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A Study Comparing Maintenance Subcutaneous Rituximab With Observation Only in Participants With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma Who Had Responded to Rituximab-based Immunochemotherapy Induction and 2-year Maintenance With Subcutaneous Rituximab (MabCute)

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ClinicalTrials.gov Identifier: NCT01461928
Recruitment Status : Completed
First Posted : October 28, 2011
Results First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non-Hodgkin's Lymphoma
Interventions Drug: Chemotherapy (Induction Period)
Drug: Rituximab
Enrollment 692
Recruitment Details Participants were identified for potential recruitment using pre-screening enrolment logs.
Pre-assignment Details Participants were treated with an induction regimen (6 months) and received SC rituximab at a dose of 375 mg/m2 with chemotherapy followed by 2 years of Maintenance I SC rituximab of 1400 mg alone. Responding participants at the end of Maintenance I were randomized to either Maintenance II rituximab treatment or observation only.
Arm/Group Title All Participants Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only)
Hide Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm). Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Participants were randomized to no longer receive SC rituximab but observed until the end of study.
Period Title: Induction (up to 8 Months)
Started [1] 692 0 0
Completed [1] 494 0 0
Not Completed 198 0 0
Reason Not Completed
Adverse Event             76             0             0
Death             3             0             0
Lost to Follow-up             5             0             0
Physician Decision             9             0             0
Withdrawal by Subject             18             0             0
Disease progression             45             0             0
Eligibility criteria deviation             10             0             0
Completed Induction, no Maint I received             11             0             0
Not responding to treatment             11             0             0
Termination of study in Switzerland             1             0             0
Treated before eligibility was confirmed             1             0             0
Sponsor decision             1             0             0
Protocol deviation             2             0             0
Prednisolone given prior to enrolment             1             0             0
Cycle 7 rituximab not given in error             1             0             0
Promotor request             1             0             0
Exceeded time limit for next cycle             1             0             0
Medical advisor request             1             0             0
[1]
Induction period only
Period Title: Maintenance I (24 Months)
Started [1] 494 0 0
Completed [1] 276 [2] 0 0
Not Completed 218 0 0
Reason Not Completed
Death             3             0             0
Withdrawal by Subject             32             0             0
Lost to Follow-up             2             0             0
Diseases progression             91             0             0
Adverse Event             70             0             0
Physician Decision             9             0             0
Did not meet randomization criteria             2             0             0
Did not perform scheduled assessment             2             0             0
Delay in rituximab administration             1             0             0
Not compliant             1             0             0
Did not meet criteria             5             0             0
[1]
Maintenance I only
[2]
Responders during 2 yrs Maint I treatment
Period Title: Maintenance II (15 Months)
Started [1] 0 138 138
Completed [1] 0 115 [2] 111
Not Completed 0 23 27
Reason Not Completed
Adverse Event             0             2             0
Death             0             10             8
Physician Decision             0             0             4
Lost to Follow-up             0             1             0
Moved to another town             0             1             0
Disease progression             0             0             3
Withdrawal by Subject             0             9             8
Changed physician in another hospital             0             0             1
Squamous lung carcinoma             0             0             1
Withdrew informed consent             0             0             1
Refused to be transferred to other site             0             0             1
[1]
Maintenance II only
[2]
6 participants did not receive treatment
Arm/Group Title All Participants
Hide Arm/Group Description Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Baseline Participants 692
Hide Baseline Analysis Population Description
The Intent-to-Treat (ITT) population was used for the analysis of secondary efficacy parameters and Baseline variables. The randomised ITT population (ITTrand) included only randomised participants of Maintenance II period and was used for the analysis of the primary efficacy endpoint of PFS and the secondary analysis endpoint overall survival (OS)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 692 participants
64.6  (11.14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 692 participants
Female
346
  50.0%
Male
346
  50.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 692 participants
Caucasian 579
Black 7
Asian 5
Other 32
Not applicable as per local regulation 69
1.Primary Outcome
Title Maintenance II: Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
Hide Description Progression free survival from randomization (PFSrand) is defined as the time from date of randomization to the date of first documented disease progression or death, whichever occurs first. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed. The Observation arm did not include one participant with AE outcome of death reported retrospectively 2 months after discontinuation from study (censored as having no event on Day 456 post-randomization).
Time Frame From randomization (Maintenance II) up to disease progression or death, whichever occurs first (up to approximately 24 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis population was the ITT population (ITTrand), which included only randomised participants (Maintenance II only) and was used for the analysis of the primary efficacy endpoint of PFS and the secondary analysis endpoint overall survival (OS). The PFS end point was not reached.
Arm/Group Title Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only)
Hide Arm/Group Description:
Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study.
Participants were randomized to no longer receive SC rituximab but observed until the end of study.
Overall Number of Participants Analyzed 138 138
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(39.75 to NA)
[1]
The endpoint could not be analyzed due to the limited number of PFS events
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Maintenance II - Arm A (Rituximab), Maintenance II - Arm B (Observation Only)
Comments The stratified log rank test p-value was derived using the following randomization stratification strata : Follicular Lymphoma International Prognostic Index (FLIPI) risk category (low, intermediate, high) and indolent NHL subtype (follicular lymphoma, non-follicular lymphoma). Power at time of final analysis was less than 40%. Final analysis was not able to address it's primary objective.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.410
Comments Power at time of final analysis was less than 40%. Final analysis was not able to address its primary objective.
