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IXAZOMIB Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT01850524
Recruitment Status : Active, not recruiting
First Posted : May 9, 2013
Results First Posted : February 1, 2021
Last Update Posted : February 1, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Multiple Myeloma
Interventions Drug: Ixazomib
Drug: Placebo
Drug: Dexamethasone
Drug: Lenalidomide
Enrollment 705
Recruitment Details Participants took part in the study at 168 investigative sites in multiple countries from 17 May 2013 up to data-cut-off: 2 December 2019. This study is ongoing.
Pre-assignment Details Participants with newly diagnosed multiple myeloma were enrolled in 1:1 ratio to receive ixazomib or placebo in addition to the background therapy of Lenalidomide and Dexamethasone (LenDex) in this study.
Arm/Group Title Placebo + LenDex Ixazomib + LenDex
Hide Arm/Group Description Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019. Participants received Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
Period Title: Overall Study
Started 354 351
Intent-to-Treat (ITT) Population 354 351
Safety Population [1] 349 [2] 354 [3]
Participants Completed Study Treatment Per Protocol [4] 270 264
Per Protocol (PP) Population 295 298
Participants With Exposure of ≥ 19 Cycles 189 191
Completed [5] 0 0
Not Completed 354 351
Reason Not Completed
Ongoing on Treatment             57             54
Adverse Event             96             122
Lost to Follow-up             2             0
Progressive Disease             166             123
Protocol Violation             1             2
Withdrawal by Subject             8             19
Participant Wished to Discontinue Treatment             15             22
Investigator Decision             4             4
Participants Removed From Study             0             1
Medical Monitor Decision             0             1
Participants Decision             2             2
Progressive Disease Per Local Lab             1             0
Lack of Improvement             0             1
Minimal Response             1             0
Comorbidities             1             0
[1]
Includes all treated participants. Participants were analyzed as treated.
[2]
1 participant in this arm who withdrew from the study was not included in the safety population.
[3]
Included 4 participants from placebo who received ixazomib; 1 participant who withdrew was excluded.
[4]
Includes participants who completed treatment per protocol and are being followed for safety.
[5]
Completed=who completed the study.
Arm/Group Title Placebo + LenDex Ixazomib + LenDex Total
Hide Arm/Group Description Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019. Participants received Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019. Total of all reporting groups
Overall Number of Baseline Participants 354 351 705
Hide Baseline Analysis Population Description
ITT population included all participants who are randomized.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 354 participants 351 participants 705 participants
73.7  (5.91) 73.5  (6.53) 73.6  (6.22)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 354 participants 351 participants 705 participants
Female
172
  48.6%
179
  51.0%
351
  49.8%
Male
182
  51.4%
172
  49.0%
354
  50.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 354 participants 351 participants 705 participants
Hispanic or Latino
14
   4.0%
12
   3.4%
26
   3.7%
Not Hispanic or Latino
340
  96.0%
337
  96.0%
677
  96.0%
Unknown or Not Reported
0
   0.0%
2
   0.6%
2
   0.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 354 participants 351 participants 705 participants
American Indian or Alaska Native
1
   0.3%
2
   0.6%
3
   0.4%
Asian
52
  14.7%
44
  12.5%
96
  13.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   0.3%
1
   0.1%
Black or African American
13
   3.7%
11
   3.1%
24
   3.4%
White
285
  80.5%
291
  82.9%
576
  81.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
3
   0.8%
2
   0.6%
5
   0.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 354 participants 351 participants 705 participants
France
136
  38.4%
126
  35.9%
262
  37.2%
Belgium
37
  10.5%
36
  10.3%
73
  10.4%
Russia
3
   0.8%
2
   0.6%
5
   0.7%
Japan
28
   7.9%
31
   8.8%
59
   8.4%
South Korea
20
   5.6%
11
   3.1%
31
   4.4%
New Zealand
3
   0.8%
3
   0.9%
6
   0.9%
United States
68
  19.2%
79
  22.5%
147
  20.9%
Canada
59
  16.7%
63
  17.9%
122
  17.3%
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 354 participants 351 participants 705 participants
164.7  (10.04) 164.3  (10.13) 164.5  (10.08)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 354 participants 351 participants 705 participants
70.53  (15.353) 72.67  (16.995) 71.59  (16.215)
Body Surface Area (BSA)   [1] 
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 354 participants 351 participants 705 participants
1.789  (0.2306) 1.810  (0.2456) 1.800  (0.2383)
[1]
Measure Description: BSA = square root of (height x weight/3600)
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause according to International Myeloma Working Group (IMWG) criteria whichever occurs first. PD required one of the following: Increase of >=25% from nadir in: Serum M-component and/or (the absolute increase must be >=0.5 g/dL); Urine M-component and/or (the absolute increase must be >=200 mg/24 hours); in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Bone marrow plasma cell percentage: the absolute % must be >10%; development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.85 mmol/L).
Time Frame Up to data cut off: 2 December 2019 (Up to approximately 79 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants who are randomized.
Arm/Group Title Placebo + LenDex Ixazomib + LenDex
Hide Arm/Group Description:
Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
Participants received Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
Overall Number of Participants Analyzed 354 351
Median (95% Confidence Interval)
Unit of Measure: months
21.8
(19.65 to 30.78)
35.3
(26.45 to 43.70)
2.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS is defined as the time from the date of randomization to the date of death.
Time Frame From the date of randomization to death due to any cause (Up to 87 months)
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Complete Response (CR) Rate
Hide Description CR rate is defined as the percentage of participants who achieve CR assessed by an IRC relative to the intent-to-treat (ITT) population during the treatment period. Percentage of participants with CR, as assessed by IMWG disease assessment criteria will be reported.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Pain Response Rate as Assessed by the Brief Pain Inventory- Short Form (BPI-SF) and Analgesic Use
Hide Description Pain response rate is defined as percentage of participants with pain response. Pain response is defined as the occurrence of at least a 30% reduction from baseline in BPI-SF worst pain score over the last 24 hours without an increase in analgesic use for 2 consecutive measurements > 28 days apart, will be reported. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable).
