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Ibrutinib Plus Venetoclax in Subjects With Treatment-naive Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma (CLL/SLL) (Captivate)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02910583
Recruitment Status : Completed
First Posted : September 22, 2016
Results First Posted : February 18, 2022
Last Update Posted : April 3, 2024
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Pharmacyclics LLC.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Leukemia
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Interventions Drug: ibrutinib
Drug: venetoclax
Drug: Placebo
Enrollment 323
Recruitment Details

This study was conducted at 39 centers in the United States (US), Australia, New Zealand, Spain, and Italy.

This record presents results data as of the date of database lock for the primary analysis (15 December 2020).
Pre-assignment Details Upon completion of a pre-randomization phase, participants in the MRD Cohort with confirmed undetectable minimal residual disease (uMRD) were randomized to blinded ibrutinib or placebo. Participants in the MRD Cohort with uMRD not confirmed were randomized to open-label ibrutinib or open-label ibrutinib + venetoclax.
Arm/Group Title Fixed Duration (FD) Cohort: All Treated Minimal Residual Disease (MRD) Cohort: All Treated
Hide Arm/Group Description Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until disease progression or unacceptable toxicity. Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Period Title: Overall Study
Started 159 164
MRD Cohort/ Not Randomized 0 [1] 15
MRD Cohort/ Confirmed uMRD: Randomized to Ibrutinib (Blinded) 0 [1] 43
MRD Cohort/ Confirmed uMRD: Randomized Placebo (Blinded) 0 [1] 43
MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label) 0 [1] 31
MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label) 0 [1] 32
Completed [2] 152 157
Not Completed 7 7
Reason Not Completed
Withdrawal by Subject             6             7
Other, Not Specified             1             0
[1]
Not applicable to this cohort.
[2]
Participants who were still on study or died as of the data extraction.
Arm/Group Title FD Cohort: All Treated MRD Cohort: All Treated Total
Hide Arm/Group Description Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity. Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 159 164 323
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 164 participants 323 participants
< 65 years
114
  71.7%
123
  75.0%
237
  73.4%
>= 65 years
45
  28.3%
41
  25.0%
86
  26.6%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 164 participants 323 participants
Female
53
  33.3%
61
  37.2%
114
  35.3%
Male
106
  66.7%
103
  62.8%
209
  64.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 164 participants 323 participants
Hispanic or Latino
5
   3.1%
11
   6.7%
16
   5.0%
Not Hispanic or Latino
149
  93.7%
150
  91.5%
299
  92.6%
Unknown or Not Reported
5
   3.1%
3
   1.8%
8
   2.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 159 participants 164 participants 323 participants
American Indian or Alaska Native
0
   0.0%
1
   0.6%
1
   0.3%
Asian
3
   1.9%
5
   3.0%
8
   2.5%
Native Hawaiian or Other Pacific Islander
1
   0.6%
0
   0.0%
1
   0.3%
Black or African American
1
   0.6%
2
   1.2%
3
   0.9%
White
147
  92.5%
147
  89.6%
294
  91.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
7
   4.4%
9
   5.5%
16
   5.0%
1.Primary Outcome
Title MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants
Hide Description DFS is defined as time from randomization date to MRD-positive relapse, or disease progression per investigator assessment (per 2008 International Workshop for Chronic Lymphocytic Leukemia [IWCLL] criteria [Halleck et al]) or death from any cause, whichever occurred first. 1-year DFS estimated using Kaplan-Meier method at 12 months landmark time.
Time Frame 1 year after randomization
Hide Outcome Measure Data
Hide Analysis Population Description
Confirmed uMRD Randomized Population: all participants who achieved confirmed MRD-negative clinical response at the end of the pre-randomization phase, randomized to either blinded placebo arm or blinded ibrutinib arm.
Arm/Group Title MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded)
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Overall Number of Participants Analyzed 43 43
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
100.0
(100.0 to 100.0)
95.3
(82.7 to 98.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded), MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1475
Comments P-value is from Z test for the difference of two proportions based on Kaplan-Meier estimates with standard error of each arm computed using Greenwood's formula.
Method Z test
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Rates
Estimated Value 4.7
Confidence Interval (2-Sided) 95%
-1.6 to 10.9
Estimation Comments comparison: ibrutininb vs. placebo
2.Primary Outcome
Title FD Cohort: Complete Response Rate (CRR; Complete Response/Complete Response With Incomplete Blood Count Recovery [CR/CRi]) Rate
Hide Description CR/CRi rate is defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi) per 2008 IWCLL criteria (halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier.
Time Frame From the first dose of ibrutinib to the first confirmed PD up to primary analysis data cutoff date of 15 December 2020. Median follow-up time was 27.9 months at the time of the primary analysis.
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol, the primary analysis of the primary endpoint for the FD cohort was based on the FD Cohort, Non-Del 17p Population only.
Arm/Group Title FD Cohort, Non-Del 17p Population: All Treated FD Cohort: All Treated
Hide Arm/Group Description:
Participants in the FD cohort without del 17p abnormality (according to non-missing baseline fluorescent in situ hybridization [FISH] results) received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 136 159
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
55.9
(47.5 to 64.2)
55.3
(47.6 to 63.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FD Cohort, Non-Del 17p Population: All Treated
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments One-sided P-value from asymptotic test for the binomial proportion (CRR <= 37% vs CRR > 37%).
Method asymptotic test for binomial proportion
Comments [Not Specified]
3.Secondary Outcome
Title MRD Cohort: CRR (CR/CRi Rate)
Hide Description CR/CRi rate is defined as the percentage of participants achieving a best overall response of CR or CRi per 2008 IWCLL criteria (Halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier.
Time Frame From the first dose of ibrutinib to the first confirmed PD (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
MRD Cohort - All Treated Population
Arm/Group Title MRD Cohort: All Treated MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded) MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
Hide Arm/Group Description:

Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase).

Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity.

Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. If venetoclax were to be reintroduced, venetoclax treatment was to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 164 43 43 31 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
62.8
(55.4 to 70.2)
72.1
(58.7 to 85.5)
60.5
(45.9 to 75.1)
74.2
(58.8 to 89.6)
56.3
(39.1 to 73.4)
4.Secondary Outcome
Title MRD Cohort: Overall Response Rate (ORR)
Hide Description ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), partial response (PR), or PR with lymphocytosis (PRL) evaluated in accordance with the 2008 IWCLL criteria (Halleck et al). Participants who did not have any postbaseline response assessment were considered as non-responders. This table is based on response assessments performed on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurs earlier. Kaplan-Meier estimate.
Time Frame From the first dose of ibrutinib to the first confirmed PD (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
MRD Cohort - All Treated Population
Arm/Group Title MRD Cohort: All Treated MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded) MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 164 43 43 31 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
97.0
(94.3 to 99.6)
100.0
(100.0 to 100.0)
100.0
(100.0 to 100.0)
100.0
(100.0 to 100.0)
100.0
(100.0 to 100.0)
5.Secondary Outcome
Title MRD Cohort: Duration of Response (DOR)
Hide Description Duration of response was calculated for participants achieving a response (CR, CRi, nPR, PR) based on 2008 IWCLL response criteria (Halleck et al.) and defined as the interval between the date of initial documentation of a response including PR with lymphocytosis, until disease progression (PD) or death from any cause, whichever occurred first. As the median DOR was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of DOR at 36 months landmark time was presented.
Time Frame From initial documentation of a response, until PD or death from any cause, whichever occurs first. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
MRD Cohort: Participants who achieved PR or better
Arm/Group Title MRD Cohort: All Treated MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded) MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. If venetoclax were to be reintroduced, venetoclax treatment was to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 159 43 43 31 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
94.7
(88.6 to 97.4)
100.0
(100.0 to 100.0)
95.3
(82.7 to 98.8)
96.7
(78.6 to 99.5)
96.7
(78.6 to 99.5)
6.Secondary Outcome
Title MRD Cohort: MRD-Negativity Rate (MRR)
Hide Description

MRR is defined as the percentage of participants who achieve MRD-negativity in either peripheral blood (PB) or bone marrow (BM) and achieve confirmed clinical response PR or better per 2008 IWCLL criteria (Halleck et al.). MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10^4), as assessed by flow cytometry of a PB or BM aspirate sample. Confirmed MRD-negative response for randomization purposes requires MRD-negativity serially over at least 3 cycles, with negativity in both BM and PB.

This rate is calculated in the uMRD Not Confirmed randomized population during the period from randomization date and before any reintroduced treatment.
Time Frame From randomization date until before any reintroduced treatment. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
MRD All Treated Population
Arm/Group Title MRD Cohort: All Treated MRD Cohort/uMRD Not Confirmed: All Participants MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 164 63 31 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
PB or BM
81.1
(75.1 to 87.1)
63.5
(51.6 to 75.4)
51.6
(34.0 to 69.2)
75.0
(60.0 to 90.0)
BM
76.8
(70.4 to 83.3)
54.0
(41.7 to 66.3)
41.9
(24.6 to 59.3)
65.6
(49.2 to 82.1)
PB
79.3
(73.1 to 85.5)
58.7
(46.6 to 70.9)
48.4
(30.8 to 66.0)
68.8
(52.7 to 84.8)
7.Secondary Outcome
Title MRD Cohort: Tumor Lysis Syndrome (TLS) Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in)
Hide Description TLS risk reduction was summarized by the percentage of participants with TLS risk reduced from high at baseline to medium or low after ibrutinib lead-in. A reduction in TLS risk from high risk to medium or low risk is clinically meaningful because there is a reduction in the extent of TLS monitoring and risk of hospitalization. TLS risk category is defined as the tumor burden category, where: Low=All lymph nodes (LN) < 5 cm AND absolute lymphocyte count (ALC) < 25 x 10^9/L; Medium=Any LN 5 cm to < 10 cm OR ALC ≥ 25 x 10^9/L; High=Any LN ≥ 10 cm OR ALC ≥ 25 x10^9/L AND any LN ≥ 5 cm.
Time Frame Baseline, and last post-baseline value on or prior to venetoclax first dose date (cycle 4 day 1) or, for participants who never received venetoclax, the post-baseline value closest to cycle 4 day 1 (i.e. 84 days after the first dose date of ibrutinib).
Hide Outcome Measure Data
Hide Analysis Population Description
MRD Cohort: All Treated Population with baseline TLS high risk
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 40
Measure Type: Number
Unit of Measure: percentage of participants
90.0
8.Secondary Outcome
Title MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 36 Months Landmark Time
Hide Description PFS was defined as time from the first dose date of study treatment until disease progression (PD) or death from any cause, whichever occurs first. Assessment of PD was conducted in accordance with the 2008 IWCLL criteria (Halleck et al). As the median PFS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of PFS rate at 36 months landmark time was presented.