Method Stratified Long-rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.37 to 1.53
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With Adverse Events (AEs), Serious AEs, and Infusion/Administration-related Reactions (IRRs/ARRs)
Hide Description An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Not all AEs were followed up for the randomized Observation arm. Only Serious AEs and AE grade 3-5 (obtained retrospectively) were collected for this arm. Therefore arms are not comparable overall.
Time Frame From day of first rituximab induction dose up to day of disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all participants who received at least one dose of study drug and had a safety assessment performed post randomization.
Arm/Group Title All Participants
Hide Arm/Group Description:
Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Participants Analyzed 692
Measure Type: Number
Unit of Measure: Participants
Number of Participants with Adverse Events 643
Number of Participants with Serious Adverse Events 339
Number of Participants with IRRs/ARRs 330
3.Secondary Outcome
Title Event-free Survival (Time to Treatment Failure) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
Hide Description Event-Free Survival was measured from the day of first rituximab Induction dose through Maintenance I and Maintenance II rituximab arm until the date of any treatment failure, including disease progression, or discontinuation of treatment for any reason (e.g. disease progression, toxicity, patient preference, initiation of new anti-lymphoma treatment, or death). Treatment discontinuation was considered as an event and was not applicable to the randomized observation arm.
Time Frame From day of first rituximab induction dose up to day of any treatment failure, including disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who were enrolled into the given study period and had received at least one dose of study treatment at any time were included in the ITT population for each period of the study; Induction, Maintenance I and Maintenance I
Arm/Group Title Maintenance II - Arm A (Rituximab) All Participants
Hide Arm/Group Description:
Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study.
Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Participants Analyzed 138 692
Median (95% Confidence Interval)
Unit of Measure: Months
65.38 [1] 
(60.98 to NA)
24.99
(20.73 to 27.99)
[1]
Not reached because the upper 95% CI of median could not be calculated based on Greenwood formula due to limited events.
4.Secondary Outcome
Title Time to Next Lymphoma Treatment (TNLT)
Hide Description Time to next lymphoma treatment (TNLT) is defined as the time from date of first rituximab induction dose to the date date of first documented intake of any new antilymphoma treatment (chemotherapy, radiotherapy, immunotherapy, etc.).
Time Frame From day of first rituximab induction dose up to any new lymphoma treatment (up to approximately 87 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population was the randomised ITT population (ITTrand), which included only randomised participants (Maintenance II only) as well as the ITT population, that included all participants who had completed a Baseline visit and at least one on-treatment assessment (Induction, Maintenance I and Maintenance II).
Arm/Group Title Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only) All Participants
Hide Arm/Group Description:
Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study.
Participants were randomized to no longer receive SC rituximab but observed until the end of study.
Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Participants Analyzed 138 138 692
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [2] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
The end point could not be analyzed due to the limited number of events.
[2]
The end point could not be analyzed due to a limited number of events. Biased as subjects stopped treatment and were likely to receive NLT earlier.
5.Secondary Outcome
Title Overall Survival
Hide Description Overall survival from first induction treatment (OSRegist) is defined as the time from date of first rituximab induction dose to the date of death, irrespective of cause. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed.
Time Frame From day of first rituximab induction dose up to death (up to approximately 87 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all participants who had completed a Baseline visit and at least one on-treatment assessment and were enrolled into each period of the study; Induction, Maintenance I and Maintenance II.
Arm/Group Title All Participants
Hide Arm/Group Description:
Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Participants Analyzed 692
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
[1]
The end point could not be analyzed due to a limited number of events. Randomized arms pooled as it included information prior to randomization. Interpret with caution.
6.Secondary Outcome
Title Maintenance II: Overall Survival
Hide Description Overall survival from randomization (OSrand) is defined as the time from date of randomization to the date of death, irrespective of cause.
Time Frame From randomization (Maintenance II) up to death (up to approximately 24 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population was the randomised ITT population (ITTrand), which included only randomised participants (Maintenance II only) and was used for the analysis of the primary efficacy endpoint of PFS and the secondary analysis endpoint overall survival (OS).
Arm/Group Title Maintenance II - Arm A (Rituximab) Maintenance II - Arm B (Observation Only)
Hide Arm/Group Description:
Participants were randomized to receive SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study.
Participants were randomized to no longer receive SC rituximab but observed until the end of study.
Overall Number of Participants Analyzed 138 138
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
The end point could not be analyzed due to the limited number of events
7.Secondary Outcome
Title Percentage of Participants With Partial or Complete Tumor Response (PR/CR) Assessment at End of Induction Using 1999 International Working Group Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
Hide Description Overall response rate is defined as the proportion of responders at the end of the Induction period. A responder is defined as a participant experiencing either CR or PR tumor response according to the Cheson response criteria for indolent lymphoma or the recommendations for Waldenström’s macroglobulinemia.
Time Frame From day of first rituximab induction dose up to end of induction period (up to approximately 8 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all participants who had completed a Baseline visit and at least one on-treatment assessment and were enrolled into each period of the study; Induction, Maintenance I and Maintenance II.
