration of PLX4032

• Patients in the Extension cohorts (melanoma or adenocarcinoma of the colon or rectum) must have both a V600E+ BRAF mutation and measurable disease (by RECIST V 1.0 criteria) prior to the administration of PLX4032. All patients enrolled must provide archival or fresh melanoma tumor biopsy for confirmation of V600E+ BRAF mutation status by TaqMan assay

• ECOG performance status 0 or 1

• Life expectancy ≥ 3 months

• Adequate hematologic, hepatic, and renal function

Exclusion Criteria:

• Brain metastases that are progressing or have been documented to be stable for less than 3 months, or for which systemic corticosteroids are required

• Investigational drug use within 28 days of the first dose of PLX4032

• Uncontrolled intercurrent illness

• Refractory nausea and vomiting, malabsorption, or significant bowel resection that would preclude adequate absorption

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles	Los Angeles	California	United States	90095
2	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
3	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
4	Vanderbilt Ingram Cancer Center	Nashville	Tennessee	United States	37232
5	MD Anderson Cancer Center	Houston	Texas	United States	77030
6	Peter MacCallum Cancer Centre	East Melbourne	Victoria	Australia	3002
7	Royal Melbourne Hospital	Parkville	Victoria	Australia

Sponsors and Collaborators

• Plexxikon
• Roche Pharma AG

Investigators

• Study Director: Henry Hsu, MD, Plexxikon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Plexxikon
• ClinicalTrials.gov Identifier: NCT00405587
• Other Study ID Numbers: PLX06-02
• First Posted: Nov 30, 2006
• Last Update Posted: Aug 22, 2017
• Last Verified: Oct 1, 2016

• Additional relevant MeSH terms: Melanoma; Colorectal Neoplasms; Vemurafenib

Study Results

Participant Flow

Pre-assignment Detail	Enrollment to "Dose Escalation: Original Formulation" was halted based on bioavailability results and the drug was reformulated as microprecipitated bulk powder (MBP) and then the enrollment was resumed in "Dose Escalation: MBP Formulation" arm

Arm/Group Title	Dose Escalation: Original Formulation	Dose Escalation: MBP Formulation	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Cohorts of 3 to 6 participants received RO5185426 capsules in original (crystalline) formulation at a starting dose of 200 mg BID for 4 weeks. After Day 15 pharmacokinetic assessment and adequate safety and tolerability was shown, next cohort of 3 to 6 participants received 50 % to 100% increased dose of RO5185426 original formulation for 4 weeks. Dose escalation was continued up to 1600 mg BID dose level.	Cohorts of 3 to 6 participants received RO5185426 capsules/tablets in MBP formulation at a starting dose of 160 mg BID for 4 weeks. After Day 15 pharmacokinetic assessment and adequate safety and tolerability was shown, next cohort of 3 to 6 participants received 50 % to 100% increased dose of RO5185426 MBP formulation for 4 weeks. Dose escalation was continued up to unacceptable toxicity or disease progression occurred.	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg BID until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg BID until disease progression, death, or withdrawal from the study.
Period Title: Overall Study
STARTED	26	30	32	21
COMPLETED	0	2	10	1
NOT COMPLETED	26	28	22	20

Baseline Characteristics

Arm/Group Title	Dose Escalation: Original Formulation	Dose Escalation: MBP Formulation	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC	Total
Arm/Group Description	Cohorts of 3 to 6 participants received RO5185426 capsules in original (crystalline) formulation at a starting dose of 200 mg BID for 4 weeks. After Day 15 pharmacokinetic assessment and adequate safety and tolerability was shown, next cohort of 3 to 6 participants received 50 % to 100% increased dose of RO5185426 original formulation for 4 weeks. Dose escalation was continued up to 1600 mg BID dose level.	Cohorts of 3 to 6 participants received RO5185426 capsules/tablets in MBP formulation at a starting dose of 160 mg BID for 4 weeks. After Day 15 pharmacokinetic assessment and adequate safety and tolerability was shown, next cohort of 3 to 6 participants received 50 % to 100% increased dose of RO5185426 MBP formulation for 4 weeks. Dose escalation was continued up to unacceptable toxicity or disease progression occurred.	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg BID until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg BID until disease progression, death, or withdrawal from the study.	Total of all reporting groups
Overall Participants	26	30	32	21	109
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.5 (13.75)	58.0 (14.77)	50.4 (13.54)	63.6 (14.86)	58.6 (15.24)
Sex: Female, Male (Count of Participants)
Female	11 42.3%	11 36.7%	14 43.8%	10 47.6%	46 42.2%
Male	15 57.7%	19 63.3%	18 56.3%	11 52.4%	63 57.8%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	4	4	4
AUC (0-8 hour) (n= 6, 4, 4, 4)	2.02 (1.03)	3.28 (1.66)	4.47 (0.61)	4.23 (2.0)
AUC (0-24 hour) (n= 6, 4, 4, 4)	8.43 (4.84)	14.86 (7.89)	21.66 (10.59)	22.34 (10.59)

2. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	3	3	4
AUC (0-8 hour) (n=6, 3, 3, 4)	9.37 (6.18)	30.90 (11.44)	30.58 (7.08)	33.89 (17.24)
AUC (0-24 hour) (n= 2, 2, 3, 4)	46.28 (10.47)	105.10 (65.41)	91.01 (26.86)	101.13 (48.40)

3. Primary Outcome

Title	Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Outcome Measure Data

Analysis Population Description

PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	4	4	3
Mean (Standard Deviation) [Micrograms per milliliter]	0.37 (0.2)	0.58 (0.27)	0.85 (0.06)	0.73 (0.38)

4. Primary Outcome

Title	Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16

Outcome Measure Data

Analysis Population Description

PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	3	3	4
Mean (Standard Deviation) [Micrograms per milliliter]	1.34 (0.81)	4.57 (2.07)	5.41 (2.26)	5.34 (3.04)

5. Primary Outcome

Title	Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Outcome Measure Data

Analysis Population Description

PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	4	4	3
Median (Full Range) [hours]	9.98	4	3.01	4

6. Primary Outcome

Title	Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16

Outcome Measure Data

Analysis Population Description

PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	3	3	4
Median (Full Range) [hours]	0.02	0.5	0	3

7. Primary Outcome

Title	AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	3	4	4	4	6	5
Mean (Standard Deviation) [ug*hr/mL]	5.98 (3.31)	15.85 (1.53)	14.95 (4.99)	39.09 (35.82)	39.48 (19.58)	44.94 (20.88)

8. Primary Outcome

Title	AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	4	4	4	4	3	4
AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4)	33.91 (19.14)	71.64 (30.09)	114.50 (35.33)	212.28 (123.24)	229.96 (42.75)	536.47 (137.18)
AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3)	87.18 (88.78)	228.97 (81.03)	373.94 (94.51)	622.21 (406.89)	649.29 (200.95)	1494.27 (367.68)

9. Primary Outcome

Title	Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation
Description	Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Time Frame	Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	3	4	4	3	3	3
Mean (Standard Deviation) [ratio]	4.75 (3.14)	4.47 (1.57)	8.66 (5.37)	8.89 (6.03)	10.11 (3.09)	13.86 (4.68)

10. Primary Outcome

Title	Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Description	Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Time Frame	Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	13	13
Mean (Standard Deviation) [ratio]	11.61 (4.59)	9.31 (3.90)

11. Primary Outcome

Title	Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	3	4	4	4	6	5
Mean (Standard Deviation) [micrograms per milliliter]	1.14 (0.48)	2.93 (0.39)	2.72 (0.94)	7.2 (6.06)	7.12 (3.71)	7.73 (3.54)

12. Primary Outcome

Title	Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	4	4	4	4	3	4
Mean (Standard Deviation) [micrograms per milliliter]	5.16 (2.72)	11.64 (4.55)	17.90 (8.01)	31.15 (15.56)	34.10 (5.47)	84.30 (23.51)

13. Primary Outcome

Title	Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	3	4	4	4	6	5
Median (Full Range) [hours]	2	3	3.21	6.29	3.29	4.33

14. Primary Outcome

Title	Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg	Dose Escalation: MBP Formulation - 240 mg	Dose Escalation: MBP Formulation - 360 mg	Dose Escalation: MBP Formulation - 720 mg	Dose Escalation: MBP Formulation - 960 mg	Dose Escalation: MBP Formulation - 1120 mg
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 960 mg BID for 4 weeks.	Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.
Measure Participants	4	4	4	4	3	4
Median (Full Range) [hours]	1.5	2.0	4.10	4.07	4.33	0.41

15. Primary Outcome

Title	AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	29	21
AUC (0-8 hour) (n= 29, 21)	31.35 (15.51)	31.53 (15.1)
AUC (0-24 hour) (n= 5, 0)	108.52 (42.36)	NA (NA)

16. Primary Outcome

Title	AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	14	13
AUC (0-8 hour) (n= 14, 13 )	289.26 (105.88)	262.42 (101.37)
AUC (0-24 hour) (n= 9, 11)	924.65 (317.71)	752.64 (314.47)

17. Primary Outcome

Title	Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Outcome Measure Data

Analysis Population Description

Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	29	21
Mean (Standard Deviation) [microgram/milliliter]	5.84 (2.61)	5.53 (2.27)

18. Primary Outcome

Title	Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16

Outcome Measure Data

Analysis Population Description

Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	14	13
Mean (Standard Deviation) [microgram/milliliter]	44.31 (16.38)	38.55 (15.92)

19. Primary Outcome

Title	Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Outcome Measure Data

Analysis Population Description

Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	29	21
Median (Full Range) [hours]	4	4

20. Primary Outcome

Title	Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Outcome Measure Data

Analysis Population Description

Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	14	13
Median (Full Range) [hours]	1.01	2.0

21. Primary Outcome

Title	Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma
Description	BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Outcome Measure Data

Analysis Population Description

Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	32
Confirmed BOR	56.3 216.5%
Unconfirmed BOR	81.3 312.7%

22. Primary Outcome

Title	Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC
Description	BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Outcome Measure Data

Analysis Population Description

Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.