Time Frame Up to 27 months
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Overall Response Rate (ORR)
Hide Description ORR is defined as the percentage of participants who achieved partial response (PR) or better relative to the ITT population during treatment period.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Time to Response
Hide Description Time to response is defined as the time from the date of randomization to the first documentation of PR or better, as measured by IMWG criteria.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Duration of Response
Hide Description Duration of response is measured as the time from the date of first documentation of PR or better to the date of first documented progression (PD) for responders, as measured by IMWG criteria.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
8.Secondary Outcome
Title Time to Progression (TTP)
Hide Description Time to progression is defined as the time from randomization to the date of first documented disease progression.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
9.Secondary Outcome
Title Progression Free Survival (PFS)-2
Hide Description PFS2 is defined as the time from the date of randomization to the date of documentation of disease progression on the subsequent line of anticancer therapy, as assessed by the investigator in accordance with IMWG criteria, or death due to any cause, whichever occurs first.
Time Frame Up to 87 months
Outcome Measure Data Not Reported
10.Secondary Outcome
Title Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Score
Hide Description Eastern Cooperative Oncology Group (ECOG) scale score ranged from 0 to 5, where 0 indicated normal activity and 5 indicated death.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
11.Secondary Outcome
Title Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Time Frame From the first dose of study drug through 30 days after administration of the last dose of study drug (Up to 28 months)
Outcome Measure Data Not Reported
12.Secondary Outcome
Title Percentage of Participants With Abnormal Laboratory Values
Hide Description The laboratory evaluations will include hematology, clinical chemistry and urinalysis.
Time Frame From the first dose of study drug through 30 days after administration of the last dose of study drug (Up to 28 months)
Outcome Measure Data Not Reported
13.Secondary Outcome
Title Change From Baseline in Health-Related Quality of Life (HRQOL) Measured by European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale Total Score
Hide Description EORTC-QLQ-C30 scale is used to assess HRQOL in cancer participants and contains 30 items. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better HRQOL; whereas for the symptom scales lower scores represent better HRQOL.
Time Frame Baseline to Month 27
Outcome Measure Data Not Reported
14.Secondary Outcome
Title Change From Baseline in HRQOL Measured by EORTC-QLQ)-MY20 Scale
Hide Description EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. The scale has 20 questions. Raw scores are averaged, and transformed to 0-100 scale, where higher score is better quality of life.
Time Frame Baseline to Month 27
Outcome Measure Data Not Reported
15.Secondary Outcome
Title OS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations
Hide Description OS is defined as the time from the date of randomization to the date of death, as assessed in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16) mutations.
Time Frame From the date of randomization to death due to any cause (Up to 87 months)
Outcome Measure Data Not Reported
16.Secondary Outcome
Title PFS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations
Hide Description PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease based on central laboratory results and IMWG criteria as evaluated by an independent review committee (IRC) or death due to any cause, whichever occurs first, as assessed in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16) mutations.
Time Frame Up to 87 months
Outcome Measure Data Not Reported
17.Secondary Outcome
Title Percentage of Participants With MRD-Negative Status as Assessed by Flow Cytometry
Hide Description The absence of minimal residual disease (MRD negativity) will be tested in all participants who achieve a CR and maintained it until Cycle 18, using bone marrow aspirates. The frequency of MRD negativity, in each treatment arm will be determined, and its association with TTP, PFS, and OS will be evaluated.
Time Frame Up to 27 months
Outcome Measure Data Not Reported
18.Secondary Outcome
Title Time to Pain Progression
Hide Description Time to pain progression will be assessed as the time from randomization to the date of initial progression classification. Pain progression is defined as the occurrence of 1 of the following and confirmed by 2 consecutive evaluations (To qualify as progression, the participant must have a BPI-SF worst pain score > 4 during pain progression): 1) a ≥ 2 point and 30% increase from Baseline in BPI-SF worst pain score without an increase in analgesic use, or 2) a 25% or more increase in analgesic use from Baseline without a decrease in BPI-SF worst pain score from Baseline. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable).
Time Frame Up to 27 months
Outcome Measure Data Not Reported
19.Secondary Outcome
Title Cmax: Maximum Plasma Concentration for IXAZOMIB and Its Metabolite MLN2238
Hide Description [Not Specified]
Time Frame Cycle 1, Day 1 at multiple time points (up to 4 hours) post-dose and Day 14 at any time; Cycle 2-3, Day 1 pre-dose and Day 14 at any time; Cycles 4-12 pre-dose (Cycle length is 28 days)
Outcome Measure Data Not Reported
20.Secondary Outcome
Title Percentage of Participants With New or Worsening of Existing Skeletal-related Events (SREs)
Hide Description SRE is defined as new fractures [including vertebral compression fractures]), irradiation of or surgery on bone, or spinal cord compression).
Time Frame Baseline and up to Month 27
Outcome Measure Data Not Reported
Time Frame From randomization to 30 days of last dose, or up to data cut-off date 2 December 2019 (up to approximately Month 79)
Adverse Event Reporting Description Safety population included all participants who received at least 1 dose of any drug. 4 participants who were randomized to the placebo received ixazomib during the study and were included in the ixazomib arm for the safety population. 1 participant randomized to each arm withdrew from the study and were not included in the safety population. Data for safety is summarized as per the duration of exposure to study treatment (exposure up to 18 cycles; exposure ≥19 cycles).