Time Frame From the first dose of ibrutinib to the first confirmed PD or death. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).
Hide Outcome Measure Data
Hide Analysis Population Description
MRD Cohort - All Treated Population
Arm/Group Title MRD Cohort: All Treated MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded) MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
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Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 164 43 43 31 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
95.6
(91.0 to 97.9)
100.0
(100.0 to 100.0)
95.3
(82.7 to 98.8)
96.7
(78.6 to 99.5)
96.7
(78.6 to 99.5)
9.Secondary Outcome
Title MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 36 Months Landmark Time
Hide Description OS is defined as the time from the first dose date of study treatment until date of death due to any cause. As the median OS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of OS rate at 36 months landmark time was presented.
Time Frame From the first dose of ibrutinib to the first confirmed PD or death (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).
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Hide Analysis Population Description
MRD Cohort - All Treated Population
Arm/Group Title MRD Cohort: All Treated MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded) MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
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Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 164 43 43 31 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
99.4
(95.6 to 99.9)
100.0
(100.0 to 100.0)
100.0
(100.0 to 100.0)
96.7
(78.6 to 99.5)
100.0
(100.0 to 100.0)
10.Secondary Outcome
Title MRD Cohort: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs
Hide Description An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires unplanned in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity of events were graded according to the Common Terminology Criteria for Adverse Events version 4.03: mild=grade1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. Causal relation of study drug and event was assessed as not related, unlikely, possibly or probably related to the study drug.
Time Frame From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Treatment duration for the MRD cohort was 28.7 months for ibrutinib and 15.4 for venetoclax.
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Hide Analysis Population Description
All Treated Population
Arm/Group Title MRD Cohort: All Treated MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded) MRD Cohort/Confirmed uMRD: Randomized to Placebo (Blinded) MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib MRD Cohort/uMRD Not Confirmed: Randomized to Open-Label Ibrutinib + Venetoclax
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, PD, or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.
Overall Number of Participants Analyzed 164 43 43 31 32
Measure Type: Number
Unit of Measure: percentage of participants
Any TEAE 100.0 100.0 100.0 100.0 100.0
Any Grade >=3 TEAE 73.8 79.1 65.1 71.0 75.0
Any Ibrutinib (Ibr)-Related TEAE 94.5 93.0 93.0 96.8 93.8
Any Grade >=3 Ibrutinib-Related TEAE 57.9 55.8 48.8 61.3 62.5
Any Venetoclax (Ven)-Related TEAE 80.5 86.0 76.7 80.6 96.9
Any Grade >=3 Venetoclax-Related TEAE 44.5 51.2 34.9 45.2 56.3
Any TEAE Leading to Ibr or Ven Discontinuation 12.8 4.7 0 9.7 12.5
Any TEAE Leading to Ibr or Ven Discontinuation: Ibr Only 7.3 2.3 0 9.7 3.1
Any TEAE Leading to Ibr or Ven Discontinuation: Ven Only 1.2 2.3 0 0 0
Any TEAE Leading to Ibr or Ven Discontinuation: Both Ibr and Ven 4.3 0 0 0 9.4
Any TEAE Leading to Ibr or Ven Dose Reduction 24.4 20.9 23.3 22.6 31.3
Any TEAE Leading to Ibr Only Dose Reduction 14.6 14.0 9.3 16.1 21.9
Any TEAE Leading to Ven Only Dose Reduction 5.5 4.7 11.6 0 3.1
Any TEAE Leading to Both Ibr and Ven Dose Reduction 4.3 2.3 2.3 6.5 6.3
Any SAE 31.1 27.9 18.6 35.5 37.5
Any Grade >= 3 SAE 26.2 25.6 16.3 29.0 28.1
Any SAE Related to Ibr or Ven 18.3 16.3 11.6 22.6 18.8
Any Ibr-related SAE 15.9 11.6 9.3 19.4 18.8
Any Ven-related SAE 5.5 4.7 7.0 9.7 3.1
Fatal TEAE 0.6 0 0 3.2 0
Major Hemorrhage TEAE 2.4 2.3 0 3.2 6.3
Grade >= 3 Major Hemorrhage TEAE 1.8 2.3 0 3.2 3.1
Major Hemorrhage SAE 2.4 2.3 0 3.2 6.3
11.Secondary Outcome
Title FD Cohort: ORR
Hide Description ORR is defined as the percentage of participants who achieve a best overall response CR, CRi, nPR, PR, or PRL as evaluated by investigator using 2008 IWCLL criteria (Halleck et al.). Participants who did not have any postbaseline response assessment were considered as non-responders. This table is based on response assessments performed on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurs earlier. Kaplan-Meier estimate.
Time Frame From the first dose of ibrutinib to the first confirmed PD up to primary analysis data cutoff date of 15 December 2020. Median follow-up time was 27.9 months at the time of the primary analysis.
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FD Cohort: All Treated Population
Arm/Group Title FD Cohort, Non-Del 17p Population: All Treated FD Cohort: All Treated
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Participants in the FD cohort without del 17p abnormality (according to non-missing baseline FISH results) received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 136 159
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
95.6
(92.1 to 99.0)
96.2
(93.3 to 99.2)
12.Secondary Outcome
Title FD Cohort: DOR
Hide Description Duration of response was calculated for participants achieving a response (CR, CRi, nPR, PR) based on 2008 IWCLL response criteria (Halleck et al.) and defined as the interval between the date of initial documentation of a response including PR with lymphocytosis, until disease progression (PD) or death from any cause, whichever occurred first. As the median DOR was not reached as of the median 27.9 months study follow-up, the Kaplan-Meier estimate of DOR at 24 months landmark time was presented.
Time Frame From initial documentation of a response, until PD or death from any cause, whichever occurs first. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).
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FD Cohort: Participants who achieved PR or better.
Arm/Group Title FD Cohort, Non-Del 17p Population: All Treated FD Cohort: All Treated
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Participants in the FD cohort without del 17p abnormality (according to non-missing baseline FISH results) received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 130 153
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
96.1
(90.8 to 98.3)
94.7
(89.6 to 97.3)
13.Secondary Outcome
Title FD Cohort: MRR
Hide Description MRR is defined as the percentage of participants who achieve MRD-negativity in either peripheral blood (PB) or bone marrow (BM) and achieve confirmed clinical response PR or better per 2008 IWCLL criteria (Halleck et al.). MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10^4), as assessed by flow cytometry of a PB or BM aspirate sample. Confirmed MRD-negative response for randomization purposes requires MRD-negativity serially over at least 3 cycles, with negativity in both BM and PB.
Time Frame From randomization date until before any reintroduced treatment. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).
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Hide Analysis Population Description
FD Cohort - All Treated Population
Arm/Group Title FD Cohort, Non-Del 17p Population: All Treated FD Cohort: All Treated
Hide Arm/Group Description:
Participants in the FD cohort without del 17p abnormality (according to non-missing baseline FISH results) received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 136 159
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
BM or PB
78.7
(71.8 to 85.6)
78.6
(72.2 to 85.0)
BM
61.8
(53.6 to 69.9)
59.7
(52.1 to 67.4)
PB
76.5
(69.3 to 83.6)
76.7
(70.2 to 83.3)
14.Secondary Outcome
Title FD Cohort: Kaplan-Meier Estimate of PFS Rate at 24 Months Landmark Time
Hide Description PFS was defined as time from the first dose date of study treatment until disease progression (PD) or death from any cause, whichever occurs first. Assessment of PD was conducted in accordance with the 2008 IWCLL criteria (Halleck et al). As the median PFS was not reached as of the median 27.9 months study follow-up, the Kaplan-Meier estimate of PFS rate at 24 months landmark time was presented.
Time Frame From the first dose of ibrutinib to the first confirmed PD or death. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).
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FD Cohort - All Treated Population
Arm/Group Title FD Cohort, Non-Del 17p Population: All Treated FD Cohort: All Treated
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Participants in the FD cohort without del 17p abnormality (according to non-missing baseline FISH results) received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 136 159
Median (95% Confidence Interval)
Unit of Measure: percentage of participants
96.2
(91.1 to 98.4)
94.8
(89.8 to 97.3)
15.Secondary Outcome
Title FD Cohort: Kaplan-Meier Estimate of OS Rate at 24 Months Landmark Time
Hide Description OS is defined as the time from the first dose date of study treatment until date of death due to any cause. As the median OS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of OS rate at 24 months landmark time was presented.
Time Frame From the first dose of ibrutinib to time of death. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).
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Hide Analysis Population Description
FD Cohort - All Treated Population
Arm/Group Title FD Cohort, Non-Del 17p Population: All Treated FD Cohort: All Treated
Hide Arm/Group Description:
Participants in the FD cohort without del 17p abnormality (according to non-missing baseline FISH results) received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 136 159
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
97.7
(93.2 to 99.3)
98.1
(94.2 to 99.4)
16.Secondary Outcome
Title FD Cohort: TLS Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in)
Hide Description TLS risk reduction was summarized by the percentage of participants with TLS risk reduced from high at baseline to medium or low after ibrutinib lead-in. A reduction in TLS risk from high risk to medium or low risk is clinically meaningful because there is a reduction in the extent of TLS monitoring and risk of hospitalization. TLS risk category is defined as the tumor burden category, where: Low=All lymph nodes (LN) < 5 cm AND absolute lymphocyte count (ALC) < 25 x 10^9/L; Medium=Any LN 5 cm to < 10 cm OR ALC ≥ 25 x 10^9/L; High=Any LN ≥ 10 cm OR ALC ≥ 25 x10^9/L AND any LN ≥ 5 cm.
Time Frame Baseline, and last post-baseline value on or prior to venetoclax first dose date (cycle 4 day 1) or, for participants who never received venetoclax, the post-baseline value closest to cycle 4 day 1 (i.e. 84 days after the first dose date of ibrutinib).
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FD Cohort: All Treated Population with baseline TLS high risk
Arm/Group Title FD Cohort: All Treated
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Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 34
Measure Type: Number
Unit of Measure: percentage of participants
94.1
17.Secondary Outcome
Title FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs
Hide Description An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires unplanned in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity of events were graded according to the Common Terminology Criteria for Adverse Events version 4.03: mild=grade1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. Causal relation of study drug and event was assessed as not related, unlikely, possibly or probably related to the study drug.
Time Frame From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Treatment duration for the FD cohort was 13.3 months for ibrutinib and 11.1 for venetoclax.