Arm/Group Title	Extension: BRAFV600E- Positive CRC
Arm/Group Description	Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	20
Number (95% Confidence Interval) [percentage of participants]	5.0 19.2%

23. Primary Outcome

Title	Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation
Description	BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Outcome Measure Data

Analysis Population Description

Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.

Arm/Group Title	Dose Escalation: Original Formulation - 200 mg	Dose Escalation: Original Formulation - 400 mg	Dose Escalation: Original Formulation - 800 mg	Dose Escalation: Original Formulation - 1600 mg
Arm/Group Description	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.	Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.
Measure Participants	6	6	10	4
Number (95% Confidence Interval) [percentage of participants]	0 0%	0 0%	10.0 31.3%	0 0%

24. Primary Outcome

Title	Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation
Description	BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Outcome Measure Data

Analysis Population Description

Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.

Arm/Group Title	Dose Escalation: MBP Formulation -160 mg	Dose Escalation: MBP Formulation -240 mg	Dose Escalation: MBP Formulation -320 mg	Dose Escalation: MBP Formulation -360 mg	Dose Escalation: MBP Formulation -720 mg	Dose Escalation: MBP Formulation -1120 mg
Arm/Group Description	Participants received RO5185426 hard gelatin capsules at a dose of 160 mg BID for 4 weeks.	Participants received RO5185426 hard gelatin capsules at a dose of 240 mg BID for 4 weeks.	Participants received RO5185426 hard gelatin capsules at a dose of 320 mg BID for 4 weeks.	Participants received RO5185426 hard gelatin capsules at a dose of 360 mg BID for 4 weeks.	Participants received RO5185426 hard gelatin capsules at a dose of 720 mg BID for 4 weeks.	Participants received RO5185426 hard gelatin capsules at a dose of 1120 mg BID for 4 weeks.
Measure Participants	4	4	3	5	7	6
Number (95% Confidence Interval) [percentage of participants]	0 0%	25.0 83.3%	33.3 104.1%	40.0 190.5%	28.6 26.2%	50.0 NaN

25. Secondary Outcome

Title	Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma
Description	Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Outcome Measure Data

Analysis Population Description

Modified ITT population: Participants with confirmed CR or PR with a measurable disease at BL, and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Seven participants were censored for analysis.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	18
Median (95% Confidence Interval) [days]	227

26. Secondary Outcome

Title	Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort
Description	PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.
Time Frame	Month 1, 3, 4, 6, 9, and Last event (350) days

Outcome Measure Data

Analysis Population Description

Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Eight participants were censored for analysis.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	32
Month 1	96.9 372.7%
Month 3	87.5 336.5%
Month 4	75.0 288.5%
Month 6	59.4 228.5%
Month 9	43.3 166.5%
1 Year	16.9 65%
Last Event (350 Days)	16.9 65%

27. Secondary Outcome

Title	PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma
Description	PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)

Outcome Measure Data

Analysis Population Description

Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Eight participants were censored for analysis.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	32
Median (95% Confidence Interval) [days]	233

28. Secondary Outcome

Title	Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Outcome Measure Data

Analysis Population Description

Modified ITT Population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	32
Month 1	0 0%
Month 3	3.1 11.9%
Month 4	6.2 23.8%
Month 6	12.7 48.8%
Month 9	29.4 113.1%
Month 12	43.2 166.2%

29. Secondary Outcome

Title	Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma
Description	OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.
Time Frame	Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Outcome Measure Data

Analysis Population Description

Modified ITT Population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Twenty participants were censored for analysis.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	32
Median (95% Confidence Interval) [days]	NA

30. Secondary Outcome

Title	Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma
Description	Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.
Time Frame	Screening, BL, and up to 168 days

Outcome Measure Data

Analysis Population Description

Modified ITT population: Participants with a confirmed CR or PR with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered.

Arm/Group Title	Extension: BRAFV600E- Positive Melanoma
Arm/Group Description	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
Measure Participants	18
Median (Full Range) [days]	56.5

31. Secondary Outcome

Title	Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma
Description	AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time Frame	Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Outcome Measure Data

Analysis Population Description

The analysis was planned only for those participants who received 80 or 120 mg dose of RO5185426 up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.

