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A Study of Durvalumab or Tremelimumab Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Advanced Hepatocellular Carcinoma

Sponsor
MedImmune LLC (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02519348
Collaborator
(none)
433
Enrollment
44
Locations
9
Arms
86.4
Anticipated Duration (Months)
9.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, open-label, stratified, randomized study to evaluate the safety, tolerability, antitumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of durvalumab or tremelimumab monotherapy, or durvalumab in combination with tremelimumab or bevacizumab in advanced hepatocellular carcinoma.

Condition or Disease Intervention/Treatment Phase
  • Biological: Tremelimumab
  • Biological: Durvalumab
  • Biological: Bevacizumab
 Phase 2

Detailed Description

The study will comprise of 6 parts. Participants in Part 1A (safety run-in cohort), Part 1B (efficacy-gating cohort), Part 2A, and Part 4 will receive weight-based dosing regimens; and participants in Part 2B and Part 3 will receive fixed dosing regimens. Part 1A Stage 2 of the study may start after the first 3 participants in Stage 1 have been observed on study for at least 4 weeks. In addition, a separate cohort of participants will be enrolled in mainland China (China cohort) once global recruitment in Part 2A will be closed.

  • In Part 1 (both 1A and 1B), participants will receive tremelimumab 1 mg/kg intravenous (IV) every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W.

  • In Part 2A, participants will be randomized in a 1:1:1 ratio to receive:

  • Durvalumab 20 mg/kg Q4W

  • Tremelimumab 10 mg/kg Q4W × 7 doses followed by every 12 weeks (Q12W)

  • Tremelimumab 1 mg/kg Q4W × 4 doses + durvalumab 20 mg/kg Q4W, followed by durvalumab 20 mg/kg Q4W

  • In China cohort, Part 2A study design will be followed.

  • In Part 2B, participants will receive tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W.

  • In Part 3, participants will be randomized in a 2:2:1:2 ratio to receive:

  • Durvalumab 1500 mg Q4W

  • Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W

  • Tremelimumab 750 mg Q4W for 7 doses followed by Q12W

  • Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg Q4W, followed by durvalumab 1500 mg Q4W.

Following protocol amendment 5, enrollment into 'Tremelimumab 75 mg Q4W × 4 doses + durvalumab 1500 mg' arm will close. Participants will be randomized at a ratio of 2:1:2 in 'Durvalumab 1500 mg Q4W', 'Tremelimumab 750 mg Q4W for 7 doses followed by Q12W', and 'Tremelimumab 300 mg × 1 dose + durvalumab 1500 mg Q4W' arms, respectively.

• In Part 4, participants will receive durvalumab 1120 mg (15 mg/kg) + bevacizumab 15 mg/kg every 3 weeks (Q3W).

Participants will receive the treatment until confirm progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

All participants will be followed for survival until the end of study visit (last participant discontinues the study treatment).

Study Design

Study Type:
Interventional
Actual Enrollment :
433 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Study of Safety, Tolerability, and Clinical Activity of Durvalumab and Tremelimumab Administered as Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Subjects With Advanced Hepatocellular Carcinoma
Actual Study Start Date :
Oct 19, 2015
Actual Primary Completion Date :
Nov 6, 2020
Anticipated Study Completion Date :
Dec 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg

Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) will receive tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

Biological: Tremelimumab
Tremelimumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.

Biological: Durvalumab
Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
Other Names:
  • MEDI4736

    		•
    Experimental: Parts 2 and 3: Durvalumab 1500 mg

    Participants will receive durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

    Biological: Durvalumab
    Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Other Names:
  • MEDI4736

    		•
    Experimental: Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg

    Participants will receive tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurs first.

    Biological: Tremelimumab
    Tremelimumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.

    Biological: Durvalumab
    Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Other Names:
  • MEDI4736

    		•
    Experimental: Parts 2 and 3: Tremelimumab 750 mg

    Participants will receive tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

    Biological: Tremelimumab
    Tremelimumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Experimental: Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg

    Participants will receive tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. Participant recruitment to this arm was closed following protocol amendment 5.

    Biological: Tremelimumab
    Tremelimumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.

    Biological: Durvalumab
    Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Other Names:
  • MEDI4736

    		•
    Experimental: Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg

    Participants will receive durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first

    Biological: Durvalumab
    Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Other Names:
  • MEDI4736

    • Biological: Bevacizumab
    Bevacizumab 15 mg/kg will be administered by IV infusion every 3 weeks until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Experimental: China Cohort: Durvalumab 20 mg/kg

    Participants will receive durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

    Biological: Durvalumab
    Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Other Names:
  • MEDI4736

    		•
    Experimental: China Cohort: Tremelimumab 10 mg/kg

    Participants will receive tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

    Biological: Tremelimumab
    Tremelimumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Experimental: China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg

    Participants will receive tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first.

    Biological: Tremelimumab
    Tremelimumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.

    Biological: Durvalumab
    Durvalumab will be administered by IV infusion according to doses and frequency mentioned in arms' description.
    Other Names:
  • MEDI4736

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose Limiting Toxicities (DLTs) [From Day 1 to Day 28 after first dose of study drug]

      A DLT was defined as treatment-related toxicity that occurred during DLT evaluation period including: any Grade 4 immune-related adverse event (irAE), any Grade 3 colitis or any Grade 3 noninfectious pneumonitis irrespective of duration, any >= Grade 2 pneumonitis that does not resolve to <= Grade 1 within 7 days of initiation of maximal supportive care, any other Grade 3 irAE (excluding colitis or pneumonitis) that does not downgrade to Grade 2 within 7 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to <= Grade 1 or baseline within 14 days, liver transaminase elevation > 8 × upper limit of normal (ULN) or total bilirubin > 5 × ULN, aspartate aminotransferase or alanine aminotransferase > 3 × ULN with concurrent increase in total bilirubin > 2 × ULN without evidence of cholestasis or alternative explanations, and any >= Grade 3 non-irAE (except for the protocol stated conditions).

    2. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. There will be no updated results for this outcome measure at the time of end of study.

    3. Number of Participants With Clinically Important Changes in Hematology and Clinical Chemistry Parameters [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Participants with clinically important Common Terminology Criteria for Adverse Events (CTCAE) grade changes to 3 or 4 in hematology and chemistry parameters are reported. There will be no updated results for this outcome measure at the time of end of study.

    4. Number of Participants With Abnormal Vital Signs Reported as TEAEs [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Vital sign assessment included pulse rate, blood pressure, temperature, weight, and respiratory rate. Vital signs abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.

    5. Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Number of participants with ECG abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.

    Secondary Outcome Measures

    1. Overall Objective Response Rate (ORR) Based on Investigator Assessments and Blinded Independent Central Review (BICR) [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Disease assessments based on investigator assessments and BICR review were determined by using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) guidelines. The ORR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR). The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. There will be no updated results for this outcome measure at the time of end of study.

    2. Disease Control Rate (DCR) Based on Investigator Assessments and BICR [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The DCR is defined as a BOR of confirmed CR, confirmed PR, or stable disease (SD). A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as two PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) that were separated by at least 4 weeks with no evidence of progression in-between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. There will be no updated results for this outcome measure at the time of end of study.

    3. Time to Response (TTR) Based on Investigator Assessments and BICR [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The TTR is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until the first documentation of a subsequently confirmed OR (confirmed CR or confirmed PR). A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as two PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) that were separated by at least 4 weeks with no evidence of progression in-between. The TTR was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.

    4. Duration of Response (DoR) Based on Investigator Assessments and BICR [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      The DoR is defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments and BICR review by using RECIST v1.1 or death in absence of disease progression. A confirmed CR is defined in above outcome measures. The PD is defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. The DoR was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.

    5. Time to Progression (TTP) Based on Investigator Assessments and BICR [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The TTP was defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 to the first documentation of radiographic disease progression. However, if the participant died without tumor progression, they were censored at the time of death. Participants with no documented PD by the data cutoff date for TTP analysis were censored at the date of their last evaluable disease assessment. The TTP was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.

    6. Progression Free Survival (PFS) Based on Investigator Assessments and BICR [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The PFS is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until the first documentation of radiographic disease progression or death due to any cause, whichever occurs first. The PD is defined at least 20% increase in the sum of diameters of target lesions (compared with the nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. Participants who were alive with no documented PD by the data cutoff date for PFS analysis were censored at the date of their last evaluable disease assessment. The PFS was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.