Arm/Group Title All Participants
Hide Arm/Group Description:
Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Participants Analyzed 692
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
84.7
(81.8 to 87.3)
8.Secondary Outcome
Title Maintenance I: Percentage of Participants With Conversion of PR to CR Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
Hide Description [Not Specified]
Time Frame From day of first rituximab induction dose up to end of Maintenance I period (up to approximately 32 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The Maintenance I participant analysis group consisted of a subgroup of responding participants who completed Induction and successfully enrolled into Maintenance I. Participants who had partial response (PR) at the end of Induction were included in this analysis.
Arm/Group Title Maintenance I
Hide Arm/Group Description:
Participants received 12 cycles of rituximab administered as a single SC injection of 1400 mg without chemotherapy every 8 weeks for 2 years
Overall Number of Participants Analyzed 357
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage
21.6
(17.4 to 26.2)
9.Secondary Outcome
Title Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia
Hide Description Progression free survival from first induction treatment (PFSregist) is defined as the time from date of first rituximab induction dose to the date of first documented disease progression or death by any cause, whichever occurs first.
Time Frame From day of first rituximab induction dose up to disease progression or death, whichever occurs first (up to approximately 87 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all participants who had completed a Baseline visit and at least one on-treatment assessment and were enrolled into each period of the study; Induction, Maintenance I and Maintenance II.
Arm/Group Title All Participants
Hide Arm/Group Description:
Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
Overall Number of Participants Analyzed 692
Median (95% Confidence Interval)
Unit of Measure: Months
59.33
(50.33 to 71.36)
Time Frame From Baseline up to 47 months
Adverse Event Reporting Description The SAF population included all participants who had received at least one dose of rituximab during the study (Induction, Maint I, Maint II) and were assigned to treatment groups. Not all AEs were followed up for the randomized Observation arm. Only Serious AEs and AE grade 3-5 were collected for this arm, therefore arms are not comparable overall. All AEs reported in Arm A and Arm B are also included in All Participants.
 
Arm/Group Title Arm A Arm B (Observation Only) All Participants
Hide Arm/Group Description Subjects received SC rituximab administered as a single injection of 1400 mg fixed dose without chemotherapy every 8 weeks until disease progression or until the end of study. Subjects did not receive further rituximab treatment until the end of study. Participants were enrolled in an Induction period (up to 8 months) and received SC rituximab at a dose of 375 mg/m2 body surface area (BSA) followed by standard chemotherapy then continued into Maintenance I period (up to 24 months) and received SC rituximab of 1400 mg without chemotherapy. Participants who completed the Induction and Maintenance I periods with SC rituximab and for whom Partial Response (PR) or Complete Response (CR) was confirmed, were considered responders and were then randomized to receive either prolonged SC rituximab continued until disease progression or until the end of study (Maintenance II; Rituximab arm) or observation with no further treatment until the end of study (Maintenance II; Observation arm).
All-Cause Mortality
Arm A Arm B (Observation Only) All Participants
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/138 (7.25%)      8/138 (5.80%)      161/692 (23.27%)    
Show Serious Adverse Events Hide Serious Adverse Events
Arm A Arm B (Observation Only) All Participants
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   59/138 (42.75%)      58/138 (42.03%)      339/692 (48.99%)    
Blood and lymphatic system disorders       
Thrombocytopenia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 5/692 (0.72%)  5
Neutropenia * 1  1/138 (0.72%)  1 6/138 (4.35%)  12 22/692 (3.18%)  29
Lymphopenia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Leukopenia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Hyperviscosity syndrome * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Febrile Neutropenia * 1  4/138 (2.90%)  5 2/138 (1.45%)  2 36/692 (5.20%)  42
Bone marrow failure * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Anaemia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 8/692 (1.16%)  10
Cardiac disorders       
Ventricular tachycardia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Myocardial ischaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Myocardial infarction * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Coronary artery disease * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Congestive cardiomyopathy * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cardiopulmonary failure * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Cardiac failure congestive * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cardiac failure acute * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Cardiac failure * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Cardic arrest * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Atrial fibrillation * 1  2/138 (1.45%)  2 2/138 (1.45%)  2 7/692 (1.01%)  7
Aortic valve incompetence * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Aortic valve calcification * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Acute myocardial infarction * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Acute coronary syndrome * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Congenital, familial and genetic disorders       
Atrial septal defect * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Ear and labyrinth disorders       
Vertigo positional * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Vertigo * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Endocrine disorders       
Thyrotxic crisis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Goitre * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Eye disorders       
Dacryostenosis acquired * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Cataract * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastrointestinal disorders       
Vomiting * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 4/692 (0.58%)  4
Retroperitoneal haematoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Proctitis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Pancreatitis acute * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Pancreatitis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Oesophagitis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Intestinal pseudo-obstruction * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Inflammatory bowel disease * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Haemorrhoidal haemorrhage * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Gastrooesophageal reflux disease * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastrointestinal toxicity * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Gastritis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Dyspepsia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Duodenal ulcer * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Diverticular perporation * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Diarrhoea * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 10/692 (1.45%)  12