Arm/Group Title	Dose Escalation: MBP Formulation - 80 mg Capsule	Dose Escalation: MBP Formulation and Extension: BRAFV600E- Pos
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 320 mg BID dose escalation/paired biopsy cohort, or 720 mg BID dose escalation/paired biopsy cohort, or 1120 mg BID dose escalation for 4 weeks.	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules in MBP formulation at a dose of 960 mg BID , or 960 mg BID dose escalation
Measure Participants	10	19
AUC (0-8hour) (n= 10, 19)	0.179 (0.081)	0.197 (0.091)
AUC (0-24 hour) (n= 7, 9)	0.524 (0.233)	0.482 (0.165)

32. Secondary Outcome

Title	Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16

Outcome Measure Data

Analysis Population Description

PK Population: The analysis was planned only for those participants who received 80 or 120 mg dose of RO5185426 up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.

Arm/Group Title	Dose Escalation: MBP Formulation - 80 mg Capsule	Dose Escalation: MBP Formulation and Extension: BRAFV600E- Pos
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 320 mg BID dose escalation/paired biopsy cohort, or 720 mg BID dose escalation/paired biopsy cohort, or 1120 mg BID dose escalation for 4 weeks.	Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules in MBP formulation at a dose of 960 mg BID , or 960 mg BID dose escalation
Measure Participants	10	19
Mean (Standard Deviation) [ug/mL]	0.028 (0.012)	0.030 (0.013)

33. Secondary Outcome

Title	Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)
Description	Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)
Time Frame	BL and Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

34. Secondary Outcome

Title	Cmax of RO5185426 - Food Effect
Time Frame	Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