    7. Overall Survival (OS) [From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)]

      The OS is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until death due to any cause. If there was no death reported for a participant by the data cut-off date for overall survival analysis, OS was censored at the last known alive date. The OS was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 99 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Male or female participants

    2. 18 years and older (Japan-20 years and older)

    3. Confirmed hepatocellular carcinoma (HCC) based on histopathological findings from tumor tissues. Advanced HCC with diagnosis confirmed pathologically or with noninvasive methods.

    4. Immunotherapy-naïve

    5. Have either progressed on, are intolerant to, or refused treatment with sorafenib or another approved TKI. For arm 5 only: Have not received any prior systemic therapy for HCC.

    Exclusion Criteria:

    1. Prior exposure to immune-mediated therapy

    2. Hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy

    3. Gastrointestinal bleeding (eg, esophageal varices or ulcer bleeding) within 12 months

    4. Ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose.

    5. Main portal vein thrombosis (Vp4) as documented on imaging

    6. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment

    7. Active or prior documented autoimmune or inflammatory disease with some exceptions

    8. Current or prior use of immunosuppressive medication within 14 days with some exceptions

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Phoenix Arizona United States 85054
    2 Research Site San Francisco California United States 94158
    3 Research Site New Haven Connecticut United States 06510
    4 Research Site Jacksonville Florida United States 32224
    5 Research Site Tampa Florida United States 33612
    6 Research Site Indianapolis Indiana United States 46202
    7 Research Site Boston Massachusetts United States 02114
    8 Research Site New York New York United States 10065
    9 Research Site Stony Brook New York United States 11794
    10 Research Site Durham North Carolina United States 27705
    11 Research Site Portland Oregon United States 97213
    12 Research Site Philadelphia Pennsylvania United States 19107
    13 Research Site Philadelphia Pennsylvania United States 19111
    14 Research Site Nashville Tennessee United States 37203
    15 Research Site Dallas Texas United States 75390
    16 Research Site Seattle Washington United States 98109
    17 Research Site Hangzhou China 310016
    18 Research Site Nanjing China 210002
    19 Research Site Shanghai China 200032
    20 Research Site Hong Kong Hong Kong
    21 Research Site Sha Tin Hong Kong
    22 Research Site Benevento Italy 82100
    23 Research Site Milano Italy 20133
    24 Research Site Roma Italy 00168
    25 Research Site Chuo-ku Japan 104-0045
    26 Research Site Kashiwa Japan 277-8577
    27 Research Site Osakasayama-shi Japan 589-8511
    28 Research Site Busan Korea, Republic of 49241
    29 Research Site Jung-gu Korea, Republic of 41944
    30 Research Site Seongnam-si Korea, Republic of 13620
    31 Research Site Seoul Korea, Republic of 03080
    32 Research Site Seoul Korea, Republic of 05505
    33 Research Site Seoul Korea, Republic of 06273
    34 Research Site Seoul Korea, Republic of 06351
    35 Research Site Bukit Merah Singapore 169610
    36 Research Site Singapore Singapore 119074
    37 Research Site Singapore Singapore 308433
    38 Research Site Barcelona Spain 08035
    39 Research Site Barcelona Spain 08036
    40 Research Site Cordoba Spain 14004
    41 Research Site Pamplona Spain 31008
    42 Research Site Kaohsiung City Taiwan 83301
    43 Research Site Taipei Taiwan 100
    44 Research Site Taoyuan City Taiwan 333

    Sponsors and Collaborators

    • MedImmune LLC

    Investigators

    • Study Director: MedImmune, LLC MedImmune, LLC, MedImmune LLC

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    MedImmune LLC
    ClinicalTrials.gov Identifier:
    NCT02519348
    Other Study ID Numbers:
    • D4190C00022
    First Posted:
    Aug 10, 2015
    Last Update Posted:
    Jun 24, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by MedImmune LLC
    Hepatocellular Carcinoma
    Immunotherapy
    Antibodies, Monoclonal
    Tremelimumab
    MEDI4736
    Durvalumab
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Hepatocellular
    Bevacizumab
    Durvalumab
    Tremelimumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail The results data are reported per the primary completion date (data cut-off date of 06Nov2020).
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Period Title: Overall Study
    STARTED 40 104 75 69 84 47 3 5 6
    Treated 40 101 74 69 82 47 3 5 5
    COMPLETED 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 40 104 75 69 84 47 3 5 6

    Baseline Characteristics

    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Total
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Total of all reporting groups
    Overall Participants 40 104 75 69 84 47 3 5 6 433
    Age, Customized (Count of Participants)
    < 65 years
    27
    67.5%
    52
    50%
    34
    45.3%
    41
    59.4%
    48
    57.1%
    26
    55.3%
    3
    100%
    5
    100%
    5
    83.3%
    241
    55.7%
    >=65 to < 75 years
    8
    20%
    33
    31.7%
    31
    41.3%
    18
    26.1%
    26
    31%
    13
    27.7%
    0
    0%
    0
    0%
    1
    16.7%
    130
    30%
    > 75 years
    5
    12.5%
    19
    18.3%
    10
    13.3%
    10
    14.5%
    10
    11.9%
    8
    17%
    0
    0%
    0
    0%
    0
    0%
    62
    14.3%
    Sex: Female, Male (Count of Participants)
    Female
    10
    25%
    12
    11.5%
    10
    13.3%
    12
    17.4%
    14
    16.7%
    6
    12.8%
    1
    33.3%
    0
    0%
    0
    0%
    65
    15%
    Male
    30
    75%
    92
    88.5%
    65
    86.7%
    57
    82.6%
    70
    83.3%
    41
    87.2%
    2
    66.7%
    5
    100%
    6
    100%
    368
    85%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    5%
    5
    4.8%
    4
    5.3%
    4
    5.8%
    5
    6%
    0
    0%
    0
    0%
    1
    20%
    0
    0%
    21
    4.8%
    Not Hispanic or Latino
    38
    95%
    99
    95.2%
    71
    94.7%
    65
    94.2%
    79
    94%
    47
    100%
    3
    100%
    4
    80%
    6
    100%
    412
    95.2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    2.5%
    1
    1%
    0
    0%
    0
    0%
    1
    1.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    0.7%
    Asian
    19
    47.5%
    55
    52.9%
    44
    58.7%
    39
    56.5%
    47
    56%
    39
    83%
    3
    100%
    5
    100%
    6
    100%
    257
    59.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    2
    1.9%
    0
    0%
    1
    1.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    0.7%
    Black or African American
    3
    7.5%
    10
    9.6%
    4
    5.3%
    2
    2.9%
    5
    6%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    25
    5.8%
    White
    15
    37.5%
    35
    33.7%
    27
    36%
    26
    37.7%
    30
    35.7%
    7
    14.9%
    0
    0%
    0
    0%
    0
    0%
    140
    32.3%
    More than one race
    1
    2.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.2%
    Unknown or Not Reported
    1
    2.5%
    1
    1%
    0
    0%
    1
    1.4%
    1
    1.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    0.9%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose Limiting Toxicities (DLTs)
    Description A DLT was defined as treatment-related toxicity that occurred during DLT evaluation period including: any Grade 4 immune-related adverse event (irAE), any Grade 3 colitis or any Grade 3 noninfectious pneumonitis irrespective of duration, any >= Grade 2 pneumonitis that does not resolve to <= Grade 1 within 7 days of initiation of maximal supportive care, any other Grade 3 irAE (excluding colitis or pneumonitis) that does not downgrade to Grade 2 within 7 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to <= Grade 1 or baseline within 14 days, liver transaminase elevation > 8 × upper limit of normal (ULN) or total bilirubin > 5 × ULN, aspartate aminotransferase or alanine aminotransferase > 3 × ULN with concurrent increase in total bilirubin > 2 × ULN without evidence of cholestasis or alternative explanations, and any >= Grade 3 non-irAE (except for the protocol stated conditions).
    Time Frame From Day 1 to Day 28 after first dose of study drug