Crohn's disease * 1  1/138 (0.72%)  1 1/138 (0.72%)  2 2/692 (0.29%)  3
Colitis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Ascites * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Abdominal pain upper * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Abdominal pain * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
General disorders       
Sudden death * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Pyrexia * 1  1/138 (0.72%)  1 3/138 (2.17%)  3 11/692 (1.59%)  16
Oedema peripheral * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Malaise * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site reaction * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 5/692 (0.72%)  5
Injection site pain * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site induration * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site haematoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site erythema * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Infusion site erythema * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  5
Inflammation * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
General physical health deterioration * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 5/692 (0.72%)  5
Feeling hot * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Face oedema * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Death * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  3
Chills * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 4/692 (0.58%)  4
Chest pain * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 2/692 (0.29%)  2
Hepatobiliary disorders       
Liver disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Jaundice * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic steatosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic failure * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cholecystitis acute * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cholecystitis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Cholangitis acute * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Bile duct stone * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Immune system disorders       
Immunosupression * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypersensitivity * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 4/692 (0.58%)  5
Drug hypersensitivity * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Infections and infestations       
Viral upper respiratory tract infection * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Viral infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  3
Varicella * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 2/692 (0.29%)  2
Urosepsis * 1  1/138 (0.72%)  2 0/138 (0.00%)  0 2/692 (0.29%)  3
Urinary tract infection * 1  3/138 (2.17%)  4 2/138 (1.45%)  2 12/692 (1.73%)  13
Upper respiratory tract infection * 1  0/138 (0.00%)  0 3/138 (2.17%)  4 8/692 (1.16%)  9
Tracheobronchitis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Soft tissue infection * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Skin infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Septic shock * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 6/692 (0.87%)  6
Sepsis syndrome * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Sepsis * 1  3/138 (2.17%)  3 2/138 (1.45%)  2 18/692 (2.60%)  18
Salmonellosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Respiratory tract infection * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 9/692 (1.30%)  9
Pyelonephritis chronic * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Pulmonary sepsis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Pseudomonas infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Progressive multifocal leukoencephalopathy * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  3
Pneumonia * 1  14/138 (10.14%)  14 6/138 (4.35%)  7 54/692 (7.80%)  65
Pneumocystis Jirovecii pneumonia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  3
Pneumococcal infection * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Pharyngitis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Periorbital cellulitis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Perineal cellulitis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Paraspinal abscess * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Neutropenic sepsis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Necrotising fasciitis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Myocarditis septic * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Myocarditis infectious * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Meningitis aseptic * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Lung infection * 1  2/138 (1.45%)  2 4/138 (2.90%)  4 7/692 (1.01%)  7
Lower respiratory tract infection * 1  1/138 (0.72%)  1 5/138 (3.62%)  6 10/692 (1.45%)  11
Kidney infection * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Intestinal sepsis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Influenza * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Infective exacerbation of chronic obstructive airways disease * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Infection * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Herpes zoster * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 4/692 (0.58%)  5
Hepatitis viral * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatitis C * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic candidiasis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Haemophilus infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastrointestinal infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastroenteritis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Escherichia urinary tract infection * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Erysipelas * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 3/692 (0.43%)  3
Enterobacter sepsis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Diverticulitis * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 3/692 (0.43%)  4
Device related sepsis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Cytomegalovirus infection * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Cellulitis * 1  1/138 (0.72%)  2 0/138 (0.00%)  0 2/692 (0.29%)  4
Candida infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Campylobacter gastroenteritis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Bronchopulmonary aspergillosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Bronchitis * 1  0/138 (0.00%)  0 4/138 (2.90%)  4 5/692 (0.72%)  5
Appendicitis * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Abscess * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Abdominal wall abscess * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Abdominal infection * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Injury, poisoning and procedural complications       
Upper limb fracture * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Tooth avulsion * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Subarachnoid haemorrhage * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Spinal compression fracture * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 3/692 (0.43%)  3
Pubis fracture * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Lumbar vertebral fracture * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Infusion related reaction * 1  3/138 (2.17%)  3 0/138 (0.00%)  0 7/692 (1.01%)  7
Hip fracture * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Head injury * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Femur fracture * 1  0/138 (0.00%)  0 2/138 (1.45%)  2 2/692 (0.29%)  2