35. Secondary Outcome

Title	Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67
Description	The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.
Time Frame	BL and Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	For MBP Formulation, one patient not dosed, so only 29 patients are evaluable for safety measures although at the beginning of the study 30 patients started.
Arm/Group Title	Dose Escalation: MBP Formulation - 160 mg		Dose Escalation: MBP Formulation - 240 mg		Dose Escalation: MBP Formulation - 320 mg		Dose Escalation: MBP Formulation - 360 mg		Dose Escalation: MBP Formulation - 720 mg		Dose Escalation: MBP Formulation - 1120 mg		Dose Escalation: Original Formulation - 200 mg		Dose Escalation: Original Formulation - 400 mg		Dose Escalation: Original Formulation - 800 mg		Dose Escalation: Original Formulation - 1600 mg		Extension: BRAFV600E-Positive Melanoma		Extension: BRAFV600E-Positive CRC
Arm/Group Description	Participants received RO5185426 capsules in MBP formulation at a dose of 160 mg BID for 4 weeks.		Participants received RO5185426 capsules in MBP formulation at a dose of 240 mg BID for 4 weeks.		Participants received RO5185426 capsules in MBP formulation at a dose of 320 mg BID for 4 weeks.		Participants received RO5185426 capsules in MBP formulation at a dose of 360 mg BID for 4 weeks.		Participants received RO5185426 capsules in MBP formulation at a dose of 720 mg BID for 4 weeks.		Participants received RO5185426 capsules in MBP formulation at a dose of 1120 mg BID for 4 weeks.		Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 200 mg BID for 4 weeks.		Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 400 mg BID for 4 weeks.		Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 800 mg BID for 4 weeks.		Participants received RO5185426 capsules in original (crystalline) formulation at a dose of 1600 mg BID for 4 weeks.		Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185246 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.		Participants with CRC that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185246 capsules/tablets in MBP formulation at a dose of 960 mg bid until disease progression, death, or withdrawal from the study.
All Cause Mortality
	Dose Escalation: MBP Formulation - 160 mg		Dose Escalation: MBP Formulation - 240 mg		Dose Escalation: MBP Formulation - 320 mg		Dose Escalation: MBP Formulation - 360 mg		Dose Escalation: MBP Formulation - 720 mg		Dose Escalation: MBP Formulation - 1120 mg		Dose Escalation: Original Formulation - 200 mg		Dose Escalation: Original Formulation - 400 mg		Dose Escalation: Original Formulation - 800 mg		Dose Escalation: Original Formulation - 1600 mg		Extension: BRAFV600E-Positive Melanoma		Extension: BRAFV600E-Positive CRC
	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	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Escalation: MBP Formulation - 160 mg		Dose Escalation: MBP Formulation - 240 mg		Dose Escalation: MBP Formulation - 320 mg		Dose Escalation: MBP Formulation - 360 mg		Dose Escalation: MBP Formulation - 720 mg		Dose Escalation: MBP Formulation - 1120 mg		Dose Escalation: Original Formulation - 200 mg		Dose Escalation: Original Formulation - 400 mg		Dose Escalation: Original Formulation - 800 mg		Dose Escalation: Original Formulation - 1600 mg		Extension: BRAFV600E-Positive Melanoma		Extension: BRAFV600E-Positive CRC
	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	0/4 (0%)		2/4 (50%)		2/3 (66.7%)		3/5 (60%)		1/7 (14.3%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		18/32 (56.3%)		9/21 (42.9%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Leukopenia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Neutropenia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Thrombocytopenia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
White blood cell count increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Cardiac disorders
Atrial fibrillation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Pericardial effusion	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Pericarditis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Eye disorders
Iridocyclitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Uveitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Vitritis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Gastrointestinal disorders
Diarrhoea	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Pancreatitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		1/21 (4.8%)
Vomiting	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Abdominal pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
General disorders
Chest pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pyrexia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Asthenia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Hepatobiliary disorders
Cholangitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Hepatotoxicity	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Hyperbilirubinaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Infections and infestations
Abdominal abscess	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Lobar pneumonia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Staphylococcal infection	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Investigations
Alanine aminotransferase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Aspartate aminotransferase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood alkaline phosphatase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood bilirubin increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Blood amylase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Lipase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Hypertriglyceridaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Hyponatraemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Arthralgia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	0/4 (0%)		2/4 (50%)		1/3 (33.3%)		2/5 (40%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		10/32 (31.3%)		5/21 (23.8%)
Basal cell carcinoma	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Malignant melanoma	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Nervous system disorders
Hemiparesis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Psychiatric disorders
Anxiety	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Confusional state	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		1/21 (4.8%)
Pleural effusion	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndroma	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Photosensitivity reaction	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Rash	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Rash papular	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Surgical and medical procedures
Tooth extraction	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		1/32 (3.1%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Dose Escalation: MBP Formulation - 160 mg		Dose Escalation: MBP Formulation - 240 mg		Dose Escalation: MBP Formulation - 320 mg		Dose Escalation: MBP Formulation - 360 mg		Dose Escalation: MBP Formulation - 720 mg		Dose Escalation: MBP Formulation - 1120 mg		Dose Escalation: Original Formulation - 200 mg		Dose Escalation: Original Formulation - 400 mg		Dose Escalation: Original Formulation - 800 mg		Dose Escalation: Original Formulation - 1600 mg		Extension: BRAFV600E-Positive Melanoma		Extension: BRAFV600E-Positive CRC
	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	4/4 (100%)		4/4 (100%)		3/3 (100%)		5/5 (100%)		7/7 (100%)		6/6 (100%)		6/6 (100%)		6/6 (100%)		10/10 (100%)		4/4 (100%)		32/32 (100%)		21/21 (100%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)		2/4 (50%)		3/3 (100%)		2/5 (40%)		3/7 (42.9%)		1/6 (16.7%)		2/6 (33.3%)		2/6 (33.3%)		1/10 (10%)		1/4 (25%)		9/32 (28.1%)		4/21 (19%)
Lymphopenia	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		3/5 (60%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		7/32 (21.9%)		6/21 (28.6%)
Leukopenia	1/4 (25%)		0/4 (0%)		1/3 (33.3%)		2/5 (40%)		0/7 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Neutropenia	1/4 (25%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Thrombocytopenia	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Microcytic anaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Thrombocytosis	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Lymphadenopathy	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Cardiac disorders