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FD Cohort: All Treated Population
Arm/Group Title FD Cohort: All Treated
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Participants received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 159
Measure Type: Number
Unit of Measure: percentage of participants
Any TEAE 99.4
Any Grade >=3 TEAE 62.3
Any Ibrutinib (Ibr)-Related TEAE 92.5
Any Grade >=3 Ibrutinib-Related TEAE 44.7
Any Venetoclax (Ven)-Related TEAE 84.3
Any Grade >=3 Venetoclax-Related TEAE 44.7
Any TEAE Leading to Ibr or Ven Discontinuation 5.0
Any TEAE Leading to Ibr or Ven Discontinuation: Ibr Only 3.1
Any TEAE Leading to Ibr or Ven Discontinuation: Ven Only 0
Any TEAE Leading to Ibr or Ven Discontinuation: Both Ibr and Ven 1.9
Any TEAE Leading to Ibr or Ven Dose Reduction 20.8
Any TEAE Leading to Ibr Only Dose Reduction 5.7
Any TEAE Leading to Ven Only Dose Reduction 11.3
Any TEAE Leading to Both Ibr and Ven Dose Reduction 3.8
Any SAE 22.6
Any Grade >= 3 SAE 19.5
Any SAE Related to Ibr or Ven 13.2
Any Ibr-related SAE 11.3
Any Ven-related SAE 8.2
Fatal TEAE 0.6
Major Hemorrhage TEAE 1.9
Grade >= 3 Major Hemorrhage TEAE 1.3
Major Hemorrhage SAE 1.3
18.Secondary Outcome
Title MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax)
Hide Description [Not Specified]
Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 130
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
88.5
(74.3%)
19.Secondary Outcome
Title MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Time to Cmax (Tmax); Time of Last Measurable Concentration (Tlast); Terminal Elimination Half-Life (t1/2,Term)
Hide Description [Not Specified]
Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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Hide Analysis Population Description
MRD Cohort: All treated participants who were evaluable for each PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 130
Median (Full Range)
Unit of Measure: hours
tmax
2.00
(0.970 to 7.00)
tlast
24.0
(5.75 to 24.0)
t1/2term
5.30
(1.47 to 10.5)
20.Secondary Outcome
Title MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Area Under the Plasma Concentration-Time Curve (AUC) Over the Last 24-hour Dosing Interval (AUC0-24h); AUC From Time Zero to the Time of Last Quantifiable Concentration (AUClast)
Hide Description [Not Specified]
Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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Hide Analysis Population Description
MRD Cohort: All treated participants who were evaluable for each PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 128
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUC0-24h
504
(76.3%)
AUClast
480
(78.5%)
21.Secondary Outcome
Title MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Terminal Elimination Rate Constant (λz)
Hide Description [Not Specified]
Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
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Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 91
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/h
0.132
(44.5%)
22.Secondary Outcome
Title MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Apparent Total Clearance at Steady-State (CLss/F)
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Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 128
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/h
833
(90.9%)
23.Secondary Outcome
Title MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Cmax
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Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 131
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
3034
(56.3%)
24.Secondary Outcome
Title MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Tmax
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Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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Hide Analysis Population Description
MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 131
Median (Full Range)
Unit of Measure: hours
6.00
(0.00 to 8.08)
25.Secondary Outcome
Title MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: AUC0-24h
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Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 131
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
48993
(66.2%)
26.Secondary Outcome
Title MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: CLss/F
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Time Frame Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
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Hide Analysis Population Description
MRD Cohort: All treated participants who were evaluable for PK analysis. Data were collected for the MRD cohort only, and without regard to uMRD confirmation status/randomization group, as pre-specified for this analysis.
Arm/Group Title MRD Cohort: All Treated
Hide Arm/Group Description:
Participants received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until clinical PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg tablets orally once daily on a continuous schedule until PD or unacceptable toxicity.
Overall Number of Participants Analyzed 131
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/h
8.16
(69.7%)
Time Frame From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Mean treatment duration for the MRD cohort was 28.7 months for ibrutinib and 15.4 months for venetoclax; for the FD cohort mean treatment duration was 13.3 months for ibrutinib and 11.1 months for venetoclax.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Fixed Duration Cohort: Overall Study MRD Cohort: All Participants Pre-Randomization MRD Cohort: All Participants Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Overall Study
Hide Arm/Group Description Participants in the Fixed Duration Cohort received 420 mg of single agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until PD or unacceptable toxicity. Participants in the MRD Cohort received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants in the MRD Cohort received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive blinded ibrutinib 420 mg or placebo orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg or open-label ibrutinib 420 mg plus venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants in the MRD Cohort with confirmed uMRD received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants in the MRD Cohort with confirmed uMRD received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (prerandomization phase). Participants with confirmed uMRD were randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, clinical PD, or unacceptable toxicity. Participants in the MRD Cohort with confirmed uMRD received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants in the MRD Cohort with confirmed uMRD received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD were randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, clinical PD or unacceptable toxicity. Participants in the MRD Cohort with uMRD not confirmed received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants in the MRD Cohort with uMRD not confirmed received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Participants in the MRD Cohort with uMRD not confirmed received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants in the MRD Cohort with uMRD not confirmed received 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with uMRD not confirmed were randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
All-Cause Mortality
Fixed Duration Cohort: Overall Study MRD Cohort: All Participants Pre-Randomization MRD Cohort: All Participants Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Overall Study
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/159 (1.89%)      0/164 (0.00%)      1/164 (0.61%)      0/43 (0.00%)      0/43 (0.00%)      0/43 (0.00%)      0/43 (0.00%)      0/31 (0.00%)      1/31 (3.23%)      0/32 (0.00%)      0/32 (0.00%)    
Hide Serious Adverse Events
Fixed Duration Cohort: Overall Study MRD Cohort: All Participants Pre-Randomization MRD Cohort: All Participants Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Overall Study
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   36/159 (22.64%)      34/164 (20.73%)      51/164 (31.10%)      7/43 (16.28%)      12/43 (27.91%)      8/43 (18.60%)      8/43 (18.60%)      8/31 (25.81%)      11/31 (35.48%)      3/32 (9.38%)      12/32 (37.50%)    
Blood and lymphatic system disorders                       
ANAEMIA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