Femoral neck fracture * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Fall * 1  0/138 (0.00%)  0 2/138 (1.45%)  3 3/692 (0.43%)  4
Complications of bone marrow transplant * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Chest injury * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Ankle fracture * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Anastomotic leak * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Investigations       
Neutrophil count decreased * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Lymphocyte count decreased * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Metabolism and nutrition disorders       
Tumour lysis syndrome * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Hypophosphataemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hyponatraemia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Hyperglycaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Musculoskeletal and connective tissue disorders       
Spinal osteoarthritis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Spinal column stenosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Pain in extremity * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Osteoporotic fracture * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Osteoarthritis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Neck pain * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Musculoskeletal chest pain * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Intervertebral disc protrusion * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Haemarthrosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Compartment syndrome * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Bone pain * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Back pain * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Arthralgia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Transitional cell carcinoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Squamous cell carcinoma of skin * 1  1/138 (0.72%)  1 2/138 (1.45%)  4 5/692 (0.72%)  7
Squamous cell carcinoma of lung * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Squamous cell carcinoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Small intestine adenocarcinoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Refractory Anaemia With An Excess Of Blasts * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Rectal cancer * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Prostatic adenoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Prostate cancer * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 4/692 (0.58%)  4
Pancreatic carcinoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Nodal Marginal Zone B-Cell Lymphoma * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Neuroendocrine tumour * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Naevoid melanoma * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Myeloid leukaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Myelodysplastic syndrome * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 9/692 (1.30%)  9
Metastatic squamous cell carcinoma * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Malignant melanoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Lung neoplasm malignant * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Lung adenocarcinoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Lentigo maligna * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Large cell lung cancer * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Invasive ductal breast carcinoma * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 3/692 (0.43%)  3
Hodgkin's disease * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Hepatocellular Carcinoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Colorectal cancer * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cholangiocarcinoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Carcinoid tumour of the stomach * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Breast cancer * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Bowen's disease * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Bladder cancer * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Basal cell carcinoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  3
Anaplastic astrocytoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Anal squamous cell carcinoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Adenocarcinoma pancreas * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Adenocarcinoma of colon * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Acute myeloid leukaemia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 4/692 (0.58%)  4
Nervous system disorders       
Transient ischaemic attack * 1  0/138 (0.00%)  0 1/138 (0.72%)  2 1/692 (0.14%)  2
Syncope * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 4/692 (0.58%)  4
Presyncope * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Peripheral sensory neuropathy * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Ischaemic stroke * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Hemiplegic migraine * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Headache * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Haemorrhage intracranial * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cognitive disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cerebrovascular disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cerebrovascular accident * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 4/692 (0.58%)  4
Cerebral infarction * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Cerebral haemorrhage * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Cerebral atrophy * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Carotid artery stenosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Psychiatric disorders       
Depression * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Delirium * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Renal and urinary disorders       
Urethral haemorrhage * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Ureterolithiasis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Haematuria * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Nephrolithiasis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Acute kidney injury * 1  0/138 (0.00%)  0 3/138 (2.17%)  3 6/692 (0.87%)  6
Reproductive system and breast disorders       
Menometrorrhagia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Respiratory, thoracic and mediastinal disorders       
Throat irritation * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Sleep apnoea syndrome * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Respiratory failure * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 4/692 (0.58%)  4
Respiratory disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Pulmonary embolism * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 5/692 (0.72%)  5
Pleural effusion * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Oropharyngeal pain * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Lung disorder * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Haemoptysis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Dyspnoea * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 6/692 (0.87%)  7
Chronic obstructive pulmonary disease * 1  2/138 (1.45%)  5 0/138 (0.00%)  0 3/692 (0.43%)  6
Bronchospasm * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Bronchiectasis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  3