Atrial flutter	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pericardial effusion	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Sinus bradycardia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Trachycardia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Ventricular tachycardia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Ear and labyrinth disorders
Ear congestion	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Ear pain	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Vertigo	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Eye disorders
Dry eye	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Photophobia	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Uveitis	0/4 (0%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Visual impairment	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Altered visual depth perception	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Conjunctival irritation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Eye discharge	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Lacrimation increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Ocular hyperaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Photopsia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Vitreous floaters	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Vision blurred	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Eye irritation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Iridocyclitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Gastrointestinal disorders
Nausea	2/4 (50%)		2/4 (50%)		2/3 (66.7%)		3/5 (60%)		2/7 (28.6%)		3/6 (50%)		2/6 (33.3%)		1/6 (16.7%)		2/10 (20%)		0/4 (0%)		14/32 (43.8%)		7/21 (33.3%)
Constipation	2/4 (50%)		0/4 (0%)		2/3 (66.7%)		3/5 (60%)		2/7 (28.6%)		1/6 (16.7%)		2/6 (33.3%)		1/6 (16.7%)		2/10 (20%)		2/4 (50%)		7/32 (21.9%)		4/21 (19%)
Diarrhoea	0/4 (0%)		1/4 (25%)		2/3 (66.7%)		1/5 (20%)		1/7 (14.3%)		3/6 (50%)		1/6 (16.7%)		1/6 (16.7%)		1/10 (10%)		1/4 (25%)		11/32 (34.4%)		8/21 (38.1%)
Vomiting	1/4 (25%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		2/7 (28.6%)		1/6 (16.7%)		2/6 (33.3%)		3/6 (50%)		1/10 (10%)		1/4 (25%)		12/32 (37.5%)		7/21 (33.3%)
Abdominal pain	1/4 (25%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		3/6 (50%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		4/32 (12.5%)		3/21 (14.3%)
Abdominal discomfort	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
faeces pale	0/4 (0%)		2/4 (50%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Flatulence	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		2/21 (9.5%)
Abdominal pain upper	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		3/21 (14.3%)
Anorectal discomfort	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dry mouth	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dyspepsia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		2/6 (33.3%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dysphagia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Faecal incontinence	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Gastrooesophageal reflux disease	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Intestinal perforation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Large intestine polyp	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Lip Swelling	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Peptic Ulcer	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Abdominal distension	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Gastritis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Hypoaesthesia oral	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Paraesthesia oral	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Tongue atrophy	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Crohn's disease	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Stomatitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
General disorders
Fatigue	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		4/5 (80%)		3/7 (42.9%)		4/6 (66.7%)		2/6 (33.3%)		3/6 (50%)		6/10 (60%)		0/4 (0%)		22/32 (68.8%)		12/21 (57.1%)
Oedema peripheral	1/4 (25%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Pyrexia	0/4 (0%)		1/4 (25%)		0/3 (0%)		2/5 (40%)		2/7 (28.6%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		2/4 (50%)		9/32 (28.1%)		6/21 (28.6%)
Asthenia	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		2/5 (40%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Chest pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Face oedema	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		0/32 (0%)		0/21 (0%)
Fibrosis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Malaise	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Chills	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		3/21 (14.3%)
Influenza like illness	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Mucosal inflammation	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Oedema	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		0/5 (0%)		2/7 (28.6%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Xerosis	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Local Swelling	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		4/32 (12.5%)		6/21 (28.6%)
Immune system disorders
Allergy to arthropod sting	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Infections and infestations
Urinary tract infection	1/4 (25%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		4/21 (19%)
Upper respiratory tract infection	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Bronchitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		0/32 (0%)		0/21 (0%)
Candida infection	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
cystitis	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Folliculitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Gingivitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Impetigo	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Nasopharyngitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Oral herpes	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Rhinitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Sinusitis	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Vaginal infection	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Viral infection	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Cellulitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Device related infection	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Diverticulitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Laryngitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Peritonitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pneumonia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Conjunctivitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
oral candidiasis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Injury, poisoning and procedural complications
Sunburn	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		10/32 (31.3%)		2/21 (9.5%)
Arthropod bite	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		2/21 (9.5%)
Contusion	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Excoriation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Laceration	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
post procedural discharge	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Procedural pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Radiation skin injury	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Wound	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Post procedural complication	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Post procedural inflammation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Spinal fracture	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Wound complication	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Investigations
Blood creatinine increased	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		1/5 (20%)		2/7 (28.6%)		3/6 (50%)		0/6 (0%)		2/6 (33.3%)		0/10 (0%)		0/4 (0%)		8/32 (25%)		4/21 (19%)
Blood alkaline phosphatase increased	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		1/5 (20%)		3/7 (42.9%)		2/6 (33.3%)		2/6 (33.3%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		13/32 (40.6%)		5/21 (23.8%)