 
Arm/Group Title Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
Hide Arm/Group Description Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Participants received ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib placebo matching capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019. Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
All-Cause Mortality
Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   17/160 (10.63%)   21/163 (12.88%)   5/189 (2.65%)   6/191 (3.14%) 
Hide Serious Adverse Events
Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   105/160 (65.63%)   119/163 (73.01%)   113/189 (59.79%)   114/191 (59.69%) 
Blood and lymphatic system disorders         
Anaemia  1  2/160 (1.25%)  5/163 (3.07%)  2/189 (1.06%)  2/191 (1.05%) 
Febrile neutropenia  1  2/160 (1.25%)  4/163 (2.45%)  2/189 (1.06%)  2/191 (1.05%) 
Thrombocytopenia  1  1/160 (0.63%)  4/163 (2.45%)  1/189 (0.53%)  0/191 (0.00%) 
Heparin-induced thrombocytopenia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Cardiac disorders         
Cardiac failure  1  1/160 (0.63%)  3/163 (1.84%)  1/189 (0.53%)  2/191 (1.05%) 
Cardiac failure congestive  1  5/160 (3.13%)  1/163 (0.61%)  2/189 (1.06%)  2/191 (1.05%) 
Atrial fibrillation  1  3/160 (1.88%)  3/163 (1.84%)  3/189 (1.59%)  4/191 (2.09%) 
Supraventricular tachycardia  1  2/160 (1.25%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Atrial flutter  1  2/160 (1.25%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Sinus bradycardia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Acute coronary syndrome  1  1/160 (0.63%)  0/163 (0.00%)  3/189 (1.59%)  1/191 (0.52%) 
Acute myocardial infarction  1  1/160 (0.63%)  2/163 (1.23%)  0/189 (0.00%)  0/191 (0.00%) 
Angina unstable  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Myocardial infarction  1  2/160 (1.25%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Angina pectoris  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Myocardial ischaemia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Atrioventricular block complete  1  0/160 (0.00%)  1/163 (0.61%)  2/189 (1.06%)  3/191 (1.57%) 
Cardiac arrest  1  0/160 (0.00%)  4/163 (2.45%)  0/189 (0.00%)  0/191 (0.00%) 
Cardio-respiratory arrest  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Ventricular tachycardia  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Ischaemic cardiomyopathy  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Cardiomyopathy  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Coronary artery disease  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Hypertensive heart disease  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Right ventricular failure  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Eye disorders         
Eyelid ptosis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Angle closure glaucoma  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Optic nerve sheath haemorrhage  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Amaurosis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Cataract  1  0/160 (0.00%)  0/163 (0.00%)  3/189 (1.59%)  0/191 (0.00%) 
Gastrointestinal disorders         
Diarrhoea  1  1/160 (0.63%)  8/163 (4.91%)  1/189 (0.53%)  6/191 (3.14%) 
Small intestinal obstruction  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  4/191 (2.09%) 
Vomiting  1  0/160 (0.00%)  2/163 (1.23%)  1/189 (0.53%)  0/191 (0.00%) 
Nausea  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Rectal haemorrhage  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Lower gastrointestinal haemorrhage  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Small intestinal haemorrhage  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Colitis  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Enterocolitis haemorrhagic  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Constipation  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  1/191 (0.52%) 
Gastrooesophageal reflux disease  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Intestinal obstruction  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Volvulus  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Gastritis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Intestinal perforation  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Large intestine perforation  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  0/191 (0.00%) 
Pancreatitis acute  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Pancreatitis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Faecaloma  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Abdominal wall haematoma  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Rectal prolapse  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Abdominal pain upper  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Intestinal ischaemia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Oesophagitis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Retroperitoneal haemorrhage  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Umbilical hernia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Inguinal hernia  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  0/191 (0.00%) 
Proctalgia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Dental caries  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Periodontal disease  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Duodenal ulcer  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Gastric volvulus  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Enteritis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Diverticular perforation  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Haemorrhoids  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Abdominal adhesions  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Stomatitis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
General disorders         
General physical health deterioration  1  5/160 (3.13%)  5/163 (3.07%)  2/189 (1.06%)  3/191 (1.57%) 
Influenza like illness  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Multiple organ dysfunction syndrome  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Pyrexia  1  3/160 (1.88%)  3/163 (1.84%)  3/189 (1.59%)  4/191 (2.09%) 
Sudden death  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  2/191 (1.05%) 
Death  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Asthenia  1  2/160 (1.25%)  1/163 (0.61%)  1/189 (0.53%)  1/191 (0.52%) 
Malaise  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  1/191 (0.52%) 