Asthma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Acute respiratory failure * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Acute pulmonary oedema * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Skin and subcutaneous tissue disorders       
Urticaria * 1  0/138 (0.00%)  0 2/138 (1.45%)  2 2/692 (0.29%)  2
Toxic skin eruption * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Skin reaction * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Rash papular * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Rash * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 5/692 (0.72%)  5
Pruritus * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Peau D'orange * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Erythema * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Surgical and medical procedures       
Venous thrombosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Vena cava thrombosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Phlebitis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Peripheral arterial occlusive disease * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Orthostatic hypotension * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Jugular vein thrombosis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypotension * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypertension * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Haemorrhagic vasculitis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Haematoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Flushing * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Deep vein thrombosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Abdominal hernia repair * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
1
Term from vocabulary, MedDRA 20.1
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm A Arm B (Observation Only) All Participants
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   133/138 (96.38%)      133/138 (96.38%)      643/692 (92.92%)    
Blood and lymphatic system disorders       
Thrombocytopenia * 1  9/138 (6.52%)  12 10/138 (7.25%)  13 49/692 (7.08%)  75
Pancytopenia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  4
Neutropenia * 1  48/138 (34.78%)  134 51/138 (36.96%)  173 226/692 (32.66%)  604
Microcytosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Lymphopenia * 1  4/138 (2.90%)  13 1/138 (0.72%)  1 16/692 (2.31%)  34
Lymphocytosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Lymphadenopathy * 1  0/138 (0.00%)  0 3/138 (2.17%)  3 3/692 (0.43%)  3
Lymph node pain * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Leukopenia * 1  14/138 (10.14%)  47 9/138 (6.52%)  18 52/692 (7.51%)  126
Leukocytosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Iron deficiency anaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypoglobulinaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypochromic anaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Haematotoxicity * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Febrile neutropenia * 1  3/138 (2.17%)  3 2/138 (1.45%)  8 15/692 (2.17%)  22
Eosinophilia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 4/692 (0.58%)  4
Coagulopathy * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Anaemia * 1  23/138 (16.67%)  35 21/138 (15.22%)  32 106/692 (15.32%)  172
Agranulocytosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Cardiac disorders       
Vantricular arrhythmia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Tachycardia * 1  0/138 (0.00%)  0 4/138 (2.90%)  4 10/692 (1.45%)  10
Supraventricular tachycardia * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Sinus tachycardia * 1  2/138 (1.45%)  3 0/138 (0.00%)  0 3/692 (0.43%)  4
Sinus bradycardia * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Pericardial effusion * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Palpitations * 1  3/138 (2.17%)  3 4/138 (2.90%)  5 9/692 (1.30%)  11
Myocardial ischaemia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Mitral valve incompetence * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Left ventricular failure * 1  1/138 (0.72%)  2 0/138 (0.00%)  0 1/692 (0.14%)  2
Left ventricular dysfunction * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hyperkinetic heart syndrome * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Extrasystoles * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Cardiac failure congestive * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Cardiac failure chronic * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Cardiac failure * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Bundle branch block left * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Bradycardia * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Atrioventricular block complete * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Atrial tachycardia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Atrial fibrillation * 1  2/138 (1.45%)  3 2/138 (1.45%)  2 8/692 (1.16%)  12
Atrial flutter * 1  0/138 (0.00%)  0 1/138 (0.72%)  2 3/692 (0.43%)  4
Arrhythmia supraventricular * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Arrhythmia * 1  3/138 (2.17%)  3 0/138 (0.00%)  0 5/692 (0.72%)  5
Aortic valve incompetence * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Angina pectoris * 1  1/138 (0.72%)  1 4/138 (2.90%)  5 7/692 (1.01%)  8
Acute coronary syndrome * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Congenital, familial and genetic disorders       
Porokeratosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Thyroglossal cyst * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Ear and labyrinth disorders       
Vestibular disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Vertigo * 1  7/138 (5.07%)  10 2/138 (1.45%)  2 18/692 (2.60%)  21
Tympanic membrane disorder * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Tinnitus * 1  5/138 (3.62%)  6 2/138 (1.45%)  2 9/692 (1.30%)  10
Middle ear inflammation * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypoacusis * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 4/692 (0.58%)  4
Ear pain * 1  4/138 (2.90%)  4 2/138 (1.45%)  2 11/692 (1.59%)  12
Deafness unilateral * 1  0/138 (0.00%)  0 2/138 (1.45%)  2 3/692 (0.43%)  3
Deafness * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Endocrine disorders       
Hypothyroidism * 1  2/138 (1.45%)  3 2/138 (1.45%)  2 4/692 (0.58%)  5
Autoimmune thyroiditis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Goitre * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Hypoaldosteronism * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Thyroid disorder * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Thyroid mass * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Thyroiditis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Hyperthyroidism * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 4/692 (0.58%)  4
Inappropriate antidiuretic hormone secretion * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Eye disorders       
Vitreous floaters * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Visual impairment * 1  2/138 (1.45%)  2 1/138 (0.72%)  1 6/692 (0.87%)  6
Visual acuity reduced * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 2/692 (0.29%)  2
Vision blurred * 1  2/138 (1.45%)  2 1/138 (0.72%)  1 5/692 (0.72%)  5
Periorbital oedema * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Ocular hyperaemia * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Noninfective conjunctivitis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Lacrimation increased * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Glaucoma * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 2/692 (0.29%)  2