    Outcome Measure Data

    Analysis Population Description
    DLT evaluable set included all Part 1A participants who received at least 1 dose of study drug and completed the safety follow-up through the DLT evaluation period (Days 1 to 28 after first dose of study drug) or experienced any DLT.
    Arm/Group Title Part 1A: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 16
    Count of Participants [Participants]
    0
    0%
    2. Primary Outcome
    Title Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
    Description An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who received at least one dose of study drug.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 101 74 69 82 47 3 5 5
    Any TEAEs
    38
    95%
    95
    91.3%
    73
    97.3%
    67
    97.1%
    80
    95.2%
    45
    95.7%
    3
    100%
    5
    100%
    5
    83.3%
    Any TESAEs
    22
    55%
    45
    43.3%
    32
    42.7%
    36
    52.2%
    37
    44%
    17
    36.2%
    1
    33.3%
    3
    60%
    4
    66.7%
    3. Primary Outcome
    Title Number of Participants With Clinically Important Changes in Hematology and Clinical Chemistry Parameters
    Description Participants with clinically important Common Terminology Criteria for Adverse Events (CTCAE) grade changes to 3 or 4 in hematology and chemistry parameters are reported. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who received at least one dose of study drug. 'Number of participants analyzed' denotes only those participants for whom hematological and clinical chemistry parameter were analyzed. 'Number Analyzed' denotes the participants analyzed for the specified laboratory parameter.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 39 100 74 68 81 46 3 5 4
    Hemoglobin
    0
    0%
    5
    4.8%
    6
    8%
    6
    8.7%
    6
    7.1%
    0
    0%
    0
    0%
    1
    20%
    1
    16.7%
    Leukocytes
    1
    2.5%
    1
    1%
    1
    1.3%
    1
    1.4%
    2
    2.4%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Lymphocytes
    3
    7.5%
    7
    6.7%
    10
    13.3%
    4
    5.8%
    8
    9.5%
    2
    4.3%
    0
    0%
    1
    20%
    0
    0%
    Neutrophils
    0
    0%
    1
    1%
    1
    1.3%
    0
    0%
    0
    0%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Platelets
    3
    7.5%
    5
    4.8%
    0
    0%
    2
    2.9%
    4
    4.8%
    3
    6.4%
    1
    33.3%
    0
    0%
    0
    0%
    Activated Partial Thromboplastin Time
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.2%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Fibrinogen
    5
    12.5%
    5
    4.8%
    5
    6.7%
    2
    2.9%
    5
    6%
    3
    6.4%
    0
    0%
    0
    0%
    0
    0%
    Prothrombin Intl. Normalized Ratio
    0
    0%
    1
    1%
    3
    4%
    1
    1.4%
    0
    0%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Alanine Aminotransferase
    3
    7.5%
    7
    6.7%
    13
    17.3%
    5
    7.2%
    10
    11.9%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Albumin
    1
    2.5%
    5
    4.8%
    0
    0%
    3
    4.3%
    3
    3.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alkaline Phosphatase
    3
    7.5%
    13
    12.5%
    4
    5.3%
    6
    8.7%
    8
    9.5%
    3
    6.4%
    1
    33.3%
    0
    0%
    1
    16.7%
    Aspartate Aminotransferase
    5
    12.5%
    25
    24%
    19
    25.3%
    16
    23.2%
    17
    20.2%
    4
    8.5%
    0
    0%
    1
    20%
    1
    16.7%
    Bilirubin
    2
    5%
    12
    11.5%
    4
    5.3%
    6
    8.7%
    9
    10.7%
    2
    4.3%
    0
    0%
    0
    0%
    0
    0%
    Calcium - Hyper
    0
    0%
    4
    3.8%
    0
    0%
    1
    1.4%
    3
    3.6%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Calcium - Hypo
    1
    2.5%
    2
    1.9%
    1
    1.3%
    1
    1.4%
    1
    1.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Creatinine
    2
    5%
    2
    1.9%
    3
    4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Glucose - Hyper
    4
    10%
    8
    7.7%
    14
    18.7%
    6
    8.7%
    5
    6%
    2
    4.3%
    0
    0%
    0
    0%
    0
    0%
    Glucose - Hypo
    2
    5%
    1
    1%
    0
    0%
    1
    1.4%
    0
    0%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Magnesium - Hyper
    2
    5%
    7
    6.7%
    3
    4%
    2
    2.9%
    2
    2.4%
    2
    4.3%
    0
    0%
    0
    0%
    0
    0%
    Magnesium - Hypo
    0
    0%
    2
    1.9%
    0
    0%
    1
    1.4%
    0
    0%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Potassium - Hyper
    4
    10%
    4
    3.8%
    2
    2.7%
    0
    0%
    3
    3.6%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    Potassium - Hypo
    0
    0%
    2
    1.9%
    2
    2.7%
    2
    2.9%
    1
    1.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Sodium - Hyper
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Sodium - Hypo
    9
    22.5%
    12
    11.5%
    7
    9.3%
    13
    18.8%
    11
    13.1%
    6
    12.8%
    0
    0%
    0
    0%
    1
    16.7%
    4. Primary Outcome
    Title Number of Participants With Abnormal Vital Signs Reported as TEAEs
    Description Vital sign assessment included pulse rate, blood pressure, temperature, weight, and respiratory rate. Vital signs abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who received at least one dose of study drug.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 101 74 69 82 47 3 5 5
    Hypertension
    1
    2.5%
    4
    3.8%
    4
    5.3%
    2
    2.9%
    3
    3.6%
    6
    12.8%
    0
    0%
    0
    0%
    0
    0%
    Hypotension
    0
    0%
    4
    3.8%
    0
    0%
    3
    4.3%
    2
    2.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Systolic hypertension
    0
    0%
    1
    1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Weight decreased
    4
    10%
    4
    3.8%
    4
    5.3%
    4
    5.8%
    4
    4.8%
    2
    4.3%
    0
    0%
    0
    0%
    1
    16.7%
    Weight increased
    2
    5%
    0
    0%
    1
    1.3%
    1
    1.4%
    2
    2.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Palpitations
    1
    2.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    Pyrexia
    6
    15%
    6
    5.8%
    14
    18.7%
    9
    13%
    14
    16.7%
    4
    8.5%
    2
    66.7%
    2
    40%
    1
    16.7%
    5. Primary Outcome
    Title Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment-Emergent Adverse Events
    Description Number of participants with ECG abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who received at least one dose of study drug.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 101 74 69 82 47 3 5 5
    Acute myocardial infarction
    0
    0%
    0
    0%
    1
    1.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Angina pectoris
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    1
    1.2%
    2
    4.3%
    0
    0%
    0
    0%
    0
    0%
    Angina unstable
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Atrial fibrillation
    1
    2.5%
    1
    1%
    1
    1.3%
    0
    0%
    3
    3.6%
    1
    2.1%
    1
    33.3%
    0
    0%
    0
    0%
    Cardiac failure chronic
    0
    0%
    0
    0%
    1
    1.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Cardiac failure congestive
    0
    0%
    1
    1%
    1
    1.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Coronary artery disease
    0
    0%
    1
    1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Sinus bradycardia
    0
    0%