Fatigue  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Non-cardiac chest pain  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  1/191 (0.52%) 
Pain  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Chest pain  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Oedema peripheral  1  2/160 (1.25%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Generalised oedema  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Systemic inflammatory response syndrome  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Stent-graft endoleak  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Hyperthermia  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Complication associated with device  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Incarcerated hernia  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hepatobiliary disorders         
Cholecystitis acute  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  2/191 (1.05%) 
Cholecystitis  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Cholelithiasis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Cholecystitis chronic  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Hepatic function abnormal  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Cholangitis acute  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hepatic cirrhosis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Immune system disorders         
Anaphylactic reaction  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Infections and infestations         
Pneumonia  1  15/160 (9.38%)  20/163 (12.27%)  12/189 (6.35%)  19/191 (9.95%) 
Bronchitis  1  0/160 (0.00%)  3/163 (1.84%)  5/189 (2.65%)  4/191 (2.09%) 
Lung infection  1  1/160 (0.63%)  2/163 (1.23%)  1/189 (0.53%)  3/191 (1.57%) 
Lower respiratory tract infection  1  2/160 (1.25%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Atypical pneumonia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Pleural infection  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Sepsis  1  4/160 (2.50%)  4/163 (2.45%)  4/189 (2.12%)  1/191 (0.52%) 
Septic shock  1  4/160 (2.50%)  4/163 (2.45%)  0/189 (0.00%)  0/191 (0.00%) 
Pulmonary sepsis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Sepsis syndrome  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Urosepsis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Urinary tract infection  1  1/160 (0.63%)  3/163 (1.84%)  3/189 (1.59%)  5/191 (2.62%) 
Pyelonephritis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Cellulitis  1  2/160 (1.25%)  1/163 (0.61%)  2/189 (1.06%)  2/191 (1.05%) 
Pneumonia bacterial  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  2/191 (1.05%) 
Cystitis bacterial  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Superinfection bacterial  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Arthritis bacterial  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Gastroenteritis  1  1/160 (0.63%)  4/163 (2.45%)  2/189 (1.06%)  1/191 (0.52%) 
Diverticulitis  1  1/160 (0.63%)  0/163 (0.00%)  2/189 (1.06%)  0/191 (0.00%) 
Appendicitis  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  0/191 (0.00%) 
Appendicitis perforated  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Peritonitis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Staphylococcal sepsis  1  0/160 (0.00%)  3/163 (1.84%)  1/189 (0.53%)  0/191 (0.00%) 
Toxic shock syndrome staphylococcal  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Staphylococcal bacteraemia  1  1/160 (0.63%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Cellulitis staphylococcal  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Influenza  1  3/160 (1.88%)  1/163 (0.61%)  3/189 (1.59%)  2/191 (1.05%) 
Pneumonia influenzal  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Herpes zoster  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  3/191 (1.57%) 
Lower respiratory tract infection viral  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Viral upper respiratory tract infection  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Viral pharyngitis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Viral uveitis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Erysipelas  1  1/160 (0.63%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Pneumonia pneumococcal  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Tonsillitis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Upper respiratory tract infection  1  2/160 (1.25%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Bursitis infective  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Abscess jaw  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Osteomyelitis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Parainfluenzae virus infection  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Pneumonia parainfluenzae viral  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Bronchopulmonary aspergillosis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Sinusitis aspergillus  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Escherichia sepsis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Prostatitis Escherichia coli  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Pneumonia haemophilus  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Device related infection  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Respiratory tract infection  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Endocarditis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Pneumonia legionella  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Soft tissue infection  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Respiratory syncytial virus infection  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Clostridium difficile colitis  1  1/160 (0.63%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Campylobacter gastroenteritis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Meningitis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Tooth infection  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Bartholinitis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Fungal oesophagitis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hepatitis E  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Pseudomonal sepsis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Injury, poisoning and procedural complications         
Hip fracture  1  3/160 (1.88%)  0/163 (0.00%)  1/189 (0.53%)  4/191 (2.09%) 
Humerus fracture  1  0/160 (0.00%)  1/163 (0.61%)  2/189 (1.06%)  2/191 (1.05%) 
Femur fracture  1  1/160 (0.63%)  0/163 (0.00%)  4/189 (2.12%)  2/191 (1.05%) 
Femoral neck fracture  1  0/160 (0.00%)  1/163 (0.61%)  3/189 (1.59%)  1/191 (0.52%) 