Activated partial thromboplastin time prolonged	1/4 (25%)		1/4 (25%)		1/3 (33.3%)		1/5 (20%)		2/7 (28.6%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		4/10 (40%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Alanine aminotransferase increased	1/4 (25%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		2/6 (33.3%)		2/6 (33.3%)		0/10 (0%)		1/4 (25%)		10/32 (31.3%)		3/21 (14.3%)
Aspartate aminotransferase increased	1/4 (25%)		1/4 (25%)		0/3 (0%)		2/5 (40%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		1/4 (25%)		8/32 (25%)		3/21 (14.3%)
Weight decreased	0/4 (0%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		7/32 (21.9%)		2/21 (9.5%)
Blood uric acid increased	1/4 (25%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		2/10 (20%)		1/4 (25%)		2/32 (6.3%)		0/21 (0%)
Blood albumin decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		2/10 (20%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood bilirubin increased	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Haemoglobin decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		2/5 (40%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		2/10 (20%)		0/4 (0%)		4/32 (12.5%)		3/21 (14.3%)
Platelet count increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood albumin increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood chloride increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood glucose increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood iron decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood potassium decreased	1/4 (25%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood triglycerides	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood triglycerides increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
White blood cell count decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Gamma-glutamyltransferase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Amylase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood Phosphorus decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood Phosphorus increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Haematocrit decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Lipase increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Neutrophil count increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Blood Urea Increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		2/21 (9.5%)
CSF pressure increase	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Carbon dioxide increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Cardiac murmur	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Electrocardiogram QT prolonged	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Low density lipoprotein increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Prothrombin time prolonged	1/4 (25%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Prothombin time shortened	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood calcium decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		2/10 (20%)		1/4 (25%)		0/32 (0%)		0/21 (0%)
Blood cholesterol increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood potassium increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		0/32 (0%)		0/21 (0%)
Blood sodium decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Blood sodium increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Carbon dioxide decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
International normalised ratio increased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hypertriglyceridaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Platelet count decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Metabolism and nutrition disorders
Hypercholesterolaemia	0/4 (0%)		2/4 (50%)		1/3 (33.3%)		2/5 (40%)		3/7 (42.9%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Hyperglycaemia	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		3/5 (60%)		2/7 (28.6%)		1/6 (16.7%)		2/6 (33.3%)		1/6 (16.7%)		3/10 (30%)		2/4 (50%)		9/32 (28.1%)		9/21 (42.9%)
Anorexia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		2/10 (20%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hyperuricaemia	0/4 (0%)		2/4 (50%)		0/3 (0%)		2/5 (40%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		2/6 (33.3%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		4/21 (19%)
Hypoglycaemia	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		2/5 (40%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Hypertriglyceridaemia	1/4 (25%)		2/4 (50%)		2/3 (66.7%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Hypomagnesaemia	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hyponatraemia	0/4 (0%)		0/4 (0%)		2/3 (66.7%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		2/10 (20%)		1/4 (25%)		7/32 (21.9%)		6/21 (28.6%)
Hypophosphataemia	0/4 (0%)		2/4 (50%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		6/32 (18.8%)		2/21 (9.5%)
Decreased appetite	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		2/6 (33.3%)		2/6 (33.3%)		2/10 (20%)		1/4 (25%)		13/32 (40.6%)		5/21 (23.8%)
Dehydration	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Hypercalcaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Hyperkalaemia	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hyperphosphataemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hypocalcaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		5/21 (23.8%)
Hypokalaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		0/4 (0%)		9/32 (28.1%)		4/21 (19%)
Hypoalbuminaemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		1/4 (25%)		3/32 (9.4%)		6/21 (28.6%)
Acidosis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hypernatraemia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hypophagia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Fluid Retention	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		0/32 (0%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		3/5 (60%)		3/7 (42.9%)		3/6 (50%)		1/6 (16.7%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		22/32 (68.8%)		8/21 (38.1%)
Myalgia	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		1/5 (20%)		1/7 (14.3%)		3/6 (50%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		9/32 (28.1%)		4/21 (19%)
Back pain	1/4 (25%)		1/4 (25%)		1/3 (33.3%)		2/5 (40%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/10 (10%)		1/4 (25%)		6/32 (18.8%)		0/21 (0%)
Pain in extremity	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		1/5 (20%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		9/32 (28.1%)		4/21 (19%)
Muscle weakness	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		0/32 (0%)		0/21 (0%)
Muscle spasms	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		2/6 (33.3%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Arthritis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Joint stiffness	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Musculoskeletal pain	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Musculoskeletal stiffness	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Neck pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Pain in jaw	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Joint range of motion decreased	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/4 (0%)		2/4 (50%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		3/6 (50%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		8/32 (25%)		0/21 (0%)
Seborrhoeic keratosis	0/4 (0%)		2/4 (50%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		2/21 (9.5%)
Acrochordon	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Keratoacanthoma	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Melanocytic naevus	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Oral papilloma	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Tumor pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Metastases to central nervous system	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Basal cell carcinoma	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Fibrous histiocytoma	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Nervous system disorders
Headache	0/4 (0%)		0/4 (0%)		0/3 (0%)		2/5 (40%)		2/7 (28.6%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		12/32 (37.5%)		6/21 (28.6%)
Dysgeusia	0/4 (0%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		2/6 (33.3%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		2/21 (9.5%)