Eyelid swelling * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Eyelid oedema * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Eye pruritus * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 3/692 (0.43%)  3
Eye pain * 1  4/138 (2.90%)  4 0/138 (0.00%)  0 6/692 (0.87%)  6
Eye irritation * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Eye inflammation * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Eye discharge * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Entropion * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Dry eye * 1  3/138 (2.17%)  3 0/138 (0.00%)  0 5/692 (0.72%)  5
Diabetic retinopathy * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Conjunctivitis allergic * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Conjunctival hyperaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Chalazion * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Cataract * 1  2/138 (1.45%)  3 1/138 (0.72%)  2 5/692 (0.72%)  8
Gastrointestinal disorders       
Vomiting * 1  23/138 (16.67%)  32 16/138 (11.59%)  31 96/692 (13.87%)  160
Umbilical hernia * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Toothache * 1  5/138 (3.62%)  5 2/138 (1.45%)  2 9/692 (1.30%)  9
Tooth loss * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Tooth disorder * 1  0/138 (0.00%)  0 2/138 (1.45%)  2 2/692 (0.29%)  2
Tooth development disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Tongue ulceration * 1  0/138 (0.00%)  0 2/138 (1.45%)  2 4/692 (0.58%)  4
Tongue geographic * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Tongue coated * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Stomatitis * 1  5/138 (3.62%)  5 3/138 (2.17%)  4 17/692 (2.46%)  18
Sensitivity of teeth * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Salivary hypersecretion * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Rectal polyp * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Rectal haemorrhage * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Proctalgia * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Perianal erythema * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Paraesthesia oral * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  3
Pancreatic duct dilatation * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Pancreatic cyst * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Oral pain * 1  3/138 (2.17%)  3 5/138 (3.62%)  5 15/692 (2.17%)  16
Oral disorder * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Oesophagitis * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Odynophagia * 1  1/138 (0.72%)  1 2/138 (1.45%)  5 7/692 (1.01%)  10
Noninfective gingivitis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Nausea * 1  45/138 (32.61%)  63 37/138 (26.81%)  65 199/692 (28.76%)  312
Mouth ulceration * 1  3/138 (2.17%)  4 3/138 (2.17%)  4 12/692 (1.73%)  15
Melaena * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Lower gastrointestinal haemorrhage * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Lip ulceration * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Large intestinal ulcer * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Irritable bowel syndrome * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Intestinal obstruction * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Inguinal hernia * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 3/692 (0.43%)  3
Impaired gastric emptying * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Ileal ulcer * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Hiatus hernia * 1  2/138 (1.45%)  2 1/138 (0.72%)  1 4/692 (0.58%)  4
Haemorrhoids thrombosed * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Haemorrhoids * 1  0/138 (0.00%)  0 3/138 (2.17%)  3 12/692 (1.73%)  12
Haemorrhoidal haemorrhage * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 4/692 (0.58%)  4
Haematochezia * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 3/692 (0.43%)  3
Gingival bleeding * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Gastrooesophageal reflux disease * 1  11/138 (7.97%)  13 7/138 (5.07%)  9 20/692 (2.89%)  24
Gastrointestinal toxicity * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastrointestinal sounds abnormal * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastrointestinal inflammation * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Gastrointestinal hypomotility * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Gastrointestinal disorder * 1  2/138 (1.45%)  2 2/138 (1.45%)  2 5/692 (0.72%)  5
Gastritis * 1  1/138 (0.72%)  1 6/138 (4.35%)  6 12/692 (1.73%)  12
Gastric ulcer * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Food poisoning * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Flatulence * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 7/692 (1.01%)  7
Faeces soft * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Faecaloma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Eructation * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Epigastric discomfort * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Enterocolitis * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Dysphagia * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 10/692 (1.45%)  10
Dyspepsia * 1  10/138 (7.25%)  10 7/138 (5.07%)  7 26/692 (3.76%)  27
Dyschezia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Dry mouth * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 10/692 (1.45%)  10
Diverticulum intestinal * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Diarrhoea * 1  35/138 (25.36%)  50 28/138 (20.29%)  36 143/692 (20.66%)  211
Defaecation urgency * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  2
Crohn's disease * 1  0/138 (0.00%)  0 1/138 (0.72%)  2 1/692 (0.14%)  2
Constipation * 1  21/138 (15.22%)  26 15/138 (10.87%)  22 98/692 (14.16%)  129
Colitis * 1  3/138 (2.17%)  5 0/138 (0.00%)  0 6/692 (0.87%)  8
Chronic gastritis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Change in bowel habit * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Ascites * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  4
Aphthous ulcer * 1  0/138 (0.00%)  0 3/138 (2.17%)  3 6/692 (0.87%)  6
Anal haemorrhage * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Anal fissure * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  3
Abdominal tenderness * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 3/692 (0.43%)  3
Abdominal pain upper * 1  11/138 (7.97%)  16 4/138 (2.90%)  5 39/692 (5.64%)  49
Abdominal pain lower * 1  1/138 (0.72%)  1 1/138 (0.72%)  2 2/692 (0.29%)  3
Abdominal pain * 1  13/138 (9.42%)  15 13/138 (9.42%)  23 57/692 (8.24%)  74
Abdominal distension * 1  2/138 (1.45%)  2 1/138 (0.72%)  1 7/692 (1.01%)  8
Abdominal discomfort * 1  0/138 (0.00%)  0 2/138 (1.45%)  2 5/692 (0.72%)  5
General disorders       
Xerosis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Vessel puncture site haematoma * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Unevaluable event * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Thirst * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Swelling * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Pyrexia * 1  32/138 (23.19%)  45 29/138 (21.01%)  49 159/692 (22.98%)  258
Puncture site pain * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 3/692 (0.43%)  3
Puncture site erythema * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Polyp * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Peripheral swelling * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 7/692 (1.01%)  8
Performance status decreased * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Pain * 1  3/138 (2.17%)  3 2/138 (1.45%)  2 8/692 (1.16%)  8