FEBRILE NEUTROPENIA † 1  1/159 (0.63%)  1 3/164 (1.83%)  3 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 3/43 (6.98%)  3 3/43 (6.98%)  3 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
HAEMOLYSIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
NEUTROPENIA † 1  1/159 (0.63%)  1 1/164 (0.61%)  1 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
Cardiac disorders                       
ATRIAL FIBRILLATION † 1  2/159 (1.26%)  2 4/164 (2.44%)  6 5/164 (3.05%)  7 1/43 (2.33%)  1 2/43 (4.65%)  2 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  3 1/31 (3.23%)  3 0/32 (0.00%)  0 0/32 (0.00%)  0
BRADYCARDIA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CARDIAC ARREST † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CARDIAC FAILURE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
CONGESTIVE CARDIOMYOPATHY † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
CORONARY ARTERY STENOSIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
PALPITATIONS † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
PERICARDITIS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
SINUS BRADYCARDIA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
VENTRICULAR TACHYARRHYTHMIA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Congenital, familial and genetic disorders                       
MALFORMATION VENOUS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Ear and labyrinth disorders                       
VERTIGO † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
VERTIGO POSITIONAL † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Eye disorders                       
EYE HAEMORRHAGE † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
MACULAR OEDEMA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
RETINAL HAEMORRHAGE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Gastrointestinal disorders                       
ABDOMINAL PAIN † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
COLITIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
DIARRHOEA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
NAUSEA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
RETROPERITONEAL HAEMORRHAGE † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
VOMITING † 1  2/159 (1.26%)  2 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
General disorders                       
NON-CARDIAC CHEST PAIN † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
PAIN † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
PYREXIA † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  2
SUDDEN CARDIAC DEATH † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
SUDDEN DEATH † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Hepatobiliary disorders                       
BILE DUCT STONE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CHOLELITHIASIS † 1  1/159 (0.63%)  1 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
HEPATITIS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Immune system disorders                       
ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY POSITIVE VASCULITIS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Infections and infestations                       
ABDOMINAL ABSCESS † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 2/164 (1.22%)  2 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
APPENDICEAL ABSCESS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
APPENDICITIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
BRONCHITIS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CAMPYLOBACTER INFECTION † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CELLULITIS † 1  4/159 (2.52%)  4 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
COVID-19 † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
DISSEMINATED VARICELLA ZOSTER VIRUS INFECTION † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
EMPYEMA † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
ESCHERICHIA BACTERAEMIA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
GASTROENTERITIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
INFLUENZA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
LOWER RESPIRATORY TRACT INFECTION BACTERIAL † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
LYMPHADENITIS BACTERIAL † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
PHARYNGITIS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
PILONIDAL CYST † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
PNEUMONIA † 1  3/159 (1.89%)  4 3/164 (1.83%)  3 7/164 (4.27%)  7 1/43 (2.33%)  1 3/43 (6.98%)  3 0/43 (0.00%)  0 1/43 (2.33%)  1 2/31 (6.45%)  2 2/31 (6.45%)  2 0/32 (0.00%)  0 2/32 (6.25%)  2
PYELONEPHRITIS † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
SALMONELLOSIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
SKIN INFECTION † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
STAPHYLOCOCCAL BACTERAEMIA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
VIRAL INFECTION † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
VIRAL UPPER RESPIRATORY TRACT INFECTION † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
WEST NILE VIRAL INFECTION † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Injury, poisoning and procedural complications                       
FEMUR FRACTURE † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
SPINAL COMPRESSION FRACTURE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Investigations                       
BLOOD PRESSURE DECREASED † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
INFLUENZA B VIRUS TEST POSITIVE † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
Metabolism and nutrition disorders                       
HYPERPHOSPHATAEMIA † 1  1/159 (0.63%)  1 1/164 (0.61%)  1 1/164 (0.61%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
HYPONATRAEMIA † 1  2/159 (1.26%)  2 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Musculoskeletal and connective tissue disorders                       
ARTHRALGIA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
ARTHRITIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
BACK PAIN † 1  1/159 (0.63%)  2 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
OSTEOPOROSIS † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
SPINAL SYNOVIAL CYST † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                       
INVASIVE DUCTAL BREAST CARCINOMA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
LUNG ADENOCARCINOMA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
MYELODYSPLASTIC SYNDROME † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
PROSTATE CANCER † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
RENAL CANCER † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
RENAL ONCOCYTOMA † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Nervous system disorders                       
ALTERED STATE OF CONSCIOUSNESS † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
AMNESIA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CEREBRAL HAEMORRHAGE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
CEREBRAL VENOUS SINUS THROMBOSIS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
EPILEPSY † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
HEADACHE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
HEPATIC ENCEPHALOPATHY † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
ISCHAEMIC STROKE † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
SUBARACHNOID HAEMORRHAGE † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
TRANSIENT ISCHAEMIC ATTACK † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 2/164 (1.22%)  2 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
Psychiatric disorders                       
ANXIETY † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
SCHIZOPHRENIA † 1  1/159 (0.63%)  2 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Renal and urinary disorders                       
ACUTE KIDNEY INJURY † 1  1/159 (0.63%)  1 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
RENAL COLIC † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Reproductive system and breast disorders                       
MENORRHAGIA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                       
BRONCHOSPASM † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
DYSPNOEA † 1  2/159 (1.26%)  2 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
EMPHYSEMA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
PULMONARY EMBOLISM † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
RESPIRATORY DISTRESS † 1  0/159 (0.00%)  0 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Skin and subcutaneous tissue disorders                       
DERMATITIS BULLOUS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 1/164 (0.61%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