Dizziness	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Neuropathy peripheral	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		2/6 (33.3%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Paraesthesia	1/4 (25%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Peripheral sensory neuropathy	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Memory impairment	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Amnesia	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dysaethesia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hemianopia	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hypoaesthesia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		3/32 (9.4%)		0/21 (0%)
Lethargy	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Restless legs syndrome	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Somnolence	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Spinal cord compression	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Tremor	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Visual field defect	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Ataxia	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Migraine	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Syncope	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Burning sensation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Psychiatric disorders
Insomnia	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		4/32 (12.5%)		2/21 (9.5%)
Anxiety	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Confusional state	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Mood altered	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Depression	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Irritability	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Mental status change	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Sleep disorder	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Renal and urinary disorders
Proteinuria	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		0/10 (0%)		2/4 (50%)		10/32 (31.3%)		6/21 (28.6%)
Haemoglobinuria	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Micturition urgency	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pollakiuria	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		1/4 (25%)		2/32 (6.3%)		0/21 (0%)
Bladder discomfort	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dysuria	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		2/21 (9.5%)
Urinary incontinence	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Urinary retention	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Ketonuria	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
haematuria	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		2/21 (9.5%)
Reproductive system and breast disorders
Menopausal symptoms	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Erectile dysfunction	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Deyronie's disease	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Vaginal lesion	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pelvic pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Breast pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Nipple disorder	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		3/4 (75%)		1/3 (33.3%)		2/5 (40%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		2/4 (50%)		10/32 (31.3%)		0/21 (0%)
Dysphonia	0/4 (0%)		0/4 (0%)		0/3 (0%)		2/5 (40%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dyspnoea	1/4 (25%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/10 (10%)		2/4 (50%)		3/32 (9.4%)		0/21 (0%)
Oropharyngeal pain	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		2/21 (9.5%)
Rhinitis allergic	0/4 (0%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Epistaxis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Upper-airway cough syndrome	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Allergic pharyngitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Dyspnoea exertional	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Nasal congestion	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Pulmonary congestion	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pulmonary embolism	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Sinus congestion	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Allergic sinusitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Pleuritic pain	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Sinus disorder	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Haemoptysis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Rhinorrhoea	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		3/21 (14.3%)
Skin and subcutaneous tissue disorders
Rash	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		2/5 (40%)		5/7 (71.4%)		4/6 (66.7%)		0/6 (0%)		0/6 (0%)		2/10 (20%)		1/4 (25%)		17/32 (53.1%)		7/21 (33.3%)
Alopecia	1/4 (25%)		2/4 (50%)		1/3 (33.3%)		2/5 (40%)		1/7 (14.3%)		4/6 (66.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		18/32 (56.3%)		5/21 (23.8%)
Photosensitivity reaction	0/4 (0%)		2/4 (50%)		1/3 (33.3%)		3/5 (60%)		2/7 (28.6%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		14/32 (43.8%)		7/21 (33.3%)
Pruritus	1/4 (25%)		3/4 (75%)		0/3 (0%)		3/5 (60%)		1/7 (14.3%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		2/10 (20%)		0/4 (0%)		8/32 (25%)		3/21 (14.3%)
Dry Skin	0/4 (0%)		0/4 (0%)		2/3 (66.7%)		1/5 (20%)		3/7 (42.9%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		9/32 (28.1%)		5/21 (23.8%)
Skin Exfoliation	0/4 (0%)		2/4 (50%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Erythema	0/4 (0%)		1/4 (25%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		3/6 (50%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		10/32 (31.3%)		2/21 (9.5%)
Actinic keratosis	0/4 (0%)		2/4 (50%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		5/32 (15.6%)		0/21 (0%)
Skin lesion	0/4 (0%)		0/4 (0%)		0/3 (0%)		2/5 (40%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		2/21 (9.5%)
Hyperkeratosis	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		8/32 (25%)		0/21 (0%)
Keratosis pilaris	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		6/32 (18.8%)		0/21 (0%)
Rash papular	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Acne	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		1/4 (25%)		2/32 (6.3%)		0/21 (0%)
Campbell de Morgan spots	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hair colour changes	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Nail bed disorder	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Night sweats	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		1/4 (25%)		3/32 (9.4%)		0/21 (0%)
Psoriasis	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Rash erythematous	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Rash pruritic	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Seborrhoeic dermatitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
skin haemorrhage	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Skin mass	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Solar lentigo	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Telangiectasia	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Urticaria	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Rash maculo-papular	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Dermatitis acneiform	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Madarosis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Dermal cyst	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		2/21 (9.5%)
Hyperhidrosis	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Papule	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Blister	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		2/32 (6.3%)		0/21 (0%)
Skin burning sensation	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		2/21 (9.5%)
Musculoskeletal chest pain	0/4 (0%)		1/4 (25%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		3/32 (9.4%)		0/21 (0%)
Vascular disorders
Flushing	0/4 (0%)		1/4 (25%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		4/32 (12.5%)		0/21 (0%)
Lymphoedema	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hot Flush	0/4 (0%)		0/4 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Vasculitis	0/4 (0%)		0/4 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/10 (0%)		0/4 (0%)		0/32 (0%)		0/21 (0%)
Hypotension	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/10 (10%)		0/4 (0%)		2/32 (6.3%)		2/21 (9.5%)
Hypertension	0/4 (0%)		0/4 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/10 (10%)		1/4 (25%)		2/32 (6.3%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.