    1
    1%
    0
    0%
    0
    0%
    1
    1.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Tachycardia
    0
    0%
    0
    0%
    1
    1.3%
    0
    0%
    1
    1.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Atrioventricular block first degree
    1
    2.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Cardiac arrest
    1
    2.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Myocardial infarction
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%
    0
    0%
    0
    0%
    0
    0%
    6. Secondary Outcome
    Title Overall Objective Response Rate (ORR) Based on Investigator Assessments and Blinded Independent Central Review (BICR)
    Description Disease assessments based on investigator assessments and BICR review were determined by using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) guidelines. The ORR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR). The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. Analysis of disease assessments based on BICR for Part 1 and China cohorts were not planned and hence not performed.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 104 75 69 84 47 3 5 6
    ORR based on BICR
    11.5
    28.8%
    24.0
    23.1%
    7.2
    9.6%
    9.5
    13.8%
    21.3
    25.4%
    ORR based on Investigator assessments
    20.0
    50%
    11.5
    11.1%
    21.3
    28.4%
    8.7
    12.6%
    8.3
    9.9%
    34.0
    72.3%
    33.3
    1110%
    NA
    NaN
    NA
    NaN
    7. Secondary Outcome
    Title Disease Control Rate (DCR) Based on Investigator Assessments and BICR
    Description Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The DCR is defined as a BOR of confirmed CR, confirmed PR, or stable disease (SD). A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as two PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) that were separated by at least 4 weeks with no evidence of progression in-between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. Analysis of disease assessments based on BICR for Part 1 and China cohorts were not planned and hence not performed.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 104 75 69 84 47 3 5 6
    DCR based on BICR
    37.5
    93.8%
    45.3
    43.6%
    49.3
    65.7%
    36.9
    53.5%
    55.3
    65.8%
    DCR based on Investigator assessments
    60.0
    150%
    45.2
    43.5%
    50.7
    67.6%
    47.8
    69.3%
    34.5
    41.1%
    63.8
    135.7%
    33.3
    1110%
    20.0
    400%
    16.7
    278.3%
    8. Secondary Outcome
    Title Time to Response (TTR) Based on Investigator Assessments and BICR
    Description Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The TTR is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until the first documentation of a subsequently confirmed OR (confirmed CR or confirmed PR). A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 4 weeks with no evidence of progression in-between. A confirmed PR is defined as two PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) that were separated by at least 4 weeks with no evidence of progression in-between. The TTR was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. Analysis of disease assessments based on BICR for Part 1 and China cohorts were not planned and hence not performed. The TTR was analyzed for participants who achieved OR per BICR and/or investigator assessments. 'Number Analyzed' denotes participants who achieved OR.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 8 12 18 6 8 16 1 0 0
    TTR based on BICR
    3.65
    2.28
    1.81
    2.86
    2.10
    TTR based on Investigator assessments
    2.68
    3.68
    1.86
    2.74
    3.88
    2.10
    5.55
    9. Secondary Outcome
    Title Duration of Response (DoR) Based on Investigator Assessments and BICR
    Description The DoR is defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments and BICR review by using RECIST v1.1 or death in absence of disease progression. A confirmed CR is defined in above outcome measures. The PD is defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. The DoR was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. Analysis of disease assessments based on BICR for Part 1 and China cohorts were not planned and hence not performed. The DoR was analyzed for participants who achieved OR per BICR and/or investigator assessments. 'Number Analyzed' denotes participants who achieved OR.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 8 12 18 6 8 16 1 0 0
    DoR based on BICR
    14.95
    18.43
    23.95
    13.21
    NA
    DoR based on Investigator assessments
    16.66
    NA
    23.95
    27.53
    13.21
    10.51
    7.39
    10. Secondary Outcome
    Title Time to Progression (TTP) Based on Investigator Assessments and BICR
    Description Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The TTP was defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 to the first documentation of radiographic disease progression. However, if the participant died without tumor progression, they were censored at the time of death. Participants with no documented PD by the data cutoff date for TTP analysis were censored at the date of their last evaluable disease assessment. The TTP was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. Analysis of disease assessments based on BICR for Part 1 and China cohorts were not planned and hence not performed.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 104 75 69 84 47 3 5 6
    TTP based on BICR
    2.10
    3.71
    2.76
    1.87
    4.30
    TTP based on Investigator assessments
    3.68
    3.38
    3.68
    2.60
    1.87
    7.46
    1.81
    3.75
    2.68
    11. Secondary Outcome
    Title Progression Free Survival (PFS) Based on Investigator Assessments and BICR
    Description Disease assessments based on investigator assessments and BICR review were determined by using RECIST v1.1 guidelines. The PFS is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until the first documentation of radiographic disease progression or death due to any cause, whichever occurs first. The PD is defined at least 20% increase in the sum of diameters of target lesions (compared with the nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. Participants who were alive with no documented PD by the data cutoff date for PFS analysis were censored at the date of their last evaluable disease assessment. The PFS was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. Analysis of disease assessments based on BICR for Part 1 and China cohorts were not planned and hence not performed.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 104 75 69 84 47 3 5 6
    PFS based on BICR
    2.07
    2.17
    2.69
    1.87
    4.17
    PFS based on Investigator assessments
    3.52
    2.40
    3.52
    2.60
    1.81
    6.24
    1.81
    2.20
    1.87
    12. Secondary Outcome
    Title Overall Survival (OS)
    Description The OS is defined as the time from randomization for Parts 2A and 3, and time from first dose for Parts 1, 2B, and 4 until death due to any cause. If there was no death reported for a participant by the data cut-off date for overall survival analysis, OS was censored at the last known alive date. The OS was estimated using Kaplan-Meier method. There will be no updated results for this outcome measure at the time of end of study.
    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    Measure Participants 40 104 75 69 84 47 3 5 6
    Median (95% Confidence Interval) [Months]
    12.58
    12.91
    17.05
    17.05
    11.30
    NA
    30.69
    3.52
    6.28