Vascular disorders                       
CIRCULATORY COLLAPSE † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 0/164 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
HYPERTENSION † 1  1/159 (0.63%)  1 0/164 (0.00%)  0 1/164 (0.61%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
1
Term from vocabulary, MedDRA 23.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Fixed Duration Cohort: Overall Study MRD Cohort: All Participants Pre-Randomization MRD Cohort: All Participants Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Ibr) Overall Study MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Pre-Randomization MRD Cohort: Confirmed uMRD (IbrVen->Pbo) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->Ibr) Overall Study MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Pre-Randomization MRD Cohort: uMRD Not Confirmed (IbrVen->IbrVen) Overall Study
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   156/159 (98.11%)      162/164 (98.78%)      162/164 (98.78%)      43/43 (100.00%)      43/43 (100.00%)      42/43 (97.67%)      43/43 (100.00%)      31/31 (100.00%)      31/31 (100.00%)      32/32 (100.00%)      32/32 (100.00%)    
Blood and lymphatic system disorders                       
ANAEMIA † 1  10/159 (6.29%)  16 10/164 (6.10%)  22 12/164 (7.32%)  25 3/43 (6.98%)  7 4/43 (9.30%)  9 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  7 3/31 (9.68%)  8 4/32 (12.50%)  6 4/32 (12.50%)  6
INCREASED TENDENCY TO BRUISE † 1  35/159 (22.01%)  44 35/164 (21.34%)  47 40/164 (24.39%)  57 11/43 (25.58%)  15 12/43 (27.91%)  17 6/43 (13.95%)  7 7/43 (16.28%)  9 9/31 (29.03%)  13 11/31 (35.48%)  18 6/32 (18.75%)  8 8/32 (25.00%)  11
NEUTROPENIA † 1  65/159 (40.88%)  169 68/164 (41.46%)  223 72/164 (43.90%)  241 24/43 (55.81%)  102 24/43 (55.81%)  105 16/43 (37.21%)  35 16/43 (37.21%)  36 10/31 (32.26%)  26 12/31 (38.71%)  29 12/32 (37.50%)  40 14/32 (43.75%)  52
SPONTANEOUS HAEMATOMA † 1  2/159 (1.26%)  4 4/164 (2.44%)  8 4/164 (2.44%)  12 1/43 (2.33%)  2 1/43 (2.33%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  4 1/32 (3.13%)  4 1/32 (3.13%)  5
THROMBOCYTOPENIA † 1  21/159 (13.21%)  38 30/164 (18.29%)  59 32/164 (19.51%)  68 7/43 (16.28%)  13 8/43 (18.60%)  19 5/43 (11.63%)  9 6/43 (13.95%)  10 4/31 (12.90%)  10 5/31 (16.13%)  12 10/32 (31.25%)  20 10/32 (31.25%)  21
Cardiac disorders                       
ATRIAL FIBRILLATION † 1  5/159 (3.14%)  7 8/164 (4.88%)  10 12/164 (7.32%)  17 2/43 (4.65%)  2 2/43 (4.65%)  2 3/43 (6.98%)  3 3/43 (6.98%)  3 2/31 (6.45%)  2 3/31 (9.68%)  3 0/32 (0.00%)  0 3/32 (9.38%)  5
PALPITATIONS † 1  15/159 (9.43%)  17 21/164 (12.80%)  25 23/164 (14.02%)  32 10/43 (23.26%)  13 10/43 (23.26%)  16 6/43 (13.95%)  6 7/43 (16.28%)  9 0/31 (0.00%)  0 1/31 (3.23%)  1 4/32 (12.50%)  5 5/32 (15.63%)  7
SINUS TACHYCARDIA † 1  2/159 (1.26%)  4 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
Ear and labyrinth disorders                       
VERTIGO † 1  3/159 (1.89%)  3 7/164 (4.27%)  9 7/164 (4.27%)  9 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  2 1/43 (2.33%)  3 2/31 (6.45%)  2 2/31 (6.45%)  2 3/32 (9.38%)  4 3/32 (9.38%)  4
Endocrine disorders                       
HYPOTHYROIDISM † 1  1/159 (0.63%)  1 1/164 (0.61%)  1 3/164 (1.83%)  3 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 2/32 (6.25%)  2
Eye disorders                       
DRY EYE † 1  3/159 (1.89%)  3 6/164 (3.66%)  6 7/164 (4.27%)  7 2/43 (4.65%)  2 2/43 (4.65%)  2 1/43 (2.33%)  1 2/43 (4.65%)  2 1/31 (3.23%)  1 1/31 (3.23%)  1 2/32 (6.25%)  2 2/32 (6.25%)  2
VISION BLURRED † 1  2/159 (1.26%)  2 9/164 (5.49%)  10 12/164 (7.32%)  14 2/43 (4.65%)  3 4/43 (9.30%)  6 0/43 (0.00%)  0 0/43 (0.00%)  0 3/31 (9.68%)  3 3/31 (9.68%)  3 3/32 (9.38%)  3 4/32 (12.50%)  4
Gastrointestinal disorders                       
ABDOMINAL DISCOMFORT † 1  4/159 (2.52%)  5 10/164 (6.10%)  12 10/164 (6.10%)  12 5/43 (11.63%)  5 5/43 (11.63%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  2 1/31 (3.23%)  2 2/32 (6.25%)  3 2/32 (6.25%)  3
ABDOMINAL DISTENSION † 1  10/159 (6.29%)  11 10/164 (6.10%)  15 12/164 (7.32%)  17 3/43 (6.98%)  5 4/43 (9.30%)  6 2/43 (4.65%)  5 3/43 (6.98%)  6 3/31 (9.68%)  3 4/31 (12.90%)  4 0/32 (0.00%)  0 0/32 (0.00%)  0
ABDOMINAL PAIN † 1  13/159 (8.18%)  16 25/164 (15.24%)  29 26/164 (15.85%)  31 7/43 (16.28%)  7 7/43 (16.28%)  7 9/43 (20.93%)  10 9/43 (20.93%)  10 2/31 (6.45%)  2 2/31 (6.45%)  2 5/32 (15.63%)  6 6/32 (18.75%)  8
ABDOMINAL PAIN UPPER † 1  13/159 (8.18%)  14 16/164 (9.76%)  21 20/164 (12.20%)  25 3/43 (6.98%)  3 4/43 (9.30%)  4 3/43 (6.98%)  3 3/43 (6.98%)  4 5/31 (16.13%)  10 7/31 (22.58%)  12 4/32 (12.50%)  4 5/32 (15.63%)  5
APHTHOUS ULCER † 1  8/159 (5.03%)  10 8/164 (4.88%)  11 8/164 (4.88%)  11 2/43 (4.65%)  3 2/43 (4.65%)  3 5/43 (11.63%)  7 5/43 (11.63%)  7 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
CONSTIPATION † 1  25/159 (15.72%)  31 27/164 (16.46%)  36 31/164 (18.90%)  42 7/43 (16.28%)  10 10/43 (23.26%)  13 7/43 (16.28%)  8 8/43 (18.60%)  10 7/31 (22.58%)  9 8/31 (25.81%)  11 6/32 (18.75%)  9 6/32 (18.75%)  10
DIARRHOEA † 1  99/159 (62.26%)  201 115/164 (70.12%)  290 117/164 (71.34%)  406 33/43 (76.74%)  83 33/43 (76.74%)  85 27/43 (62.79%)  51 27/43 (62.79%)  60 23/31 (74.19%)  48 23/31 (74.19%)  56 26/32 (81.25%)  93 28/32 (87.50%)  199
DRY MOUTH † 1  6/159 (3.77%)  6 7/164 (4.27%)  7 8/164 (4.88%)  8 4/43 (9.30%)  4 4/43 (9.30%)  4 2/43 (4.65%)  2 2/43 (4.65%)  2 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
DYSPEPSIA † 1  29/159 (18.24%)  37 28/164 (17.07%)  32 30/164 (18.29%)  35 10/43 (23.26%)  10 10/43 (23.26%)  10 5/43 (11.63%)  5 5/43 (11.63%)  8 6/31 (19.35%)  10 7/31 (22.58%)  12 6/32 (18.75%)  6 7/32 (21.88%)  7
FLATULENCE † 1  6/159 (3.77%)  6 6/164 (3.66%)  6 7/164 (4.27%)  7 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 2/43 (4.65%)  2 0/31 (0.00%)  0 1/31 (3.23%)  1 3/32 (9.38%)  3 3/32 (9.38%)  3
GASTROOESOPHAGEAL REFLUX DISEASE † 1  15/159 (9.43%)  17 26/164 (15.85%)  30 27/164 (16.46%)  32 6/43 (13.95%)  7 7/43 (16.28%)  8 4/43 (9.30%)  6 4/43 (9.30%)  6 6/31 (19.35%)  7 6/31 (19.35%)  8 7/32 (21.88%)  7 7/32 (21.88%)  7
GINGIVAL BLEEDING † 1  3/159 (1.89%)  3 5/164 (3.05%)  6 7/164 (4.27%)  8 1/43 (2.33%)  1 2/43 (4.65%)  2 1/43 (2.33%)  1 1/43 (2.33%)  1 3/31 (9.68%)  4 4/31 (12.90%)  5 0/32 (0.00%)  0 0/32 (0.00%)  0
GLOSSODYNIA † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 2/164 (1.22%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 2/31 (6.45%)  3 0/32 (0.00%)  0 0/32 (0.00%)  0
HAEMORRHOIDAL HAEMORRHAGE † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 4/164 (2.44%)  4 1/43 (2.33%)  1 2/43 (4.65%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 2/32 (6.25%)  2
HAEMORRHOIDS † 1  1/159 (0.63%)  2 4/164 (2.44%)  4 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 3/43 (6.98%)  3 3/43 (6.98%)  3 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
MOUTH ULCERATION † 1  24/159 (15.09%)  30 14/164 (8.54%)  18 16/164 (9.76%)  28 3/43 (6.98%)  3 5/43 (11.63%)  7 3/43 (6.98%)  3 4/43 (9.30%)  4 5/31 (16.13%)  7 5/31 (16.13%)  9 3/32 (9.38%)  5 3/32 (9.38%)  9
NAUSEA † 1  68/159 (42.77%)  97 73/164 (44.51%)  103 78/164 (47.56%)  120 20/43 (46.51%)  29 20/43 (46.51%)  34 19/43 (44.19%)  24 19/43 (44.19%)  25 18/31 (58.06%)  31 20/31 (64.52%)  36 9/32 (28.13%)  11 12/32 (37.50%)  17
ORAL PAIN † 1  1/159 (0.63%)  1 3/164 (1.83%)  3 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
RECTAL HAEMORRHAGE † 1  2/159 (1.26%)  2 2/164 (1.22%)  2 4/164 (2.44%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 3/32 (9.38%)  3
STOMATITIS † 1  21/159 (13.21%)  33 24/164 (14.63%)  47 27/164 (16.46%)  59 8/43 (18.60%)  10 8/43 (18.60%)  11 8/43 (18.60%)  13 8/43 (18.60%)  13 3/31 (9.68%)  6 6/31 (19.35%)  11 3/32 (9.38%)  15 3/32 (9.38%)  21
TOOTHACHE † 1  2/159 (1.26%)  2 5/164 (3.05%)  5 6/164 (3.66%)  6 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  1 1/31 (3.23%)  1 2/32 (6.25%)  2 2/32 (6.25%)  2
VOMITING † 1  33/159 (20.75%)  48 35/164 (21.34%)  53 41/164 (25.00%)  68 13/43 (30.23%)  20 13/43 (30.23%)  24 6/43 (13.95%)  10 6/43 (13.95%)  10 5/31 (16.13%)  9 7/31 (22.58%)  15 6/32 (18.75%)  8 10/32 (31.25%)  13
General disorders                       
ASTHENIA † 1  7/159 (4.40%)  11 10/164 (6.10%)  13 11/164 (6.71%)  14 2/43 (4.65%)  2 2/43 (4.65%)  2 2/43 (4.65%)  3 3/43 (6.98%)  4 2/31 (6.45%)  4 2/31 (6.45%)  4 2/32 (6.25%)  2 3/32 (9.38%)  3
CHEST DISCOMFORT † 1  3/159 (1.89%)  3 3/164 (1.83%)  3 5/164 (3.05%)  5 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 2/43 (4.65%)  2 2/31 (6.45%)  2 4/31 (12.90%)  4 0/32 (0.00%)  0 0/32 (0.00%)  0