Radius fracture  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  1/191 (0.52%) 
Ankle fracture  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Upper limb fracture  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Lower limb fracture  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Ulna fracture  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Spinal compression fracture  1  3/160 (1.88%)  0/163 (0.00%)  1/189 (0.53%)  1/191 (0.52%) 
Cervical vertebral fracture  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Thoracic vertebral fracture  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Lumbar vertebral fracture  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Spinal fracture  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Accidental overdose  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  2/191 (1.05%) 
Fall  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  2/191 (1.05%) 
Pelvic fracture  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  1/191 (0.52%) 
Aortic injury  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Joint dislocation  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Overdose  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Cystitis radiation  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Skin laceration  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Post procedural haemorrhage  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Urinary retention postoperative  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Investigations         
Platelet count decreased  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  2/191 (1.05%) 
International normalised ratio increased  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Weight decreased  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Blood alkaline phosphatase increased  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Staphylococcus test positive  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Blast cells present  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Blood creatinine increased  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Metabolism and nutrition disorders         
Dehydration  1  1/160 (0.63%)  6/163 (3.68%)  1/189 (0.53%)  3/191 (1.57%) 
Decreased appetite  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  5/191 (2.62%) 
Hypercalcaemia  1  4/160 (2.50%)  1/163 (0.61%)  1/189 (0.53%)  1/191 (0.52%) 
Hypocalcaemia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Hyponatraemia  1  1/160 (0.63%)  0/163 (0.00%)  2/189 (1.06%)  3/191 (1.57%) 
Fluid overload  1  1/160 (0.63%)  2/163 (1.23%)  0/189 (0.00%)  0/191 (0.00%) 
Hypervolaemia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Hypokalaemia  1  0/160 (0.00%)  2/163 (1.23%)  2/189 (1.06%)  0/191 (0.00%) 
Malnutrition  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Failure to thrive  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hypomagnesaemia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Diabetic ketoacidosis  1  2/160 (1.25%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Tumour lysis syndrome  1  1/160 (0.63%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Hyperglycaemia  1  2/160 (1.25%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  3/160 (1.88%)  2/163 (1.23%)  2/189 (1.06%)  2/191 (1.05%) 
Musculoskeletal chest pain  1  1/160 (0.63%)  2/163 (1.23%)  2/189 (1.06%)  0/191 (0.00%) 
Musculoskeletal pain  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Pain in extremity  1  2/160 (1.25%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Neck pain  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Pathological fracture  1  4/160 (2.50%)  3/163 (1.84%)  4/189 (2.12%)  2/191 (1.05%) 
Osteoporotic fracture  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  2/191 (1.05%) 
Bone pain  1  1/160 (0.63%)  2/163 (1.23%)  0/189 (0.00%)  0/191 (0.00%) 
Spinal pain  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Kyphosis  1  2/160 (1.25%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Spinal stenosis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Arthralgia  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Chondrocalcinosis pyrophosphate  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Chondrocalcinosis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Crystal arthropathy  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Haemarthrosis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Arthritis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Sarcopenia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Muscular weakness  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Bone lesion  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Intervertebral disc protrusion  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Spinal osteoarthritis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Synovitis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Osteolysis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Mobility decreased  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Basal cell carcinoma  1  1/160 (0.63%)  2/163 (1.23%)  5/189 (2.65%)  11/191 (5.76%) 
Squamous cell carcinoma of skin  1  1/160 (0.63%)  0/163 (0.00%)  4/189 (2.12%)  5/191 (2.62%) 
Bowen's disease  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  1/191 (0.52%) 
Plasma cell myeloma  1  1/160 (0.63%)  3/163 (1.84%)  1/189 (0.53%)  0/191 (0.00%) 
Plasma cell leukaemia  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Prostate cancer  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  3/191 (1.57%) 
Prostate cancer recurrent  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Adenocarcinoma of colon  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Colorectal adenocarcinoma  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Adenocarcinoma pancreas  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Pancreatic carcinoma  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Malignant melanoma  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  1/191 (0.52%) 