    Adverse Events

    Time Frame From Day 1 through the 12 months after the first dose of study drug given to the last participant enrolled in the study (approximately 61 months)
    Adverse Event Reporting Description All-Cause Mortality was evaluated per 'Full analysis set' which included all randomized participants (Parts 2A and 3) or participants who were allocated to treatment (Parts 1, 2B, and 4), including participants who were randomized in error. The AE data was evaluated per 'Safety population' which included all participants who received at least one dose of study drug.
    Arm/Group Title Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    Arm/Group Description Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) received tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first. Participants received tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurred first.
    All Cause Mortality
    Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    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 31/40 (77.5%) 78/104 (75%) 49/75 (65.3%) 55/69 (79.7%) 64/84 (76.2%) 18/47 (38.3%) 2/3 (66.7%) 5/5 (100%) 5/6 (83.3%)
    Serious Adverse Events
    Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    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 22/40 (55%) 45/101 (44.6%) 32/74 (43.2%) 36/69 (52.2%) 37/82 (45.1%) 17/47 (36.2%) 1/3 (33.3%) 3/5 (60%) 4/5 (80%)
    Blood and lymphatic system disorders
    Anaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 2 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lymphadenitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Thrombocytopenia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Angina pectoris 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Angina unstable 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Atrial fibrillation 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 2 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cardiac arrest 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cardiac failure chronic 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cardiac failure congestive 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myocardial infarction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myocarditis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tachycardia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ear and labyrinth disorders
    Vertigo 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Endocrine disorders
    Hypophysitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 2/69 (2.9%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Adrenal insufficiency 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypopituitarism 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypothyroidism 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Inappropriate antidiuretic hormone secretion 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrointestinal disorders
    Dental caries 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Abdominal pain 0/40 (0%) 0 2/101 (2%) 2 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Abdominal pain upper 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ascites 2/40 (5%) 5 3/101 (3%) 3 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 9 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 2/5 (40%) 3
    Autoimmune colitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Autoimmune pancreatitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Colitis 2/40 (5%) 2 0/101 (0%) 0 4/74 (5.4%) 5 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Constipation 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Diarrhoea 0/40 (0%) 0 3/101 (3%) 3 2/74 (2.7%) 2 6/69 (8.7%) 6 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Duodenal ulcer haemorrhage 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dysphagia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Enteritis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Enterocolitis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Epigastric discomfort 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastric ulcer 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastric ulcer perforation 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastric varices 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastritis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrointestinal haemorrhage 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 4 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrooesophageal reflux disease 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haematemesis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haemoperitoneum 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haemorrhagic ascites 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ileus 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Immune-mediated enterocolitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Inguinal hernia strangulated 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Large intestinal haemorrhage 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mallory-weiss syndrome 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mesenteric haematoma 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oesophageal varices haemorrhage 1/40 (2.5%) 1 2/101 (2%) 2 0/74 (0%) 0 4/69 (5.8%) 6 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pancreatitis 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pancreatitis acute 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Small intestinal perforation 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Upper gastrointestinal haemorrhage 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Varices oesophageal 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vomiting 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    General disorders
    Asthenia 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Death 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Fatigue 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    General physical health deterioration 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lipogranuloma 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Non-cardiac chest pain 1/40 (2.5%) 2 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oedema 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oedema peripheral 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pyrexia 1/40 (2.5%) 1 2/101 (2%) 2 3/74 (4.1%) 3 0/69 (0%) 0 4/82 (4.9%) 4 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatobiliary disorders
    Autoimmune hepatitis 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Biliary obstruction 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cholangitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic cirrhosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic failure 0/40 (0%) 0 2/101 (2%) 2 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic function abnormal 1/40 (2.5%) 1 9/101 (8.9%) 10 0/74 (0%) 0 1/69 (1.4%) 1 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 2/5 (40%) 2 1/5 (20%) 1
    Hepatic haemorrhage 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatitis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatorenal syndrome 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperbilirubinaemia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Jaundice 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Portal vein thrombosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Infections and infestations
    Abdominal infection 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Anorectal infection 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Bacteraemia 1/40 (2.5%) 2 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Covid-19 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cellulitis 1/40 (2.5%) 1 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Clostridium difficile colitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dengue fever 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Encephalitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Influenza 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Klebsiella infection 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Listeria sepsis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Listeriosis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Liver abscess 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Meningitis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Peritonitis bacterial 0/40 (0%) 0 2/101 (2%) 2 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pneumonia 0/40 (0%) 0 1/101 (1%) 1 3/74 (4.1%) 3 2/69 (2.9%) 3 3/82 (3.7%) 3 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pneumonia mycoplasmal 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Respiratory tract infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rhinovirus infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Sepsis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tuberculosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Upper respiratory tract infection 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Urosepsis 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Injury, poisoning and procedural complications
    Femur fracture 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hip fracture 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Humerus fracture 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Overdose 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Investigations
    Ammonia increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood bilirubin increased 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood creatinine increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lipase increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Platelet count decreased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dehydration 0/40 (0%) 0 1/101 (1%) 1 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Diabetic ketoacidosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Diabetic metabolic decompensation 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Failure to thrive 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gout 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypercalcaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperglycaemia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoglycaemia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypokalaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyponatraemia 1/40 (2.5%) 1 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypophosphataemia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Back pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Bone lesion 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Muscular weakness 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Myalgia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myositis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pain in extremity 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pathological fracture 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Spinal stenosis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Intracranial tumour haemorrhage 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Liver carcinoma ruptured 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ovarian adenoma 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Prostate cancer 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour associated fever 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour haemorrhage 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour pain 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour rupture 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nervous system disorders
    Cauda equina syndrome 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cerebrovascular accident 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Depressed level of consciousness 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haemorrhage intracranial 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Haemorrhagic stroke 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic encephalopathy 2/40 (5%) 2 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperammonaemic encephalopathy 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 3 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myasthenia gravis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Seizure 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Spinal cord compression 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Subarachnoid haemorrhage 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Psychiatric disorders
    Anxiety disorder 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Confusional state 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mental status changes 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Suicide attempt 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/40 (2.5%) 1 2/101 (2%) 2 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Renal failure 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Bronchial obstruction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dyspnoea 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 2/69 (2.9%) 2 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Emphysema 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Epistaxis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haemoptysis 1/40 (2.5%) 1 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoxia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Immune-mediated pneumonitis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pleural effusion 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pneumonitis 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Pulmonary embolism 1/40 (2.5%) 1 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pulmonary haemorrhage 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pulmonary oedema 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Respiratory failure 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vascular disorders
    Hypotension 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lymphoedema 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Shock haemorrhagic 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Other (Not Including Serious) Adverse Events
    Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg Parts 2 and 3: Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg Parts 2 and 3: Tremelimumab 750 mg Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg China Cohort: Durvalumab 20 mg/kg China Cohort: Tremelimumab 10 mg/kg China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg
    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 37/40 (92.5%) 92/101 (91.1%) 73/74 (98.6%) 66/69 (95.7%) 80/82 (97.6%) 45/47 (95.7%) 3/3 (100%) 5/5 (100%) 5/5 (100%)
    Blood and lymphatic system disorders
    Anaemia 2/40 (5%) 2 6/101 (5.9%) 6 7/74 (9.5%) 12 10/69 (14.5%) 13 9/82 (11%) 16 2/47 (4.3%) 2 1/3 (33.3%) 1 1/5 (20%) 1 2/5 (40%) 2
    Coagulopathy 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Iron deficiency anaemia 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Leukocytosis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Leukopenia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lymphopenia 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Microcytic anaemia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Neutropenia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 2 1/5 (20%) 1 0/5 (0%) 0
    Thrombocytopenia 2/40 (5%) 5 2/101 (2%) 2 0/74 (0%) 0 4/69 (5.8%) 6 2/82 (2.4%) 2 3/47 (6.4%) 6 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cardiac disorders
    Angina pectoris 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Atrial fibrillation 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Atrioventricular block first degree 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cardiac failure congestive 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Coronary artery disease 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Palpitations 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Sinus bradycardia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tachycardia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ear and labyrinth disorders
    Cerumen impaction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tinnitus 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vertigo 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ear pain 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoacusis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Endocrine disorders
    Adrenal insufficiency 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Adrenocorticotropic hormone deficiency 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperthyroidism 1/40 (2.5%) 1 2/101 (2%) 2 6/74 (8.1%) 6 1/69 (1.4%) 1 4/82 (4.9%) 7 3/47 (6.4%) 3 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Hypopituitarism 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 2/69 (2.9%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypothyroidism 2/40 (5%) 2 12/101 (11.9%) 13 8/74 (10.8%) 8 4/69 (5.8%) 4 8/82 (9.8%) 11 4/47 (8.5%) 4 2/3 (66.7%) 2 0/5 (0%) 0 1/5 (20%) 1
    Immune-mediated endocrinopathy 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Thyroiditis 2/40 (5%) 2 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Eye disorders
    Cataract 0/40 (0%) 0 2/101 (2%) 2 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Conjunctivitis allergic 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dry eye 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 3/69 (4.3%) 3 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Eyelid ptosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Eyelids pruritus 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Glaucoma 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Meibomian gland dysfunction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Photopsia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Retinal tear 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vision blurred 2/40 (5%) 2 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Visual impairment 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vitreous floaters 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Abdominal distension 3/40 (7.5%) 3 10/101 (9.9%) 10 8/74 (10.8%) 8 6/69 (8.7%) 6 5/82 (6.1%) 7 3/47 (6.4%) 3 1/3 (33.3%) 1 2/5 (40%) 2 1/5 (20%) 1
    Abdominal hernia 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Abdominal mass 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Abdominal pain 7/40 (17.5%) 8 15/101 (14.9%) 17 10/74 (13.5%) 12 15/69 (21.7%) 19 11/82 (13.4%) 13 7/47 (14.9%) 8 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 2
    Abdominal pain upper 2/40 (5%) 3 5/101 (5%) 5 3/74 (4.1%) 3 6/69 (8.7%) 6 3/82 (3.7%) 3 2/47 (4.3%) 2 0/3 (0%) 0 1/5 (20%) 1 2/5 (40%) 2
    Anal incontinence 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Anorectal swelling 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Aphthous ulcer 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ascites 6/40 (15%) 6 8/101 (7.9%) 8 10/74 (13.5%) 11 6/69 (8.7%) 7 6/82 (7.3%) 6 5/47 (10.6%) 5 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Colitis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Constipation 6/40 (15%) 7 12/101 (11.9%) 14 8/74 (10.8%) 10 7/69 (10.1%) 8 10/82 (12.2%) 12 5/47 (10.6%) 7 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 1
    Diarrhoea 14/40 (35%) 17 17/101 (16.8%) 20 14/74 (18.9%) 20 19/69 (27.5%) 29 14/82 (17.1%) 23 9/47 (19.1%) 10 1/3 (33.3%) 2 0/5 (0%) 0 0/5 (0%) 0
    Dry mouth 0/40 (0%) 0 2/101 (2%) 3 3/74 (4.1%) 3 2/69 (2.9%) 2 5/82 (6.1%) 5 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Abdominal pain lower 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Anorectal discomfort 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Duodenal ulcer 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Duodenal varices 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dysbiosis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dyschezia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Dyspepsia 2/40 (5%) 2 2/101 (2%) 2 6/74 (8.1%) 6 1/69 (1.4%) 1 1/82 (1.2%) 1 5/47 (10.6%) 6 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dysphagia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Epigastric discomfort 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Flatulence 0/40 (0%) 0 3/101 (3%) 3 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Food poisoning 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Frequent bowel movements 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastric ulcer 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastric varices 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastritis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 2/69 (2.9%) 3 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 1/5 (20%) 1 0/5 (0%) 0
    Gastrointestinal inflammation 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrointestinal pain 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrooesophageal reflux disease 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gingival bleeding 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gingival pain 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Glossitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haematochezia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haemorrhoidal haemorrhage 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Haemorrhoids 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperaesthesia teeth 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ileus 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Intestinal obstruction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Melaena 1/40 (2.5%) 2 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mouth ulceration 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nausea 6/40 (15%) 6 12/101 (11.9%) 14 10/74 (13.5%) 10 14/69 (20.3%) 15 11/82 (13.4%) 11 5/47 (10.6%) 5 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Oesophageal varices haemorrhage 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oral pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Peptic ulcer 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pigmentation lip 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Portal hypertensive gastropathy 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Proctalgia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Stomatitis 1/40 (2.5%) 1 2/101 (2%) 3 2/74 (2.7%) 2 2/69 (2.9%) 2 4/82 (4.9%) 4 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Toothache 1/40 (2.5%) 1 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 2 1/47 (2.1%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Umbilical hernia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Upper gastrointestinal haemorrhage 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Varices oesophageal 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vomiting 6/40 (15%) 6 4/101 (4%) 5 7/74 (9.5%) 7 4/69 (5.8%) 4 8/82 (9.8%) 10 1/47 (2.1%) 1 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 2
    General disorders
    Adverse drug reaction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Asthenia 1/40 (2.5%) 1 3/101 (3%) 3 3/74 (4.1%) 3 3/69 (4.3%) 3 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Catheter site pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Chest discomfort 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Chest pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Chills 1/40 (2.5%) 1 0/101 (0%) 0 2/74 (2.7%) 2 2/69 (2.9%) 3 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Face oedema 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Fatigue 13/40 (32.5%) 14 23/101 (22.8%) 28 17/74 (23%) 20 19/69 (27.5%) 22 15/82 (18.3%) 19 10/47 (21.3%) 13 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gait disturbance 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Generalised oedema 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperthermia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Influenza like illness 0/40 (0%) 0 1/101 (1%) 1 3/74 (4.1%) 3 2/69 (2.9%) 3 0/82 (0%) 0 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Infusion site reaction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Injection site erythema 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Localised oedema 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Malaise 1/40 (2.5%) 1 2/101 (2%) 2 3/74 (4.1%) 3 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mucosal hyperaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mucosal inflammation 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 2/69 (2.9%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Non-cardiac chest pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oedema 2/40 (5%) 2 0/101 (0%) 0 0/74 (0%) 0 2/69 (2.9%) 2 3/82 (3.7%) 3 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oedema peripheral 4/40 (10%) 4 15/101 (14.9%) 15 12/74 (16.2%) 14 5/69 (7.2%) 6 12/82 (14.6%) 13 4/47 (8.5%) 4 1/3 (33.3%) 1 1/5 (20%) 1 1/5 (20%) 1
    Pain 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Peripheral swelling 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Puncture site pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Pyrexia 5/40 (12.5%) 6 4/101 (4%) 6 11/74 (14.9%) 20 9/69 (13%) 12 11/82 (13.4%) 15 3/47 (6.4%) 4 2/3 (66.7%) 2 2/5 (40%) 2 1/5 (20%) 3
    Swelling 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Swelling face 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Thirst 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ulcer 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Xerosis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatobiliary disorders
    Bile duct stenosis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Cholecystitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic cirrhosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic failure 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic function abnormal 0/40 (0%) 0 1/101 (1%) 1 3/74 (4.1%) 5 2/69 (2.9%) 2 2/82 (2.4%) 2 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatitis 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 2 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatomegaly 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatorenal syndrome 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperbilirubinaemia 0/40 (0%) 0 3/101 (3%) 4 1/74 (1.4%) 1 1/69 (1.4%) 1 2/82 (2.4%) 3 1/47 (2.1%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypertransaminasaemia 1/40 (2.5%) 1 0/101 (0%) 0 3/74 (4.1%) 4 2/69 (2.9%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Jaundice 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Portal vein thrombosis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Immune system disorders
    Anaphylactic shock 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Contrast media allergy 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Drug hypersensitivity 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Seasonal allergy 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Infections and infestations