CHEST PAIN † 1  4/159 (2.52%)  4 4/164 (2.44%)  4 5/164 (3.05%)  5 2/43 (4.65%)  2 2/43 (4.65%)  2 0/43 (0.00%)  0 1/43 (2.33%)  1 1/31 (3.23%)  1 2/31 (6.45%)  2 1/32 (3.13%)  1 1/32 (3.13%)  1
CHILLS † 1  5/159 (3.14%)  5 10/164 (6.10%)  12 13/164 (7.93%)  17 2/43 (4.65%)  2 4/43 (9.30%)  4 4/43 (9.30%)  5 5/43 (11.63%)  6 1/31 (3.23%)  1 1/31 (3.23%)  1 3/32 (9.38%)  4 4/32 (12.50%)  7
FATIGUE † 1  39/159 (24.53%)  50 46/164 (28.05%)  67 48/164 (29.27%)  81 11/43 (25.58%)  15 13/43 (30.23%)  21 15/43 (34.88%)  23 18/43 (41.86%)  32 10/31 (32.26%)  16 10/31 (32.26%)  20 7/32 (21.88%)  9 7/32 (21.88%)  12
INFLUENZA LIKE ILLNESS † 1  6/159 (3.77%)  6 5/164 (3.05%)  5 8/164 (4.88%)  8 1/43 (2.33%)  1 2/43 (4.65%)  2 0/43 (0.00%)  0 1/43 (2.33%)  1 3/31 (9.68%)  3 4/31 (12.90%)  4 0/32 (0.00%)  0 1/32 (3.13%)  1
INJECTION SITE BRUISING † 1  0/159 (0.00%)  0 4/164 (2.44%)  4 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
NON-CARDIAC CHEST PAIN † 1  1/159 (0.63%)  1 2/164 (1.22%)  2 4/164 (2.44%)  5 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 3/31 (9.68%)  4 1/32 (3.13%)  1 1/32 (3.13%)  1
OEDEMA PERIPHERAL † 1  11/159 (6.92%)  12 13/164 (7.93%)  20 18/164 (10.98%)  26 3/43 (6.98%)  5 5/43 (11.63%)  7 5/43 (11.63%)  7 6/43 (13.95%)  8 1/31 (3.23%)  1 3/31 (9.68%)  4 3/32 (9.38%)  6 4/32 (12.50%)  7
PAIN † 1  4/159 (2.52%)  7 6/164 (3.66%)  6 8/164 (4.88%)  8 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 2/43 (4.65%)  2 3/31 (9.68%)  3 5/31 (16.13%)  5 2/32 (6.25%)  2 2/32 (6.25%)  2
PERIPHERAL SWELLING † 1  11/159 (6.92%)  11 4/164 (2.44%)  4 6/164 (3.66%)  6 0/43 (0.00%)  0 0/43 (0.00%)  0 2/43 (4.65%)  2 2/43 (4.65%)  2 1/31 (3.23%)  1 2/31 (6.45%)  2 1/32 (3.13%)  1 2/32 (6.25%)  2
PYREXIA † 1  21/159 (13.21%)  36 21/164 (12.80%)  25 26/164 (15.85%)  33 3/43 (6.98%)  3 6/43 (13.95%)  6 4/43 (9.30%)  4 4/43 (9.30%)  4 2/31 (6.45%)  2 3/31 (9.68%)  4 8/32 (25.00%)  9 9/32 (28.13%)  12
Immune system disorders                       
SEASONAL ALLERGY † 1  1/159 (0.63%)  1 5/164 (3.05%)  5 7/164 (4.27%)  7 1/43 (2.33%)  1 1/43 (2.33%)  1 2/43 (4.65%)  2 2/43 (4.65%)  2 0/31 (0.00%)  0 2/31 (6.45%)  2 2/32 (6.25%)  2 2/32 (6.25%)  2
Infections and infestations                       
BRONCHITIS † 1  5/159 (3.14%)  6 4/164 (2.44%)  4 5/164 (3.05%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 2/31 (6.45%)  2 3/31 (9.68%)  3 1/32 (3.13%)  1 1/32 (3.13%)  1
CELLULITIS † 1  7/159 (4.40%)  7 10/164 (6.10%)  13 11/164 (6.71%)  15 2/43 (4.65%)  2 2/43 (4.65%)  2 5/43 (11.63%)  5 5/43 (11.63%)  5 0/31 (0.00%)  0 0/31 (0.00%)  0 3/32 (9.38%)  6 4/32 (12.50%)  8
CONJUNCTIVITIS † 1  5/159 (3.14%)  6 4/164 (2.44%)  4 8/164 (4.88%)  8 0/43 (0.00%)  0 1/43 (2.33%)  1 2/43 (4.65%)  2 2/43 (4.65%)  2 0/31 (0.00%)  0 2/31 (6.45%)  2 1/32 (3.13%)  1 2/32 (6.25%)  2
FOLLICULITIS † 1  3/159 (1.89%)  3 4/164 (2.44%)  8 6/164 (3.66%)  11 3/43 (6.98%)  7 4/43 (9.30%)  9 0/43 (0.00%)  0 2/43 (4.65%)  2 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
FUNGAL SKIN INFECTION † 1  4/159 (2.52%)  4 5/164 (3.05%)  5 6/164 (3.66%)  6 3/43 (6.98%)  3 3/43 (6.98%)  3 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
FURUNCLE † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
GASTROENTERITIS † 1  5/159 (3.14%)  6 6/164 (3.66%)  6 7/164 (4.27%)  7 4/43 (9.30%)  4 4/43 (9.30%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  2 0/32 (0.00%)  0 1/32 (3.13%)  1
HERPES ZOSTER † 1  1/159 (0.63%)  1 3/164 (1.83%)  4 6/164 (3.66%)  7 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 1/32 (3.13%)  1 4/32 (12.50%)  4
INFLUENZA † 1  9/159 (5.66%)  9 4/164 (2.44%)  5 7/164 (4.27%)  10 4/43 (9.30%)  5 6/43 (13.95%)  9 0/43 (0.00%)  0 1/43 (2.33%)  1 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
LOCALISED INFECTION † 1  7/159 (4.40%)  8 3/164 (1.83%)  3 6/164 (3.66%)  9 1/43 (2.33%)  1 3/43 (6.98%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 2/31 (6.45%)  4 1/32 (3.13%)  1 1/32 (3.13%)  1
LOWER RESPIRATORY TRACT INFECTION † 1  3/159 (1.89%)  4 4/164 (2.44%)  5 5/164 (3.05%)  6 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 3/31 (9.68%)  3 4/31 (12.90%)  4 0/32 (0.00%)  0 0/32 (0.00%)  0
NASOPHARYNGITIS † 1  11/159 (6.92%)  15 11/164 (6.71%)  13 23/164 (14.02%)  27 3/43 (6.98%)  4 6/43 (13.95%)  8 4/43 (9.30%)  4 6/43 (13.95%)  6 1/31 (3.23%)  1 8/31 (25.81%)  9 3/32 (9.38%)  4 5/32 (15.63%)  6
ORAL HERPES † 1  7/159 (4.40%)  8 7/164 (4.27%)  7 8/164 (4.88%)  10 2/43 (4.65%)  2 3/43 (6.98%)  5 1/43 (2.33%)  1 2/43 (4.65%)  2 1/31 (3.23%)  1 1/31 (3.23%)  1 3/32 (9.38%)  3 3/32 (9.38%)  3
PARONYCHIA † 1  4/159 (2.52%)  5 8/164 (4.88%)  11 12/164 (7.32%)  18 2/43 (4.65%)  2 4/43 (9.30%)  6 2/43 (4.65%)  2 2/43 (4.65%)  2 2/31 (6.45%)  2 3/31 (9.68%)  3 2/32 (6.25%)  5 3/32 (9.38%)  7
PHARYNGITIS † 1  3/159 (1.89%)  4 1/164 (0.61%)  1 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 1/32 (3.13%)  1 2/32 (6.25%)  2
RASH PUSTULAR † 1  0/159 (0.00%)  0 3/164 (1.83%)  4 4/164 (2.44%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  2 1/31 (3.23%)  2 1/32 (3.13%)  1 2/32 (6.25%)  2
RESPIRATORY TRACT INFECTION † 1  1/159 (0.63%)  1 5/164 (3.05%)  8 6/164 (3.66%)  9 1/43 (2.33%)  2 1/43 (2.33%)  2 4/43 (9.30%)  6 6/43 (13.95%)  8 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
RHINITIS † 1  2/159 (1.26%)  2 3/164 (1.83%)  4 5/164 (3.05%)  7 2/43 (4.65%)  3 3/43 (6.98%)  5 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 1/31 (3.23%)  1 1/32 (3.13%)  1 1/32 (3.13%)  1
SINUSITIS † 1  10/159 (6.29%)  16 10/164 (6.10%)  16 19/164 (11.59%)  30 1/43 (2.33%)  1 6/43 (13.95%)  9 3/43 (6.98%)  3 4/43 (9.30%)  5 3/31 (9.68%)  6 5/31 (16.13%)  9 3/32 (9.38%)  6 4/32 (12.50%)  8
SKIN INFECTION † 1  4/159 (2.52%)  4 4/164 (2.44%)  5 6/164 (3.66%)  7 1/43 (2.33%)  1 1/43 (2.33%)  1 2/43 (4.65%)  3 2/43 (4.65%)  3 0/31 (0.00%)  0 1/31 (3.23%)  1 1/32 (3.13%)  1 2/32 (6.25%)  2
TINEA PEDIS † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
TOOTH INFECTION † 1  1/159 (0.63%)  1 5/164 (3.05%)  6 6/164 (3.66%)  7 1/43 (2.33%)  1 1/43 (2.33%)  1 2/43 (4.65%)  3 4/43 (9.30%)  5 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
UPPER RESPIRATORY TRACT INFECTION † 1  37/159 (23.27%)  47 48/164 (29.27%)  63 64/164 (39.02%)  104 14/43 (32.56%)  19 18/43 (41.86%)  37 15/43 (34.88%)  20 20/43 (46.51%)  42 11/31 (35.48%)  13 14/31 (45.16%)  24 3/32 (9.38%)  4 11/32 (34.38%)  15
URINARY TRACT INFECTION † 1  12/159 (7.55%)  16 11/164 (6.71%)  18 19/164 (11.59%)  29 3/43 (6.98%)  3 7/43 (16.28%)  9 3/43 (6.98%)  7 5/43 (11.63%)  10 3/31 (9.68%)  3 6/31 (19.35%)  7 2/32 (6.25%)  5 3/32 (9.38%)  6
VIRAL INFECTION † 1  2/159 (1.26%)  2 5/164 (3.05%)  7 6/164 (3.66%)  8 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  2 1/31 (3.23%)  2 2/32 (6.25%)  3 3/32 (9.38%)  4
Injury, poisoning and procedural complications                       
ARTHROPOD BITE † 1  5/159 (3.14%)  5 3/164 (1.83%)  3 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
CONTUSION † 1  24/159 (15.09%)  25 31/164 (18.90%)  45 35/164 (21.34%)  54 8/43 (18.60%)  9 8/43 (18.60%)  11 8/43 (18.60%)  13 10/43 (23.26%)  16 7/31 (22.58%)  10 10/31 (32.26%)  14 6/32 (18.75%)  11 6/32 (18.75%)  13
EYE CONTUSION † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
LIMB INJURY † 1  3/159 (1.89%)  3 3/164 (1.83%)  3 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 2/43 (4.65%)  2 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
RIB FRACTURE † 1  1/159 (0.63%)  1 2/164 (1.22%)  2 3/164 (1.83%)  3 0/43 (0.00%)  0 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
SCRATCH † 1  1/159 (0.63%)  1 2/164 (1.22%)  2 4/164 (2.44%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 3/31 (9.68%)  3 1/32 (3.13%)  1 1/32 (3.13%)  1
SKIN ABRASION † 1  4/159 (2.52%)  5 5/164 (3.05%)  5 9/164 (5.49%)  9 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 6/32 (18.75%)  6
SKIN LACERATION † 1  3/159 (1.89%)  3 5/164 (3.05%)  5 6/164 (3.66%)  6 1/43 (2.33%)  1 2/43 (4.65%)  2 1/43 (2.33%)  1 1/43 (2.33%)  1 3/31 (9.68%)  3 3/31 (9.68%)  3 0/32 (0.00%)  0 0/32 (0.00%)  0
WOUND HAEMORRHAGE † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 3/32 (9.38%)  3
Investigations                       
ALANINE AMINOTRANSFERASE INCREASED † 1  6/159 (3.77%)  6 10/164 (6.10%)  18 13/164 (7.93%)  26 1/43 (2.33%)  1 2/43 (4.65%)  4 3/43 (6.98%)  3 5/43 (11.63%)  7 2/31 (6.45%)  8 3/31 (9.68%)  9 3/32 (9.38%)  4 3/32 (9.38%)  5
ASPARTATE AMINOTRANSFERASE INCREASED † 1  9/159 (5.66%)  16 13/164 (7.93%)  17 14/164 (8.54%)  19 3/43 (6.98%)  3 4/43 (9.30%)  4 5/43 (11.63%)  5 5/43 (11.63%)  6 2/31 (6.45%)  4 2/31 (6.45%)  4 2/32 (6.25%)  4 2/32 (6.25%)  5