Metastatic malignant melanoma  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Superficial spreading melanoma stage unspecified  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Bladder transitional cell carcinoma  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Gastric cancer  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Lung carcinoma cell type unspecified stage I  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Lung neoplasm malignant  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Breast cancer  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Gallbladder adenocarcinoma  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Erythroleukaemia  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Colon adenoma  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Squamous cell carcinoma of lung  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Cancer pain  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Transitional cell cancer of the renal pelvis and ureter  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Papillary thyroid cancer  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Sarcomatoid carcinoma  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Squamous cell carcinoma  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Large granular lymphocytosis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Chronic myeloid leukaemia  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Metastases to liver  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Nervous system disorders         
Cerebrovascular accident  1  2/160 (1.25%)  2/163 (1.23%)  1/189 (0.53%)  3/191 (1.57%) 
Ischaemic stroke  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  1/191 (0.52%) 
Cerebral haematoma  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Haemorrhage intracranial  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Intraventricular haemorrhage  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Thalamic infarction  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Thalamus haemorrhage  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Cerebral haemorrhage  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Cerebral infarction  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Embolic stroke  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Lacunar infarction  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Syncope  1  1/160 (0.63%)  5/163 (3.07%)  5/189 (2.65%)  3/191 (1.57%) 
Lethargy  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Loss of consciousness  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Epilepsy  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  2/191 (1.05%) 
Seizure  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Transient ischaemic attack  1  0/160 (0.00%)  2/163 (1.23%)  2/189 (1.06%)  0/191 (0.00%) 
Presyncope  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  2/191 (1.05%) 
Peripheral sensory neuropathy  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Spinal claudication  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Spinal cord compression  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Cervicobrachial syndrome  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Demyelinating polyneuropathy  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Hepatic encephalopathy  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Nervous system disorder  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Encephalopathy  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hypoxic-ischaemic encephalopathy  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Posterior reversible encephalopathy syndrome  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Peroneal nerve palsy  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hyperaesthesia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Hemiplegia  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Product Issues         
Device breakage  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Device loosening  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Device malfunction  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Psychiatric disorders         
Confusional state  1  1/160 (0.63%)  1/163 (0.61%)  5/189 (2.65%)  2/191 (1.05%) 
Delirium  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Depression  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  1/191 (0.52%) 
Anxiety  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Hallucination  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Obsessive thoughts  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Renal and urinary disorders         
Acute kidney injury  1  8/160 (5.00%)  5/163 (3.07%)  2/189 (1.06%)  3/191 (1.57%) 
Renal failure  1  3/160 (1.88%)  1/163 (0.61%)  0/189 (0.00%)  2/191 (1.05%) 
Renal impairment  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Chronic kidney disease  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Haematuria  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Urinary retention  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Urinary tract obstruction  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Focal segmental glomerulosclerosis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Nephritis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Renal tubular disorder  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Reproductive system and breast disorders         
Cystocele  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Testicular oedema  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Benign prostatic hyperplasia  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  0/191 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Asthma  1  2/160 (1.25%)  1/163 (0.61%)  0/189 (0.00%)  3/191 (1.57%) 
Chronic obstructive pulmonary disease  1  0/160 (0.00%)  2/163 (1.23%)  0/189 (0.00%)  1/191 (0.52%) 
Pulmonary embolism  1  7/160 (4.38%)  4/163 (2.45%)  5/189 (2.65%)  1/191 (0.52%) 
Respiratory failure  1  1/160 (0.63%)  3/163 (1.84%)  1/189 (0.53%)  1/191 (0.52%) 
Acute respiratory failure  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Dyspnoea  1  0/160 (0.00%)  5/163 (3.07%)  0/189 (0.00%)  0/191 (0.00%) 
Pneumonia aspiration  1  2/160 (1.25%)  3/163 (1.84%)  1/189 (0.53%)  0/191 (0.00%) 
Pneumonitis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Interstitial lung disease  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Lung infiltration  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Acute pulmonary oedema  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Acute respiratory distress syndrome  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Pulmonary oedema  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Epistaxis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Hypoxia  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Haemoptysis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Paranasal cyst  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Pleural effusion  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Skin and subcutaneous tissue disorders         