Oedema peripheral * 1  6/138 (4.35%)  6 7/138 (5.07%)  8 38/692 (5.49%)  40
Oedema * 1  3/138 (2.17%)  3 2/138 (1.45%)  2 9/692 (1.30%)  9
Mucosal inflammation * 1  6/138 (4.35%)  6 7/138 (5.07%)  8 25/692 (3.61%)  27
Malaise * 1  2/138 (1.45%)  2 1/138 (0.72%)  1 10/692 (1.45%)  10
Localised oedema * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Injection site warmth * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site thrombosis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Injection site swelling * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Injection site reaction * 1  1/138 (0.72%)  2 1/138 (0.72%)  1 10/692 (1.45%)  13
Injection site rash * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 8/692 (1.16%)  9
Injection site pruritus * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Injection site plaque * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site pain * 1  3/138 (2.17%)  3 6/138 (4.35%)  7 24/692 (3.47%)  34
Injection site oedema * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site mass * 1  0/138 (0.00%)  0 2/138 (1.45%)  3 2/692 (0.29%)  3
Injection site irritation * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Injection site inflammation * 1  0/138 (0.00%)  0 3/138 (2.17%)  3 8/692 (1.16%)  9
Injection site induration * 1  3/138 (2.17%)  9 1/138 (0.72%)  2 5/692 (0.72%)  17
Injection site hypersensitivity * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  2
Injection site haematoma * 1  1/138 (0.72%)  2 0/138 (0.00%)  0 4/692 (0.58%)  5
Injection site erythema * 1  10/138 (7.25%)  11 9/138 (6.52%)  14 38/692 (5.49%)  46
Injection site discomfort * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 2/692 (0.29%)  2
Injection site discolouration * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 3/692 (0.43%)  3
Injection site bruising * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 5/692 (0.72%)  5
Infusion site rash * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 2/692 (0.29%)  3
Infusion site pain * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Infusion site inflammation * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Infusion site haematoma * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Infusion site extravasation * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 3/692 (0.43%)  3
Infusion site erythema * 1  1/138 (0.72%)  6 0/138 (0.00%)  0 4/692 (0.58%)  16
Influenza like illness * 1  6/138 (4.35%)  24 6/138 (4.35%)  9 20/692 (2.89%)  45
Inflammation * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 5/692 (0.72%)  6
Implant site haematoma * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypothermia * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 3/692 (0.43%)  7
Hyperthermia * 1  3/138 (2.17%)  4 1/138 (0.72%)  1 7/692 (1.01%)  8
Haemorrhagic cyst * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Granuloma * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
General physical health deterioration * 1  3/138 (2.17%)  3 0/138 (0.00%)  0 5/692 (0.72%)  5
Feeling of body temperature change * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Feeling hot * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 4/692 (0.58%)  5
Feeling cold * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Feeling abnormal * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Fatigue * 1  30/138 (21.74%)  46 19/138 (13.77%)  25 115/692 (16.62%)  157
Facial pain * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Face oedema * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Discomfort * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Cyst * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 2/692 (0.29%)  2
Chills * 1  8/138 (5.80%)  8 9/138 (6.52%)  9 40/692 (5.78%)  47
Chest pain * 1  11/138 (7.97%)  12 7/138 (5.07%)  7 27/692 (3.90%)  29
Chest discomfort * 1  3/138 (2.17%)  3 3/138 (2.17%)  3 10/692 (1.45%)  10
Catheter site thrombosis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Catheter site haemorrhage * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Axillary pain * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  2
Asthenia * 1  27/138 (19.57%)  43 19/138 (13.77%)  28 113/692 (16.33%)  167
Application site pain * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Application site erythema * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Administration site pain * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Administration site inflammation * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Administration site extravasation * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  6
Hepatobiliary disorders       
Biliary colic * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Chloangitis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Choleithiasis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Hepatocellular injury * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 4/692 (0.58%)  6
Hepatotoxicity * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 3/692 (0.43%)  3
Liver disorder * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Cholestasis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 2/692 (0.29%)  4
Cholecystitis chronic * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic cyst * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic function abnormal * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic lesion * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hepatic steatosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Hyperbilirubinaemia * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Immune system disorders       
Seasonal allergy * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 4/692 (0.58%)  4
Sarcoidosis * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Iodine allergy * 1  1/138 (0.72%)  1 1/138 (0.72%)  1 2/692 (0.29%)  2
Immunodeficiency * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Immune system disorder * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Hypogammaglobulinaemia * 1  9/138 (6.52%)  9 9/138 (6.52%)  9 26/692 (3.76%)  26
Hypersensitivity * 1  3/138 (2.17%)  3 0/138 (0.00%)  0 7/692 (1.01%)  7
Drug hypersensitivity * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 5/692 (0.72%)  7
Cytokine release syndrome * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Infections and infestations       
Wound infection * 1  1/138 (0.72%)  1 2/138 (1.45%)  2 3/692 (0.43%)  3
Vulvovaginal mycotic infection * 1  1/138 (0.72%)  3 1/138 (0.72%)  2 2/692 (0.29%)  5
Vulvitis * 1  0/138 (0.00%)  0 1/138 (0.72%)  1 1/692 (0.14%)  1
Viral upper respiratory tract infection * 1  3/138 (2.17%)  3 0/138 (0.00%)  0 7/692 (1.01%)  7
Viral pharyngitis * 1  2/138 (1.45%)  2 0/138 (0.00%)  0 3/692 (0.43%)  3
Viral parotitis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Viral infection * 1  7/138 (5.07%)  8 2/138 (1.45%)  2 11/692 (1.59%)  12
Varicella zoster virus infection * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 2/692 (0.29%)  2
Vaginal infection * 1  2/138 (1.45%)  3 1/138 (0.72%)  1 3/692 (0.43%)  4
Urinary tract infection * 1  11/138 (7.97%)  14 14/138 (10.14%)  22 55/692 (7.95%)  73
Ureaplasma infection * 1  0/138 (0.00%)  0 0/138 (0.00%)  0 1/692 (0.14%)  1
Upper respiratory tract infection * 1  24/138 (17.39%)  36 20/138 (14.49%)  26 63/692 (9.10%)  85
Trichomoniasis * 1  1/138 (0.72%)  1 0/138 (0.00%)  0 1/692 (0.14%)  1
Tracheobronchitis * 1  4/138 (2.90%)  4 1/138 (0.72%)  1 6/692 (0.87%)  6
Tracheitis * 1  3/138 (2.17%)  3 3/138 (2.17%)  3 8/692 (1.16%)  8
Tooth infection * 1  1/138 (0.72%)  2 2/138 (1.45%)  2 5/692 (0.72%)  6
Tooth abscess * 1  2/138 (1.45%)  2 1/138 (0.72%)  1 5/692 (0.72%)  5