    Bacteraemia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Bronchitis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Candida infection 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cellulitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 3/82 (3.7%) 4 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Clostridium difficile infection 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Conjunctivitis 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cystitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Device related infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ear infection 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Enterococcal bacteraemia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Escherichia infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Escherichia urinary tract infection 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Folliculitis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Fungal infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Fungal skin infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Furuncle 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastroenteritis 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastroenteritis salmonella 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gastrointestinal candidiasis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gingivitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Hepatitis b 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Herpes simplex 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Herpes zoster 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hordeolum 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Influenza 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Liver abscess 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lower respiratory tract infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myringitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Nasopharyngitis 2/40 (5%) 2 1/101 (1%) 1 2/74 (2.7%) 2 2/69 (2.9%) 2 2/82 (2.4%) 2 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Onychomycosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oral candidiasis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Paronychia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Parotitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Peritonitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Peritonitis bacterial 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pneumonia 1/40 (2.5%) 1 3/101 (3%) 3 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pyuria 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash pustular 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Respiratory tract infection 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rhinitis 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Scrotal cellulitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Scrotal infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Sepsis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin bacterial infection 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Subcutaneous abscess 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tinea pedis 0/40 (0%) 0 1/101 (1%) 4 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tonsillitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tooth abscess 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Upper respiratory tract infection 4/40 (10%) 4 4/101 (4%) 5 3/74 (4.1%) 3 8/69 (11.6%) 9 3/82 (3.7%) 4 3/47 (6.4%) 3 1/3 (33.3%) 1 1/5 (20%) 1 0/5 (0%) 0
    Urethritis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Urinary tract infection 2/40 (5%) 2 7/101 (6.9%) 8 2/74 (2.7%) 2 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vaginal infection 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Viral infection 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Injury, poisoning and procedural complications
    Acquired pigmented retinopathy 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Allergic transfusion reaction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Contusion 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Fall 3/40 (7.5%) 3 2/101 (2%) 3 2/74 (2.7%) 2 0/69 (0%) 0 3/82 (3.7%) 3 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Femur fracture 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Head injury 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Infusion related reaction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 1/47 (2.1%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Limb injury 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Meniscus injury 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Post embolisation syndrome 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Procedural pain 1/40 (2.5%) 1 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Radiation skin injury 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rib fracture 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin wound 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Traumatic haematoma 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Upper limb fracture 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Wrist fracture 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Alanine aminotransferase increased 9/40 (22.5%) 11 23/101 (22.8%) 33 17/74 (23%) 28 11/69 (15.9%) 19 15/82 (18.3%) 19 2/47 (4.3%) 2 3/3 (100%) 7 2/5 (40%) 2 2/5 (40%) 3
    Ammonia increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Amylase increased 4/40 (10%) 5 8/101 (7.9%) 9 12/74 (16.2%) 20 8/69 (11.6%) 10 8/82 (9.8%) 12 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Aspartate aminotransferase increased 9/40 (22.5%) 12 26/101 (25.7%) 33 23/74 (31.1%) 38 19/69 (27.5%) 29 21/82 (25.6%) 27 6/47 (12.8%) 7 3/3 (100%) 6 3/5 (60%) 3 2/5 (40%) 3
    Bilirubin conjugated increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 2/5 (40%) 2 1/5 (20%) 1
    Blood albumin decreased 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood alkaline phosphatase increased 3/40 (7.5%) 3 11/101 (10.9%) 18 7/74 (9.5%) 7 7/69 (10.1%) 10 6/82 (7.3%) 8 0/47 (0%) 0 2/3 (66.7%) 2 1/5 (20%) 1 1/5 (20%) 1
    Blood bilirubin increased 2/40 (5%) 2 10/101 (9.9%) 14 7/74 (9.5%) 11 10/69 (14.5%) 16 7/82 (8.5%) 7 2/47 (4.3%) 2 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 2
    Blood cholesterol increased 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood creatine increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood creatine phosphokinase increased 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood creatinine increased 2/40 (5%) 2 2/101 (2%) 3 7/74 (9.5%) 12 1/69 (1.4%) 1 2/82 (2.4%) 3 1/47 (2.1%) 2 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 2
    Blood glucose increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood lactate dehydrogenase increased 0/40 (0%) 0 3/101 (3%) 3 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Blood magnesium decreased 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood potassium decreased 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood pressure increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood pressure systolic increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood sodium decreased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood thyroid stimulating hormone decreased 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood thyroid stimulating hormone increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Blood uric acid increased 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    C-reactive protein increased 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Ejection fraction decreased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gamma-glutamyltransferase increased 2/40 (5%) 2 6/101 (5.9%) 8 5/74 (6.8%) 5 6/69 (8.7%) 11 3/82 (3.7%) 3 1/47 (2.1%) 1 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 1
    Granulocyte count decreased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Heart rate decreased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatitis b dna increased 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 1
    International normalised ratio increased 0/40 (0%) 0 4/101 (4%) 4 1/74 (1.4%) 1 1/69 (1.4%) 2 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lipase increased 7/40 (17.5%) 9 5/101 (5%) 7 12/74 (16.2%) 20 14/69 (20.3%) 30 6/82 (7.3%) 10 3/47 (6.4%) 3 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Liver function test increased 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Low density lipoprotein increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lymphocyte count decreased 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Neutrophil count decreased 1/40 (2.5%) 2 4/101 (4%) 6 2/74 (2.7%) 2 3/69 (4.3%) 4 2/82 (2.4%) 2 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Platelet count decreased 2/40 (5%) 3 6/101 (5.9%) 13 2/74 (2.7%) 5 5/69 (7.2%) 7 2/82 (2.4%) 9 5/47 (10.6%) 9 1/3 (33.3%) 5 0/5 (0%) 0 1/5 (20%) 3
    Protein urine present 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Thyroid function test abnormal 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Thyroxine increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Transaminases increased 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tri-iodothyronine increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Weight decreased 5/40 (12.5%) 5 4/101 (4%) 4 4/74 (5.4%) 4 4/69 (5.8%) 5 4/82 (4.9%) 5 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Weight increased 2/40 (5%) 3 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    White blood cell count decreased 0/40 (0%) 0 1/101 (1%) 1 2/74 (2.7%) 2 0/69 (0%) 0 2/82 (2.4%) 7 0/47 (0%) 0 1/3 (33.3%) 2 0/5 (0%) 0 0/5 (0%) 0
    White blood cell count increased 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 7/40 (17.5%) 7 14/101 (13.9%) 15 10/74 (13.5%) 11 16/69 (23.2%) 16 14/82 (17.1%) 17 12/47 (25.5%) 14 0/3 (0%) 0 2/5 (40%) 2 1/5 (20%) 1
    Dehydration 1/40 (2.5%) 1 2/101 (2%) 3 1/74 (1.4%) 1 1/69 (1.4%) 1 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Diabetes mellitus 0/40 (0%) 0 2/101 (2%) 2 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Electrolyte imbalance 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Glucose tolerance impaired 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gout 0/40 (0%) 0 1/101 (1%) 2 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperalbuminaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypercalcaemia 1/40 (2.5%) 1 4/101 (4%) 4 2/74 (2.7%) 5 2/69 (2.9%) 2 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypercholesterolaemia 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperglycaemia 1/40 (2.5%) 1 8/101 (7.9%) 11 7/74 (9.5%) 8 4/69 (5.8%) 8 5/82 (6.1%) 6 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperkalaemia 2/40 (5%) 2 5/101 (5%) 5 2/74 (2.7%) 6 2/69 (2.9%) 3 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperlipidaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypermagnesaemia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypertriglyceridaemia 0/40 (0%) 0 1/101 (1%) 2 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperuricaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 3/69 (4.3%) 4 2/82 (2.4%) 3 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoalbuminaemia 3/40 (7.5%) 4 7/101 (6.9%) 10 3/74 (4.1%) 3 4/69 (5.8%) 5 4/82 (4.9%) 5 3/47 (6.4%) 3 1/3 (33.3%) 1 1/5 (20%) 1 2/5 (40%) 2
    Hypocalcaemia 1/40 (2.5%) 1 1/101 (1%) 1 1/74 (1.4%) 1 1/69 (1.4%) 2 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypochloraemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Hypoferritinaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoglycaemia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypokalaemia 2/40 (5%) 4 6/101 (5.9%) 7 5/74 (6.8%) 6 3/69 (4.3%) 3 4/82 (4.9%) 7 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Hypomagnesaemia 0/40 (0%) 0 5/101 (5%) 9 4/74 (5.4%) 4 0/69 (0%) 0 4/82 (4.9%) 7 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyponatraemia 2/40 (5%) 2 5/101 (5%) 7 2/74 (2.7%) 2 5/69 (7.2%) 9 5/82 (6.1%) 6 1/47 (2.1%) 3 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 1
    Hypophosphataemia 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoproteinaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Iron deficiency 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Type 2 diabetes mellitus 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 7/40 (17.5%) 7 8/101 (7.9%) 9 8/74 (10.8%) 9 9/69 (13%) 10 7/82 (8.5%) 8 5/47 (10.6%) 9 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Axillary mass 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Back pain 7/40 (17.5%) 8 15/101 (14.9%) 16 2/74 (2.7%) 2 6/69 (8.7%) 7 6/82 (7.3%) 6 6/47 (12.8%) 8 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Bone erosion 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Bone pain 1/40 (2.5%) 1 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Chondrocalcinosis pyrophosphate 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Flank pain 1/40 (2.5%) 1 3/101 (3%) 3 1/74 (1.4%) 1 2/69 (2.9%) 2 2/82 (2.4%) 2 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gouty arthritis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Joint effusion 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Joint stiffness 0/40 (0%) 0 1/101 (1%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Muscle spasms 1/40 (2.5%) 1 2/101 (2%) 2 2/74 (2.7%) 2 5/69 (7.2%) 6 1/82 (1.2%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Muscle twitching 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Muscular weakness 2/40 (5%) 2 4/101 (4%) 4 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Musculoskeletal chest pain 2/40 (5%) 2 2/101 (2%) 2 0/74 (0%) 0 2/69 (2.9%) 2 2/82 (2.4%) 2 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Musculoskeletal pain 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myalgia 3/40 (7.5%) 3 1/101 (1%) 1 4/74 (5.4%) 6 2/69 (2.9%) 2 2/82 (2.4%) 2 1/47 (2.1%) 1 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Myofascial pain syndrome 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myopathy 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Neck pain 1/40 (2.5%) 1 1/101 (1%) 1 2/74 (2.7%) 2 1/69 (1.4%) 1 1/82 (1.2%) 1 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Osteitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Osteonecrosis of jaw 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Osteoporosis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pain in extremity 4/40 (10%) 4 2/101 (2%) 2 4/74 (5.4%) 4 2/69 (2.9%) 3 4/82 (4.9%) 4 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pathological fracture 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Plantar fasciitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Psoriatic arthropathy 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Spinal osteoarthritis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Trigger finger 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 1/69 (1.4%) 1 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Colon adenoma 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Fibrous histiocytoma 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypergammaglobulinaemia benign monoclonal 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Laryngeal papilloma 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pituitary tumour benign 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pyogenic granuloma 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin papilloma 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour associated fever 0/40 (0%) 0 1/101 (1%) 1 2/74 (2.7%) 4 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour invasion 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour pain 0/40 (0%) 0 1/101 (1%) 1 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tumour thrombosis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nervous system disorders