Rash maculo-papular  1  0/160 (0.00%)  4/163 (2.45%)  0/189 (0.00%)  1/191 (0.52%) 
Rash macular  1  0/160 (0.00%)  2/163 (1.23%)  0/189 (0.00%)  0/191 (0.00%) 
Rash papular  1  0/160 (0.00%)  2/163 (1.23%)  0/189 (0.00%)  0/191 (0.00%) 
Rash erythematous  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Rash generalised  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Toxic skin eruption  1  0/160 (0.00%)  2/163 (1.23%)  0/189 (0.00%)  0/191 (0.00%) 
Drug eruption  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Drug reaction with eosinophilia and systemic symptoms  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Stevens-Johnson syndrome  1  1/160 (0.63%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Toxic epidermal necrolysis  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Dermatitis allergic  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Dermal cyst  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Decubitus ulcer  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Vascular disorders         
Deep vein thrombosis  1  3/160 (1.88%)  2/163 (1.23%)  5/189 (2.65%)  3/191 (1.57%) 
Venous thrombosis limb  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Hypotension  1  1/160 (0.63%)  1/163 (0.61%)  2/189 (1.06%)  1/191 (0.52%) 
Orthostatic hypotension  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Peripheral ischaemia  1  0/160 (0.00%)  1/163 (0.61%)  1/189 (0.53%)  0/191 (0.00%) 
Peripheral artery stenosis  1  0/160 (0.00%)  0/163 (0.00%)  0/189 (0.00%)  1/191 (0.52%) 
Phlebitis  1  0/160 (0.00%)  1/163 (0.61%)  2/189 (1.06%)  0/191 (0.00%) 
Aortic stenosis  1  0/160 (0.00%)  0/163 (0.00%)  1/189 (0.53%)  0/191 (0.00%) 
Embolism  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
Thrombosis  1  1/160 (0.63%)  0/163 (0.00%)  0/189 (0.00%)  0/191 (0.00%) 
Hypovolaemic shock  1  0/160 (0.00%)  1/163 (0.61%)  0/189 (0.00%)  0/191 (0.00%) 
1
Term from vocabulary, MedDRA: 22.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   160/160 (100.00%)   163/163 (100.00%)   189/189 (100.00%)   191/191 (100.00%) 
Blood and lymphatic system disorders         
Anaemia  1  56/160 (35.00%)  51/163 (31.29%)  50/189 (26.46%)  55/191 (28.80%) 
Thrombocytopenia  1  15/160 (9.38%)  32/163 (19.63%)  11/189 (5.82%)  24/191 (12.57%) 
Neutropenia  1  36/160 (22.50%)  15/163 (9.20%)  48/189 (25.40%)  38/191 (19.90%) 
Cardiac disorders         
Cardiac failure  1  3/160 (1.88%)  9/163 (5.52%)  0/189 (0.00%)  0/191 (0.00%) 
Atrial fibrillation  1  8/160 (5.00%)  6/163 (3.68%)  11/189 (5.82%)  6/191 (3.14%) 
Palpitations  1  0/160 (0.00%)  0/163 (0.00%)  8/189 (4.23%)  11/191 (5.76%) 
Ear and labyrinth disorders         
Vertigo  1  0/160 (0.00%)  0/163 (0.00%)  17/189 (8.99%)  21/191 (10.99%) 
Hypoacusis  1  0/160 (0.00%)  0/163 (0.00%)  6/189 (3.17%)  10/191 (5.24%) 
Eye disorders         
Cataract  1  0/160 (0.00%)  0/163 (0.00%)  41/189 (21.69%)  54/191 (28.27%) 
Vision blurred  1  0/160 (0.00%)  0/163 (0.00%)  22/189 (11.64%)  25/191 (13.09%) 
Dry eye  1  0/160 (0.00%)  0/163 (0.00%)  6/189 (3.17%)  17/191 (8.90%) 
Gastrointestinal disorders         
Diarrhoea  1  48/160 (30.00%)  68/163 (41.72%)  113/189 (59.79%)  144/191 (75.39%) 
Constipation  1  61/160 (38.13%)  59/163 (36.20%)  82/189 (43.39%)  91/191 (47.64%) 
Nausea  1  35/160 (21.88%)  55/163 (33.74%)  62/189 (32.80%)  76/191 (39.79%) 
Vomiting  1  13/160 (8.13%)  41/163 (25.15%)  32/189 (16.93%)  64/191 (33.51%) 
Dry mouth  1  14/160 (8.75%)  11/163 (6.75%)  12/189 (6.35%)  13/191 (6.81%) 
Stomatitis  1  9/160 (5.63%)  10/163 (6.13%)  7/189 (3.70%)  15/191 (7.85%) 
Abdominal pain upper  1  13/160 (8.13%)  8/163 (4.91%)  29/189 (15.34%)  23/191 (12.04%) 
Abdominal pain  1  10/160 (6.25%)  7/163 (4.29%)  38/189 (20.11%)  28/191 (14.66%) 
Dyspepsia  1  16/160 (10.00%)  5/163 (3.07%)  22/189 (11.64%)  21/191 (10.99%) 
Haemorrhoids  1  0/160 (0.00%)  0/163 (0.00%)  15/189 (7.94%)  12/191 (6.28%) 
Gastrooesophageal reflux disease  1  0/160 (0.00%)  0/163 (0.00%)  9/189 (4.76%)  11/191 (5.76%) 
Abdominal distension  1  0/160 (0.00%)  0/163 (0.00%)  11/189 (5.82%)  10/191 (5.24%) 
Toothache  1  0/160 (0.00%)  0/163 (0.00%)  14/189 (7.41%)  8/191 (4.19%) 
Inguinal hernia  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  5/191 (2.62%) 
General disorders         
Oedema peripheral  1  52/160 (32.50%)  66/163 (40.49%)  64/189 (33.86%)  105/191 (54.97%) 
Fatigue  1  53/160 (33.13%)  41/163 (25.15%)  52/189 (27.51%)  68/191 (35.60%) 
Asthenia  1  44/160 (27.50%)  36/163 (22.09%)  52/189 (27.51%)  59/191 (30.89%) 
Pyrexia  1  20/160 (12.50%)  30/163 (18.40%)  29/189 (15.34%)  33/191 (17.28%) 
Peripheral swelling  1  8/160 (5.00%)  8/163 (4.91%)  11/189 (5.82%)  17/191 (8.90%) 
Malaise  1  0/160 (0.00%)  0/163 (0.00%)  15/189 (7.94%)  16/191 (8.38%) 
Influenza like illness  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  16/191 (8.38%) 
Non-cardiac chest pain  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  14/191 (7.33%) 
Chills  1  10/160 (6.25%)  11/163 (6.75%)  7/189 (3.70%)  11/191 (5.76%) 
Infections and infestations         
Urinary tract infection  1  14/160 (8.75%)  19/163 (11.66%)  27/189 (14.29%)  29/191 (15.18%) 
Bronchitis  1  13/160 (8.13%)  13/163 (7.98%)  49/189 (25.93%)  73/191 (38.22%) 
Nasopharyngitis  1  13/160 (8.13%)  13/163 (7.98%)  71/189 (37.57%)  62/191 (32.46%) 
Upper respiratory tract infection  1  17/160 (10.63%)  10/163 (6.13%)  47/189 (24.87%)  48/191 (25.13%) 
Herpes zoster  1  0/160 (0.00%)  0/163 (0.00%)  4/189 (2.12%)  23/191 (12.04%) 
Rhinitis  1  0/160 (0.00%)  0/163 (0.00%)  21/189 (11.11%)  22/191 (11.52%) 
Pneumonia  1  0/160 (0.00%)  0/163 (0.00%)  16/189 (8.47%)  22/191 (11.52%) 
Sinusitis  1  0/160 (0.00%)  0/163 (0.00%)  6/189 (3.17%)  17/191 (8.90%) 
Conjunctivitis  1  0/160 (0.00%)  0/163 (0.00%)  5/189 (2.65%)  17/191 (8.90%) 
Gastroenteritis  1  0/160 (0.00%)  0/163 (0.00%)  15/189 (7.94%)  14/191 (7.33%) 
Influenza  1  0/160 (0.00%)  0/163 (0.00%)  19/189 (10.05%)  13/191 (6.81%) 
Cystitis  1  0/160 (0.00%)  0/163 (0.00%)  12/189 (6.35%)  13/191 (6.81%) 
Cellulitis  1  0/160 (0.00%)  0/163 (0.00%)  2/189 (1.06%)  11/191 (5.76%) 
Pharyngitis  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  10/191 (5.24%) 
Tooth infection  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  9/191 (4.71%) 
Injury, poisoning and procedural complications         
Fall  1  9/160 (5.63%)  8/163 (4.91%)  33/189 (17.46%)  40/191 (20.94%) 
Contusion  1  0/160 (0.00%)  0/163 (0.00%)  20/189 (10.58%)  16/191 (8.38%) 