BLOOD BILIRUBIN INCREASED † 1  6/159 (3.77%)  15 5/164 (3.05%)  9 5/164 (3.05%)  15 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 3/31 (9.68%)  7 3/31 (9.68%)  12 1/32 (3.13%)  1 1/32 (3.13%)  2
BLOOD CREATININE INCREASED † 1  7/159 (4.40%)  8 12/164 (7.32%)  12 13/164 (7.93%)  17 5/43 (11.63%)  5 5/43 (11.63%)  6 2/43 (4.65%)  2 4/43 (9.30%)  4 1/31 (3.23%)  1 2/31 (6.45%)  4 4/32 (12.50%)  4 4/32 (12.50%)  5
NEUTROPHIL COUNT DECREASED † 1  16/159 (10.06%)  38 4/164 (2.44%)  5 5/164 (3.05%)  6 1/43 (2.33%)  1 2/43 (4.65%)  2 2/43 (4.65%)  2 2/43 (4.65%)  2 1/31 (3.23%)  2 1/31 (3.23%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
PLATELET COUNT DECREASED † 1  7/159 (4.40%)  12 8/164 (4.88%)  11 8/164 (4.88%)  11 4/43 (9.30%)  7 4/43 (9.30%)  7 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
WEIGHT DECREASED † 1  6/159 (3.77%)  6 6/164 (3.66%)  6 7/164 (4.27%)  7 3/43 (6.98%)  3 4/43 (9.30%)  4 2/43 (4.65%)  2 2/43 (4.65%)  2 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
WHITE BLOOD CELL COUNT DECREASED † 1  6/159 (3.77%)  15 4/164 (2.44%)  5 4/164 (2.44%)  6 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  2 2/32 (6.25%)  3 2/32 (6.25%)  4
Metabolism and nutrition disorders                       
DECREASED APPETITE † 1  7/159 (4.40%)  9 16/164 (9.76%)  18 17/164 (10.37%)  20 4/43 (9.30%)  4 5/43 (11.63%)  6 7/43 (16.28%)  7 7/43 (16.28%)  7 4/31 (12.90%)  5 4/31 (12.90%)  5 1/32 (3.13%)  2 1/32 (3.13%)  2
HYPERGLYCAEMIA † 1  3/159 (1.89%)  4 2/164 (1.22%)  3 3/164 (1.83%)  4 1/43 (2.33%)  2 1/43 (2.33%)  2 1/43 (2.33%)  1 6/43 (13.95%)  6 0/31 (0.00%)  0 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
HYPERKALAEMIA † 1  5/159 (3.14%)  5 12/164 (7.32%)  14 12/164 (7.32%)  14 3/43 (6.98%)  5 3/43 (6.98%)  5 2/43 (4.65%)  2 2/43 (4.65%)  2 4/31 (12.90%)  4 4/31 (12.90%)  4 3/32 (9.38%)  3 3/32 (9.38%)  3
HYPERPHOSPHATAEMIA † 1  7/159 (4.40%)  9 8/164 (4.88%)  11 8/164 (4.88%)  11 4/43 (9.30%)  4 4/43 (9.30%)  4 3/43 (6.98%)  4 3/43 (6.98%)  4 1/31 (3.23%)  3 1/31 (3.23%)  3 0/32 (0.00%)  0 0/32 (0.00%)  0
HYPERURICAEMIA † 1  12/159 (7.55%)  19 9/164 (5.49%)  14 14/164 (8.54%)  23 5/43 (11.63%)  7 5/43 (11.63%)  8 2/43 (4.65%)  2 2/43 (4.65%)  2 1/31 (3.23%)  2 2/31 (6.45%)  3 1/32 (3.13%)  3 4/32 (12.50%)  7
HYPOCALCAEMIA † 1  1/159 (0.63%)  1 7/164 (4.27%)  7 7/164 (4.27%)  7 2/43 (4.65%)  2 2/43 (4.65%)  2 1/43 (2.33%)  1 1/43 (2.33%)  1 2/31 (6.45%)  2 2/31 (6.45%)  2 1/32 (3.13%)  1 1/32 (3.13%)  1
HYPOGLYCAEMIA † 1  1/159 (0.63%)  1 4/164 (2.44%)  4 5/164 (3.05%)  5 2/43 (4.65%)  2 2/43 (4.65%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 2/31 (6.45%)  2 1/32 (3.13%)  1 1/32 (3.13%)  1
HYPOKALAEMIA † 1  7/159 (4.40%)  8 11/164 (6.71%)  17 11/164 (6.71%)  20 3/43 (6.98%)  5 3/43 (6.98%)  8 3/43 (6.98%)  5 3/43 (6.98%)  5 2/31 (6.45%)  3 2/31 (6.45%)  3 2/32 (6.25%)  3 2/32 (6.25%)  3
HYPOMAGNESAEMIA † 1  0/159 (0.00%)  0 7/164 (4.27%)  14 7/164 (4.27%)  15 3/43 (6.98%)  5 3/43 (6.98%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  2 1/31 (3.23%)  2 2/32 (6.25%)  6 2/32 (6.25%)  7
IRON DEFICIENCY † 1  4/159 (2.52%)  4 8/164 (4.88%)  8 8/164 (4.88%)  9 2/43 (4.65%)  2 2/43 (4.65%)  2 3/43 (6.98%)  3 3/43 (6.98%)  3 1/31 (3.23%)  1 1/31 (3.23%)  1 2/32 (6.25%)  2 2/32 (6.25%)  3
VITAMIN B12 DEFICIENCY † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 3/164 (1.83%)  3 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 2/32 (6.25%)  2
Musculoskeletal and connective tissue disorders                       
ARTHRALGIA † 1  52/159 (32.70%)  80 56/164 (34.15%)  99 67/164 (40.85%)  129 12/43 (27.91%)  23 17/43 (39.53%)  35 13/43 (30.23%)  24 19/43 (44.19%)  36 12/31 (38.71%)  20 16/31 (51.61%)  28 14/32 (43.75%)  21 15/32 (46.88%)  30
BACK PAIN † 1  20/159 (12.58%)  22 26/164 (15.85%)  35 34/164 (20.73%)  46 7/43 (16.28%)  7 8/43 (18.60%)  8 4/43 (9.30%)  7 8/43 (18.60%)  12 4/31 (12.90%)  8 10/31 (32.26%)  17 8/32 (25.00%)  10 9/32 (28.13%)  11
BONE PAIN † 1  4/159 (2.52%)  5 7/164 (4.27%)  9 7/164 (4.27%)  10 3/43 (6.98%)  5 3/43 (6.98%)  6 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 2/32 (6.25%)  2 2/32 (6.25%)  2
JOINT STIFFNESS † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 2/43 (4.65%)  2 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
MUSCLE SPASMS † 1  47/159 (29.56%)  66 32/164 (19.51%)  40 36/164 (21.95%)  47 9/43 (20.93%)  11 11/43 (25.58%)  14 6/43 (13.95%)  9 8/43 (18.60%)  12 9/31 (29.03%)  10 10/31 (32.26%)  11 6/32 (18.75%)  8 7/32 (21.88%)  11
MUSCULOSKELETAL CHEST PAIN † 1  3/159 (1.89%)  3 2/164 (1.22%)  2 4/164 (2.44%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 2/43 (4.65%)  2 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 4/32 (12.50%)  4
MUSCULOSKELETAL PAIN † 1  0/159 (0.00%)  0 3/164 (1.83%)  4 5/164 (3.05%)  6 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/31 (0.00%)  0 1/31 (3.23%)  1 2/32 (6.25%)  3 2/32 (6.25%)  3
MYALGIA † 1  23/159 (14.47%)  29 24/164 (14.63%)  35 27/164 (16.46%)  41 9/43 (20.93%)  15 9/43 (20.93%)  17 7/43 (16.28%)  9 7/43 (16.28%)  9 3/31 (9.68%)  3 5/31 (16.13%)  6 3/32 (9.38%)  3 3/32 (9.38%)  3
NECK PAIN † 1  5/159 (3.14%)  7 5/164 (3.05%)  5 7/164 (4.27%)  7 2/43 (4.65%)  2 2/43 (4.65%)  2 0/43 (0.00%)  0 2/43 (4.65%)  2 2/31 (6.45%)  2 3/31 (9.68%)  3 0/32 (0.00%)  0 1/32 (3.13%)  1
OSTEOARTHRITIS † 1  1/159 (0.63%)  1 2/164 (1.22%)  2 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 1/31 (3.23%)  1 3/31 (9.68%)  3 0/32 (0.00%)  0 0/32 (0.00%)  0
PAIN IN EXTREMITY † 1  21/159 (13.21%)  25 22/164 (13.41%)  27 27/164 (16.46%)  34 3/43 (6.98%)  3 4/43 (9.30%)  4 7/43 (16.28%)  9 7/43 (16.28%)  10 5/31 (16.13%)  5 8/31 (25.81%)  8 6/32 (18.75%)  9 7/32 (21.88%)  12
SPINAL PAIN † 1  1/159 (0.63%)  1 1/164 (0.61%)  1 3/164 (1.83%)  4 0/43 (0.00%)  0 1/43 (2.33%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 2/32 (6.25%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                       
BASAL CELL CARCINOMA † 1  3/159 (1.89%)  4 6/164 (3.66%)  8 8/164 (4.88%)  12 1/43 (2.33%)  1 3/43 (6.98%)  3 3/43 (6.98%)  3 4/43 (9.30%)  4 1/31 (3.23%)  3 1/31 (3.23%)  5 1/32 (3.13%)  1 1/32 (3.13%)  1
Nervous system disorders                       
DIZZINESS † 1  26/159 (16.35%)  33 26/164 (15.85%)  32 30/164 (18.29%)  41 6/43 (13.95%)  8 8/43 (18.60%)  12 9/43 (20.93%)  9 9/43 (20.93%)  11 3/31 (9.68%)  4 5/31 (16.13%)  9 6/32 (18.75%)  9 6/32 (18.75%)  9
HEADACHE † 1  39/159 (24.53%)  55 46/164 (28.05%)  64 47/164 (28.66%)  74 13/43 (30.23%)  18 13/43 (30.23%)  21 16/43 (37.21%)  23 16/43 (37.21%)  26 8/31 (25.81%)  10 8/31 (25.81%)  15 7/32 (21.88%)  10 8/32 (25.00%)  12
HYPOAESTHESIA † 1  1/159 (0.63%)  1 7/164 (4.27%)  8 11/164 (6.71%)  13 2/43 (4.65%)  2 3/43 (6.98%)  3 3/43 (6.98%)  3 4/43 (9.30%)  5 2/31 (6.45%)  3 4/31 (12.90%)  6 0/32 (0.00%)  0 1/32 (3.13%)  1
MEMORY IMPAIRMENT † 1  1/159 (0.63%)  1 3/164 (1.83%)  3 4/164 (2.44%)  5 2/43 (4.65%)  2 3/43 (6.98%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
NEUROPATHY PERIPHERAL † 1  0/159 (0.00%)  0 4/164 (2.44%)  4 4/164 (2.44%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 2/43 (4.65%)  2 2/43 (4.65%)  2 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
PARAESTHESIA † 1  6/159 (3.77%)  7 10/164 (6.10%)  13 13/164 (7.93%)  16 4/43 (9.30%)  4 4/43 (9.30%)  4 3/43 (6.98%)  4 4/43 (9.30%)  6 2/31 (6.45%)  4 4/31 (12.90%)  6 1/32 (3.13%)  1 2/32 (6.25%)  2
SCIATICA † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 4/164 (2.44%)  4 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 1/43 (2.33%)  1 0/31 (0.00%)  0 1/31 (3.23%)  1 1/32 (3.13%)  1 2/32 (6.25%)  2
SYNCOPE † 1  2/159 (1.26%)  2 2/164 (1.22%)  2 6/164 (3.66%)  6 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 2/31 (6.45%)  2 1/32 (3.13%)  1 3/32 (9.38%)  3
TREMOR † 1  2/159 (1.26%)  2 1/164 (0.61%)  1 3/164 (1.83%)  4 1/43 (2.33%)  1 3/43 (6.98%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Psychiatric disorders                       
AGITATION † 1  0/159 (0.00%)  0 4/164 (2.44%)  5 4/164 (2.44%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  3 2/31 (6.45%)  3 0/32 (0.00%)  0 0/32 (0.00%)  0
ANXIETY † 1  1/159 (0.63%)  1 9/164 (5.49%)  9 12/164 (7.32%)  12 1/43 (2.33%)  1 4/43 (9.30%)  4 1/43 (2.33%)  1 2/43 (4.65%)  2 5/31 (16.13%)  5 5/31 (16.13%)  5 2/32 (6.25%)  2 2/32 (6.25%)  2
DEPRESSION † 1  1/159 (0.63%)  1 6/164 (3.66%)  6 8/164 (4.88%)  9 2/43 (4.65%)  2 4/43 (9.30%)  4 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  3 1/32 (3.13%)  1 1/32 (3.13%)  1