    Amnesia 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Balance disorder 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Carpal tunnel syndrome 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Depressed level of consciousness 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Disturbance in attention 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dizziness 4/40 (10%) 7 6/101 (5.9%) 6 1/74 (1.4%) 1 6/69 (8.7%) 6 3/82 (3.7%) 3 2/47 (4.3%) 3 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dizziness postural 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dysarthria 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dysgeusia 1/40 (2.5%) 1 1/101 (1%) 1 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Encephalopathy 0/40 (0%) 0 5/101 (5%) 5 1/74 (1.4%) 1 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Facial paralysis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Headache 1/40 (2.5%) 1 1/101 (1%) 1 2/74 (2.7%) 2 8/69 (11.6%) 9 2/82 (2.4%) 2 5/47 (10.6%) 6 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hemiparesis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hepatic encephalopathy 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoaesthesia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypokinesia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lacunar infarction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lethargy 1/40 (2.5%) 1 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Memory impairment 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Metabolic encephalopathy 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Monoparesis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Myelopathy 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Neuropathy peripheral 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 2/82 (2.4%) 3 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Paraesthesia 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 2 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Peripheral motor neuropathy 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Peripheral sensory neuropathy 1/40 (2.5%) 1 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Presyncope 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Restless legs syndrome 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Sciatica 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Somnolence 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Syncope 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Taste disorder 1/40 (2.5%) 1 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Tremor 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 2 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Psychiatric disorders
    Affect lability 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Agitation 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Anxiety 2/40 (5%) 2 2/101 (2%) 2 2/74 (2.7%) 2 1/69 (1.4%) 1 3/82 (3.7%) 3 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Confusional state 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Delirium 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Depression 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 2/69 (2.9%) 2 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Insomnia 6/40 (15%) 6 7/101 (6.9%) 7 2/74 (2.7%) 2 8/69 (11.6%) 8 2/82 (2.4%) 2 5/47 (10.6%) 5 0/3 (0%) 0 1/5 (20%) 1 1/5 (20%) 1
    Irritability 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Mood altered 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Restlessness 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 2/40 (5%) 2 3/101 (3%) 3 1/74 (1.4%) 1 2/69 (2.9%) 2 3/82 (3.7%) 3 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Azotaemia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Chronic kidney disease 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dysuria 1/40 (2.5%) 1 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haematuria 1/40 (2.5%) 1 2/101 (2%) 2 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 3/47 (6.4%) 3 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hydronephrosis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypertonic bladder 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Micturition urgency 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nephrolithiasis 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nocturia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 0/5 (0%) 0
    Pollakiuria 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Proteinuria 0/40 (0%) 0 2/101 (2%) 2 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 11/47 (23.4%) 17 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Renal failure 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Renal impairment 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Renal injury 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Urinary incontinence 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Urinary retention 1/40 (2.5%) 1 1/101 (1%) 1 2/74 (2.7%) 4 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Urinary tract obstruction 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Reproductive system and breast disorders
    Balanoposthitis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Benign prostatic hyperplasia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Genital erythema 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Gynaecomastia 1/40 (2.5%) 2 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nipple pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oedema genital 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Penile pain 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Penile rash 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Prostatitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Sexual dysfunction 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Testicular pain 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vaginal haemorrhage 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Asthma 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Bronchospasm 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Choking sensation 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Cough 5/40 (12.5%) 5 12/101 (11.9%) 12 15/74 (20.3%) 17 11/69 (15.9%) 17 15/82 (18.3%) 18 4/47 (8.5%) 4 0/3 (0%) 0 2/5 (40%) 2 0/5 (0%) 0
    Dysphonia 1/40 (2.5%) 1 1/101 (1%) 1 1/74 (1.4%) 1 1/69 (1.4%) 1 2/82 (2.4%) 2 4/47 (8.5%) 4 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dyspnoea 8/40 (20%) 8 10/101 (9.9%) 10 4/74 (5.4%) 5 5/69 (7.2%) 5 6/82 (7.3%) 9 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dyspnoea exertional 3/40 (7.5%) 3 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Eosinophilic pneumonia 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Epistaxis 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 1/69 (1.4%) 1 0/82 (0%) 0 6/47 (12.8%) 6 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haemoptysis 1/40 (2.5%) 1 1/101 (1%) 1 2/74 (2.7%) 2 1/69 (1.4%) 2 3/82 (3.7%) 3 1/47 (2.1%) 1 0/3 (0%) 0 1/5 (20%) 1 0/5 (0%) 0
    Hiccups 1/40 (2.5%) 1 0/101 (0%) 0 1/74 (1.4%) 1 2/69 (2.9%) 2 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypoxia 1/40 (2.5%) 1 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nasal congestion 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Oropharyngeal pain 3/40 (7.5%) 3 2/101 (2%) 2 2/74 (2.7%) 2 6/69 (8.7%) 6 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Paranasal sinus hypersecretion 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pleural effusion 1/40 (2.5%) 1 1/101 (1%) 1 3/74 (4.1%) 3 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pneumonitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Productive cough 3/40 (7.5%) 3 2/101 (2%) 2 3/74 (4.1%) 3 1/69 (1.4%) 1 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pulmonary embolism 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pulmonary thrombosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pulmonary toxicity 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Respiratory symptom 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rhinitis allergic 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 2 2/69 (2.9%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rhinorrhoea 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Sinus congestion 0/40 (0%) 0 1/101 (1%) 1 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Throat irritation 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Upper-airway cough syndrome 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Wheezing 0/40 (0%) 0 1/101 (1%) 1 2/74 (2.7%) 2 0/69 (0%) 0 1/82 (1.2%) 3 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 0/40 (0%) 0 0/101 (0%) 0 2/74 (2.7%) 2 1/69 (1.4%) 1 2/82 (2.4%) 2 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Angioedema 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Decubitus ulcer 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dermatitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 2/47 (4.3%) 2 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dermatitis acneiform 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dermatitis bullous 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dermatitis contact 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Drug eruption 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 1/5 (20%) 1
    Dry skin 0/40 (0%) 0 1/101 (1%) 1 2/74 (2.7%) 2 5/69 (7.2%) 5 2/82 (2.4%) 2 3/47 (6.4%) 3 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Dyshidrotic eczema 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Eczema 0/40 (0%) 0 1/101 (1%) 1 3/74 (4.1%) 3 2/69 (2.9%) 2 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Erythema 2/40 (5%) 2 1/101 (1%) 1 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 1/3 (33.3%) 1 0/5 (0%) 0 1/5 (20%) 1
    Erythema multiforme 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Erythema nodosum 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperhidrosis 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Intertrigo 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lichen planus 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Lipodystrophy acquired 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Macule 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Nail disorder 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Night sweats 2/40 (5%) 3 0/101 (0%) 0 2/74 (2.7%) 2 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Papule 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Petechiae 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Pruritus 11/40 (27.5%) 12 20/101 (19.8%) 26 29/74 (39.2%) 42 28/69 (40.6%) 38 21/82 (25.6%) 25 4/47 (8.5%) 6 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Psoriasis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 2 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Purpura senile 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash 5/40 (12.5%) 5 13/101 (12.9%) 13 27/74 (36.5%) 33 20/69 (29%) 27 14/82 (17.1%) 15 5/47 (10.6%) 5 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash erythematous 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash macular 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 2/69 (2.9%) 2 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash maculo-papular 2/40 (5%) 2 3/101 (3%) 3 2/74 (2.7%) 2 8/69 (11.6%) 10 6/82 (7.3%) 7 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash papular 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 2/69 (2.9%) 2 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Rash pruritic 1/40 (2.5%) 1 1/101 (1%) 1 2/74 (2.7%) 2 0/69 (0%) 0 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin hypopigmentation 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Skin lesion 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Urticaria 1/40 (2.5%) 1 1/101 (1%) 1 3/74 (4.1%) 4 4/69 (5.8%) 4 1/82 (1.2%) 1 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Urticarial vasculitis 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vitiligo 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 1/82 (1.2%) 1 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vascular disorders
    Bloody discharge 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 1/69 (1.4%) 1 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Embolism 0/40 (0%) 0 2/101 (2%) 2 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Flushing 0/40 (0%) 0 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 1/47 (2.1%) 1 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Haematoma 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hyperaemia 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypertension 1/40 (2.5%) 1 4/101 (4%) 6 4/74 (5.4%) 5 2/69 (2.9%) 2 3/82 (3.7%) 9 6/47 (12.8%) 6 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Hypotension 0/40 (0%) 0 4/101 (4%) 4 0/74 (0%) 0 2/69 (2.9%) 2 2/82 (2.4%) 2 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Inferior vena caval occlusion 1/40 (2.5%) 1 0/101 (0%) 0 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Intermittent claudication 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Systolic hypertension 0/40 (0%) 0 1/101 (1%) 1 0/74 (0%) 0 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Vena cava thrombosis 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0
    Venous thrombosis limb 0/40 (0%) 0 0/101 (0%) 0 1/74 (1.4%) 1 0/69 (0%) 0 0/82 (0%) 0 0/47 (0%) 0 0/3 (0%) 0 0/5 (0%) 0 0/5 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.

    Results Point of Contact

    Name/Title Global Clinical Lead
    Organization AstraZeneca Clinical Study Information Center
    Phone 1-877-240-9479
    Email information.center@astrazeneca.com
    Responsible Party:
    MedImmune LLC
    ClinicalTrials.gov Identifier:
    NCT02519348
    Other Study ID Numbers:
    • D4190C00022
    First Posted:
    Aug 10, 2015
    Last Update Posted:
    Jun 24, 2022
    Last Verified:
    Jun 1, 2022