Procedural pain  1  0/160 (0.00%)  0/163 (0.00%)  11/189 (5.82%)  6/191 (3.14%) 
Investigations         
Weight decreased  1  20/160 (12.50%)  24/163 (14.72%)  30/189 (15.87%)  35/191 (18.32%) 
Neutrophil count decreased  1  11/160 (6.88%)  5/163 (3.07%)  13/189 (6.88%)  18/191 (9.42%) 
Blood creatinine increased  1  8/160 (5.00%)  6/163 (3.68%)  11/189 (5.82%)  15/191 (7.85%) 
Platelet count decreased  1  0/160 (0.00%)  0/163 (0.00%)  12/189 (6.35%)  14/191 (7.33%) 
Metabolism and nutrition disorders         
Decreased appetite  1  45/160 (28.13%)  34/163 (20.86%)  34/189 (17.99%)  45/191 (23.56%) 
Hypokalaemia  1  16/160 (10.00%)  33/163 (20.25%)  30/189 (15.87%)  38/191 (19.90%) 
Dehydration  1  11/160 (6.88%)  10/163 (6.13%)  5/189 (2.65%)  11/191 (5.76%) 
Hyponatraemia  1  6/160 (3.75%)  10/163 (6.13%)  0/189 (0.00%)  0/191 (0.00%) 
Hypophosphataemia  1  2/160 (1.25%)  9/163 (5.52%)  0/189 (0.00%)  0/191 (0.00%) 
Hypocalcaemia  1  13/160 (8.13%)  6/163 (3.68%)  11/189 (5.82%)  4/191 (2.09%) 
Hypomagnesaemia  1  8/160 (5.00%)  6/163 (3.68%)  11/189 (5.82%)  11/191 (5.76%) 
Gout  1  0/160 (0.00%)  0/163 (0.00%)  14/189 (7.41%)  10/191 (5.24%) 
Hyperglycaemia  1  0/160 (0.00%)  0/163 (0.00%)  15/189 (7.94%)  6/191 (3.14%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  34/160 (21.25%)  26/163 (15.95%)  68/189 (35.98%)  64/191 (33.51%) 
Pain in extremity  1  29/160 (18.13%)  18/163 (11.04%)  47/189 (24.87%)  50/191 (26.18%) 
Arthralgia  1  19/160 (11.88%)  17/163 (10.43%)  65/189 (34.39%)  57/191 (29.84%) 
Muscle spasms  1  27/160 (16.88%)  15/163 (9.20%)  50/189 (26.46%)  52/191 (27.23%) 
Musculoskeletal chest pain  1  12/160 (7.50%)  12/163 (7.36%)  27/189 (14.29%)  25/191 (13.09%) 
Muscular weakness  1  12/160 (7.50%)  9/163 (5.52%)  18/189 (9.52%)  16/191 (8.38%) 
Musculoskeletal pain  1  6/160 (3.75%)  9/163 (5.52%)  50/189 (26.46%)  42/191 (21.99%) 
Neck pain  1  9/160 (5.63%)  7/163 (4.29%)  24/189 (12.70%)  21/191 (10.99%) 
Myalgia  1  9/160 (5.63%)  5/163 (3.07%)  23/189 (12.17%)  31/191 (16.23%) 
Bone pain  1  10/160 (6.25%)  4/163 (2.45%)  22/189 (11.64%)  19/191 (9.95%) 
Osteoarthritis  1  0/160 (0.00%)  0/163 (0.00%)  13/189 (6.88%)  20/191 (10.47%) 
Arthritis  1  0/160 (0.00%)  0/163 (0.00%)  4/189 (2.12%)  16/191 (8.38%) 
Joint swelling  1  0/160 (0.00%)  0/163 (0.00%)  11/189 (5.82%)  11/191 (5.76%) 
Pathological fracture  1  0/160 (0.00%)  0/163 (0.00%)  20/189 (10.58%)  9/191 (4.71%) 
Nervous system disorders         
Dizziness  1  31/160 (19.38%)  27/163 (16.56%)  36/189 (19.05%)  31/191 (16.23%) 
Peripheral sensory neuropathy  1  27/160 (16.88%)  23/163 (14.11%)  57/189 (30.16%)  83/191 (43.46%) 
Headache  1  22/160 (13.75%)  15/163 (9.20%)  35/189 (18.52%)  32/191 (16.75%) 
Tremor  1  23/160 (14.37%)  14/163 (8.59%)  27/189 (14.29%)  19/191 (9.95%) 
Dysgeusia  1  14/160 (8.75%)  9/163 (5.52%)  12/189 (6.35%)  32/191 (16.75%) 
Paraesthesia  1  13/160 (8.13%)  9/163 (5.52%)  21/189 (11.11%)  24/191 (12.57%) 
Somnolence  1  8/160 (5.00%)  3/163 (1.84%)  0/189 (0.00%)  0/191 (0.00%) 
Hypoaesthesia  1  0/160 (0.00%)  0/163 (0.00%)  11/189 (5.82%)  16/191 (8.38%) 
Sciatica  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  16/191 (8.38%) 
Neuropathy peripheral  1  0/160 (0.00%)  0/163 (0.00%)  9/189 (4.76%)  14/191 (7.33%) 
Syncope  1  0/160 (0.00%)  0/163 (0.00%)  6/189 (3.17%)  13/191 (6.81%) 
Psychiatric disorders         
Insomnia  1  27/160 (16.88%)  30/163 (18.40%)  68/189 (35.98%)  70/191 (36.65%) 
Anxiety  1  15/160 (9.38%)  22/163 (13.50%)  21/189 (11.11%)  25/191 (13.09%) 
Depression  1  10/160 (6.25%)  18/163 (11.04%)  15/189 (7.94%)  23/191 (12.04%) 
Confusional state  1  15/160 (9.38%)  16/163 (9.82%)  11/189 (5.82%)  10/191 (5.24%) 
Agitation  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  11/191 (5.76%) 
Irritability  1  0/160 (0.00%)  0/163 (0.00%)  11/189 (5.82%)  4/191 (2.09%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  24/160 (15.00%)  28/163 (17.18%)  37/189 (19.58%)  52/191 (27.23%) 
Dyspnoea  1  32/160 (20.00%)  21/163 (12.88%)  26/189 (13.76%)  38/191 (19.90%) 
Rhinorrhoea  1  0/160 (0.00%)  0/163 (0.00%)  7/189 (3.70%)  14/191 (7.33%) 
Epistaxis  1  11/160 (6.88%)  7/163 (4.29%)  16/189 (8.47%)  12/191 (6.28%) 
Dyspnoea exertional  1  0/160 (0.00%)  0/163 (0.00%)  14/189 (7.41%)  12/191 (6.28%) 
Oropharyngeal pain  1  0/160 (0.00%)  0/163 (0.00%)  12/189 (6.35%)  12/191 (6.28%) 
Productive cough  1  8/160 (5.00%)  2/163 (1.23%)  5/189 (2.65%)  12/191 (6.28%) 
Hiccups  1  0/160 (0.00%)  0/163 (0.00%)  10/189 (5.29%)  5/191 (2.62%) 
Dysphonia  1  0/160 (0.00%)  0/163 (0.00%)  12/189 (6.35%)  3/191 (1.57%) 
Skin and subcutaneous tissue disorders         
Rash maculo-papular  1  18/160 (11.25%)  37/163 (22.70%)  20/189 (10.58%)  43/191 (22.51%) 
Pruritus  1  9/160 (5.63%)  13/163 (7.98%)  23/189 (12.17%)  26/191 (13.61%) 
Dry skin  1  8/160 (5.00%)  11/163 (6.75%)  22/189 (11.64%)  31/191 (16.23%) 
Rash macular  1  3/160 (1.88%)  11/163 (6.75%)  11/189 (5.82%)  27/191 (14.14%) 
Erythema  1  2/160 (1.25%)  11/163 (6.75%)  19/189 (10.05%)  15/191 (7.85%) 
Rash  1  7/160 (4.38%)  10/163 (6.13%)  6/189 (3.17%)  16/191 (8.38%) 
Night sweats  1  9/160 (5.63%)  9/163 (5.52%)  0/189 (0.00%)  0/191 (0.00%) 
Rash papular  1  8/160 (5.00%)  8/163 (4.91%)  4/189 (2.12%)  12/191 (6.28%) 
Rash erythematous  1  10/160 (6.25%)  6/163 (3.68%)  3/189 (1.59%)  18/191 (9.42%) 
Hyperhidrosis  1  8/160 (5.00%)  5/163 (3.07%)  0/189 (0.00%)  0/191 (0.00%) 
Pruritus generalised  1  0/160 (0.00%)  0/163 (0.00%)  7/189 (3.70%)  14/191 (7.33%) 
Alopecia  1  0/160 (0.00%)  0/163 (0.00%)  8/189 (4.23%)  13/191 (6.81%) 
Urticaria  1  0/160 (0.00%)  0/163 (0.00%)  5/189 (2.65%)  10/191 (5.24%) 
Vascular disorders         
Hypertension  1  9/160 (5.63%)  6/163 (3.68%)  18/189 (9.52%)  24/191 (12.57%) 
Hypotension  1  12/160 (7.50%)  17/163 (10.43%)  11/189 (5.82%)  15/191 (7.85%) 
Haematoma  1  0/160 (0.00%)  0/163 (0.00%)  7/189 (3.70%)  10/191 (5.24%) 
Flushing  1  0/160 (0.00%)  0/163 (0.00%)  12/189 (6.35%)  6/191 (3.14%) 
Hot flush  1  0/160 (0.00%)  0/163 (0.00%)  14/189 (7.41%)  4/191 (2.09%) 
Deep vein thrombosis  1  15/160 (9.38%)  5/163 (3.07%)  13/189 (6.88%)  4/191 (2.09%) 
1
Term from vocabulary, MedDRA: 22.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier: NCT01850524    
Other Study ID Numbers: C16014
2013-000326-54 ( EudraCT Number )
U1111-1158-2646 ( Registry Identifier: WHO )
163325 ( Registry Identifier: HC-CTD )
First Submitted: April 26, 2013
First Posted: May 9, 2013
Results First Submitted: November 20, 2020
Results First Posted: February 1, 2021
Last Update Posted: February 1, 2021