INSOMNIA † 1  6/159 (3.77%)  6 12/164 (7.32%)  12 15/164 (9.15%)  15 1/43 (2.33%)  1 1/43 (2.33%)  1 3/43 (6.98%)  3 5/43 (11.63%)  5 5/31 (16.13%)  5 7/31 (22.58%)  7 2/32 (6.25%)  2 3/32 (9.38%)  3
Renal and urinary disorders                       
HAEMATURIA † 1  9/159 (5.66%)  9 12/164 (7.32%)  14 12/164 (7.32%)  14 3/43 (6.98%)  3 3/43 (6.98%)  3 2/43 (4.65%)  2 2/43 (4.65%)  2 3/31 (9.68%)  5 3/31 (9.68%)  5 4/32 (12.50%)  4 4/32 (12.50%)  4
Reproductive system and breast disorders                       
BENIGN PROSTATIC HYPERPLASIA † 1  1/159 (0.63%)  1 3/164 (1.83%)  3 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 2/31 (6.45%)  2 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
ERECTILE DYSFUNCTION † 1  2/159 (1.26%)  2 5/164 (3.05%)  5 5/164 (3.05%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  2 1/32 (3.13%)  1 1/32 (3.13%)  1
TESTICULAR SWELLING † 1  2/159 (1.26%)  2 0/164 (0.00%)  0 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 2/32 (6.25%)  2
Respiratory, thoracic and mediastinal disorders                       
COUGH † 1  27/159 (16.98%)  33 28/164 (17.07%)  33 36/164 (21.95%)  46 7/43 (16.28%)  9 13/43 (30.23%)  16 10/43 (23.26%)  12 15/43 (34.88%)  19 5/31 (16.13%)  5 7/31 (22.58%)  9 4/32 (12.50%)  4 4/32 (12.50%)  5
DYSPNOEA † 1  9/159 (5.66%)  9 14/164 (8.54%)  16 18/164 (10.98%)  20 4/43 (9.30%)  4 7/43 (16.28%)  7 6/43 (13.95%)  6 6/43 (13.95%)  6 2/31 (6.45%)  3 3/31 (9.68%)  4 0/32 (0.00%)  0 0/32 (0.00%)  0
DYSPNOEA EXERTIONAL † 1  1/159 (0.63%)  1 3/164 (1.83%)  3 4/164 (2.44%)  4 1/43 (2.33%)  1 2/43 (4.65%)  2 2/43 (4.65%)  2 3/43 (6.98%)  3 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
EPISTAXIS † 1  18/159 (11.32%)  26 24/164 (14.63%)  33 30/164 (18.29%)  44 8/43 (18.60%)  11 10/43 (23.26%)  15 7/43 (16.28%)  12 8/43 (18.60%)  14 4/31 (12.90%)  5 5/31 (16.13%)  8 4/32 (12.50%)  4 6/32 (18.75%)  7
NASAL CONGESTION † 1  4/159 (2.52%)  4 14/164 (8.54%)  17 15/164 (9.15%)  18 6/43 (13.95%)  7 7/43 (16.28%)  8 2/43 (4.65%)  3 2/43 (4.65%)  3 3/31 (9.68%)  3 3/31 (9.68%)  3 1/32 (3.13%)  1 1/32 (3.13%)  1
NASAL DRYNESS † 1  1/159 (0.63%)  1 5/164 (3.05%)  5 5/164 (3.05%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 3/43 (6.98%)  3 3/43 (6.98%)  3 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 1/32 (3.13%)  1
OROPHARYNGEAL PAIN † 1  17/159 (10.69%)  19 28/164 (17.07%)  37 36/164 (21.95%)  53 7/43 (16.28%)  11 10/43 (23.26%)  15 5/43 (11.63%)  7 7/43 (16.28%)  10 7/31 (22.58%)  8 9/31 (29.03%)  14 8/32 (25.00%)  9 10/32 (31.25%)  14
PRODUCTIVE COUGH † 1  4/159 (2.52%)  4 5/164 (3.05%)  5 7/164 (4.27%)  7 3/43 (6.98%)  3 5/43 (11.63%)  5 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
RHINITIS ALLERGIC † 1  2/159 (1.26%)  4 3/164 (1.83%)  3 6/164 (3.66%)  6 1/43 (2.33%)  1 2/43 (4.65%)  2 1/43 (2.33%)  1 1/43 (2.33%)  1 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 1/32 (3.13%)  1
SINUS CONGESTION † 1  3/159 (1.89%)  3 5/164 (3.05%)  5 7/164 (4.27%)  7 2/43 (4.65%)  2 4/43 (9.30%)  4 2/43 (4.65%)  2 2/43 (4.65%)  2 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 0/32 (0.00%)  0
Skin and subcutaneous tissue disorders                       
ALOPECIA † 1  6/159 (3.77%)  6 8/164 (4.88%)  8 8/164 (4.88%)  8 3/43 (6.98%)  3 3/43 (6.98%)  3 1/43 (2.33%)  1 2/43 (4.65%)  2 0/31 (0.00%)  0 0/31 (0.00%)  0 3/32 (9.38%)  3 3/32 (9.38%)  3
BLISTER † 1  1/159 (0.63%)  4 4/164 (2.44%)  4 6/164 (3.66%)  6 1/43 (2.33%)  1 2/43 (4.65%)  2 2/43 (4.65%)  2 2/43 (4.65%)  2 1/31 (3.23%)  1 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
BLOOD BLISTER † 1  6/159 (3.77%)  7 5/164 (3.05%)  5 5/164 (3.05%)  5 0/43 (0.00%)  0 0/43 (0.00%)  0 4/43 (9.30%)  4 4/43 (9.30%)  4 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
DERMATITIS ACNEIFORM † 1  2/159 (1.26%)  2 4/164 (2.44%)  4 4/164 (2.44%)  4 2/43 (4.65%)  2 2/43 (4.65%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
DRY SKIN † 1  16/159 (10.06%)  18 19/164 (11.59%)  19 24/164 (14.63%)  24 8/43 (18.60%)  8 10/43 (23.26%)  10 6/43 (13.95%)  6 7/43 (16.28%)  7 2/31 (6.45%)  2 3/31 (9.68%)  3 3/32 (9.38%)  3 5/32 (15.63%)  5
ECCHYMOSIS † 1  4/159 (2.52%)  4 7/164 (4.27%)  7 11/164 (6.71%)  13 3/43 (6.98%)  3 6/43 (13.95%)  7 0/43 (0.00%)  0 0/43 (0.00%)  0 3/31 (9.68%)  3 3/31 (9.68%)  4 1/32 (3.13%)  1 2/32 (6.25%)  2
ECZEMA † 1  4/159 (2.52%)  5 3/164 (1.83%)  3 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 1/43 (2.33%)  1 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
ERYTHEMA † 1  8/159 (5.03%)  8 9/164 (5.49%)  11 10/164 (6.10%)  14 1/43 (2.33%)  1 1/43 (2.33%)  1 2/43 (4.65%)  4 3/43 (6.98%)  5 2/31 (6.45%)  2 2/31 (6.45%)  3 4/32 (12.50%)  4 5/32 (15.63%)  6
HYPERHIDROSIS † 1  4/159 (2.52%)  6 5/164 (3.05%)  6 5/164 (3.05%)  6 0/43 (0.00%)  0 0/43 (0.00%)  0 1/43 (2.33%)  1 2/43 (4.65%)  2 1/31 (3.23%)  1 1/31 (3.23%)  1 2/32 (6.25%)  3 2/32 (6.25%)  3
NAIL RIDGING † 1  0/159 (0.00%)  0 3/164 (1.83%)  3 5/164 (3.05%)  5 0/43 (0.00%)  0 1/43 (2.33%)  1 3/43 (6.98%)  3 3/43 (6.98%)  3 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 1/32 (3.13%)  1
NIGHT SWEATS † 1  5/159 (3.14%)  5 8/164 (4.88%)  9 13/164 (7.93%)  16 2/43 (4.65%)  2 4/43 (9.30%)  5 1/43 (2.33%)  1 3/43 (6.98%)  3 4/31 (12.90%)  4 5/31 (16.13%)  6 1/32 (3.13%)  2 3/32 (9.38%)  4
ONYCHOCLASIS † 1  14/159 (8.81%)  14 17/164 (10.37%)  17 20/164 (12.20%)  20 4/43 (9.30%)  4 5/43 (11.63%)  5 5/43 (11.63%)  5 5/43 (11.63%)  6 3/31 (9.68%)  3 4/31 (12.90%)  4 4/32 (12.50%)  4 5/32 (15.63%)  5
PETECHIAE † 1  17/159 (10.69%)  23 20/164 (12.20%)  29 24/164 (14.63%)  33 3/43 (6.98%)  3 4/43 (9.30%)  4 3/43 (6.98%)  6 3/43 (6.98%)  6 5/31 (16.13%)  8 6/31 (19.35%)  9 6/32 (18.75%)  9 8/32 (25.00%)  11
PRURITUS † 1  17/159 (10.69%)  18 14/164 (8.54%)  17 19/164 (11.59%)  25 5/43 (11.63%)  5 6/43 (13.95%)  7 1/43 (2.33%)  1 2/43 (4.65%)  3 2/31 (6.45%)  2 3/31 (9.68%)  3 5/32 (15.63%)  8 7/32 (21.88%)  12
RASH † 1  10/159 (6.29%)  12 14/164 (8.54%)  16 18/164 (10.98%)  21 2/43 (4.65%)  2 5/43 (11.63%)  5 3/43 (6.98%)  3 4/43 (9.30%)  5 3/31 (9.68%)  4 3/31 (9.68%)  5 5/32 (15.63%)  6 6/32 (18.75%)  7
RASH ERYTHEMATOUS † 1  9/159 (5.66%)  11 10/164 (6.10%)  12 11/164 (6.71%)  14 2/43 (4.65%)  3 3/43 (6.98%)  5 4/43 (9.30%)  5 4/43 (9.30%)  5 1/31 (3.23%)  1 1/31 (3.23%)  1 2/32 (6.25%)  2 2/32 (6.25%)  2
RASH MACULO-PAPULAR † 1  27/159 (16.98%)  32 23/164 (14.02%)  30 26/164 (15.85%)  34 6/43 (13.95%)  8 8/43 (18.60%)  11 8/43 (18.60%)  8 10/43 (23.26%)  11 4/31 (12.90%)  8 5/31 (16.13%)  9 5/32 (15.63%)  6 5/32 (15.63%)  6
SKIN ATROPHY † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 2/164 (1.22%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 1/32 (3.13%)  1 2/32 (6.25%)  3
SKIN DISCOLOURATION † 1  4/159 (2.52%)  5 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 2/31 (6.45%)  2 2/31 (6.45%)  2 0/32 (0.00%)  0 0/32 (0.00%)  0
SKIN FISSURES † 1  5/159 (3.14%)  6 7/164 (4.27%)  7 8/164 (4.88%)  8 2/43 (4.65%)  2 2/43 (4.65%)  2 3/43 (6.98%)  3 3/43 (6.98%)  3 0/31 (0.00%)  0 1/31 (3.23%)  1 2/32 (6.25%)  2 2/32 (6.25%)  2
SKIN FRAGILITY † 1  0/159 (0.00%)  0 1/164 (0.61%)  1 3/164 (1.83%)  3 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 1/31 (3.23%)  1 1/31 (3.23%)  1 0/32 (0.00%)  0 2/32 (6.25%)  2
SKIN LESION † 1  8/159 (5.03%)  8 8/164 (4.88%)  8 11/164 (6.71%)  13 2/43 (4.65%)  2 4/43 (9.30%)  6 1/43 (2.33%)  1 3/43 (6.98%)  3 1/31 (3.23%)  1 1/31 (3.23%)  1 3/32 (9.38%)  3 4/32 (12.50%)  4
SKIN MASS † 1  2/159 (1.26%)  2 4/164 (2.44%)  5 4/164 (2.44%)  5 0/43 (0.00%)  0 0/43 (0.00%)  0 4/43 (9.30%)  5 4/43 (9.30%)  5 0/31 (0.00%)  0 0/31 (0.00%)  0 0/32 (0.00%)  0 0/32 (0.00%)  0
Vascular disorders                       
HYPERTENSION † 1  24/159 (15.09%)  33 25/164 (15.24%)  31 34/164 (20.73%)  48 8/43 (18.60%)  10 10/43 (23.26%)  18 6/43 (13.95%)  7 8/43 (18.60%)  13 5/31 (16.13%)  6 9/31 (29.03%)  12 5/32 (15.63%)  7 7/32 (21.88%)  9
PHLEBITIS † 1  0/159 (0.00%)  0 2/164 (1.22%)  2 2/164 (1.22%)  2 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/43 (0.00%)  0 0/31 (0.00%)  0 0/31 (0.00%)  0 2/32 (6.25%)  2 2/32 (6.25%)  2
1
Term from vocabulary, MedDRA 23.1
†
Indicates events were collected by systematic assessment
[Not Specified]
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.
AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Medical Services
Organization: AbbVie
Phone: 800-633-9110
EMail: abbvieclinicaltrials@abbvie.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT02910583    
Other Study ID Numbers: PCYC-1142-CA
2016-002293-12 ( EudraCT Number )
First Submitted: September 20, 2016
First Posted: September 22, 2016
Results First Submitted: November 9, 2021
Results First Posted: February 18, 2022
Last Update Posted: April 3, 2024