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

Sponsor

Pharmacyclics LLC. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02910583

Collaborator

Janssen Research & Development, LLC (Industry)

323

Enrollment

Locations

Arms

77.5

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, 2-cohort Phase 2 study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration therapy with the combination of ibrutinib + venetoclax in subjects with treatment-naïve CLL or SLL.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma	Drug: ibrutinib Drug: venetoclax Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

323 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Participants with confirmed undetectable minimal residual disease (uMRD) in the MRD cohort are triple masked. Allocation was not randomized for the Fixed Duration (FD) cohort.

Primary Purpose:

Treatment

Official Title:

Phase 2 Study of the Combination of Ibrutinib Plus Venetoclax in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Actual Study Start Date :

Sep 28, 2016

Actual Primary Completion Date :

Nov 12, 2020

Anticipated Study Completion Date :

Mar 15, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fixed Duration (FD) Cohort: Open Label Ibrutinib + Venetoclax Participants receive 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.	Drug: ibrutinib ibrutinib administered orally once daily (three 140 mg capsules) Drug: venetoclax venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.
Experimental: MRD Cohort/Confirmed Undetectable MRD (uMRD): Randomized to Ibrutinib (Blinded) Participants receive 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 are randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, disease progression (PD), or unacceptable toxicity. After MRD-positive relapse or disease progression (PD) by iwCLL criteria, participants can reintroduce 400 mg venetoclax with a 5-week ramp up. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.	Drug: ibrutinib ibrutinib administered orally once daily (three 140 mg capsules) Drug: venetoclax venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.
Placebo Comparator: MRD Cohort/Confirmed uMRD: Randomized Placebo (Blinded) Participants receive 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 are randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity. If MRD-positive relapse or PD is confirmed after restaging per iwCLL criteria, participants can first reintroduce oral daily ibrutinib with the option of subsequently reintroducing 400 mg venetoclax with a 5-week ramp up, if subsequent disease relapse per iwCLL criteria occurs after ibrutinib reintroduction. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.	Drug: ibrutinib ibrutinib administered orally once daily (three 140 mg capsules) Drug: venetoclax venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg. Drug: Placebo placebo capsules to match ibrutinib administered orally once daily
Experimental: MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label) Participants receive 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 orally once daily on a continuous schedule until PD or unacceptable toxicity. In case of confirmed PD after restaging per iwCLL criteria, participants can continue ibrutinib and reintroduce venetoclax treatment. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.	Drug: ibrutinib ibrutinib administered orally once daily (three 140 mg capsules) Drug: venetoclax venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.
Experimental: MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label) Participants receive 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.	Drug: ibrutinib ibrutinib administered orally once daily (three 140 mg capsules) Drug: venetoclax venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.

Outcome Measures

Primary Outcome Measures

MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants [1 year after randomization]
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.
FD Cohort: Complete Response Rate (CRR; Complete Response/Complete Response With Incomplete Blood Count Recovery [CR/CRi]) Rate [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.]
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.

Secondary Outcome Measures

MRD Cohort: CRR (CR/CRi Rate) [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).]
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.
MRD Cohort: Overall Response Rate (ORR) [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).]
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.
MRD Cohort: Duration of Response (DOR) [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).]
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.
MRD Cohort: MRD-Negativity Rate (MRR) [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).]
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.
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) [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).]
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.
MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 36 Months Landmark Time [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).]
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.
MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 36 Months Landmark Time [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).]
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.
MRD Cohort: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs [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.]
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.
FD Cohort: ORR [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.]
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.
FD Cohort: DOR [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).]
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.
FD Cohort: MRR [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).]
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.
FD Cohort: Kaplan-Meier Estimate of PFS Rate at 24 Months Landmark Time [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).]
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.
FD Cohort: Kaplan-Meier Estimate of OS Rate at 24 Months Landmark Time [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).]
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.
FD Cohort: TLS Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in) [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).]
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.
FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs [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.]
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.
MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax) [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)]
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) [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)]
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) [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)]
MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Terminal Elimination Rate Constant (λz) [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)]
MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Apparent Total Clearance at Steady-State (CLss/F) [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)]
MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Cmax [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)]
MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Tmax [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)]
MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: AUC0-24h [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)]
MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: CLss/F [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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of CLL/SLL that meets 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) diagnostic criteria (Hallek et al), with active disease meeting at least 1 IWCLL criteria for requiring treatment.
Measurable nodal disease by computed tomography (CT)
Adequate hepatic, and renal function
Adequate hematologic function
absolute neutrophil count >750/µL
platelet count >30,000 /μL
hemoglobin >8.0 g/dL

Exclusion Criteria:

Any prior therapy used for treatment of CLL/SLL
Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome (TLS)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope /ID# 1142-0047	Duarte	California	United States	91010
2	Moores Cancer Center at UC San Diego /ID# 1142-0241	La Jolla	California	United States	92093
3	UC Irvine Medical Center - Chao Family Comprehensive Cancer Center /ID# 1142-0008	Orange	California	United States	92868-3201
4	Norton Cancer Center /ID# 1142-0071	Louisville	Kentucky	United States	40202
5	Rutgers Cancer Institute of New Jersey /ID# 1142-1193	New Brunswick	New Jersey	United States	08901
6	Northwell Health/Long Island Jewish Hospital /ID# 1142-0350	New Hyde Park	New York	United States	11042
7	New York Presbyterian Hospital/Weill Cornell Med College /ID# 1142-0200	New York	New York	United States	10021
8	University of Rochester Cancer Center /ID# 1142-0127	Rochester	New York	United States	14642-0001
9	Charlotte-Mecklenberg Hospital, Carolinas Healthcare System, Levine Cancer Inst /ID# 1142-0733	Charlotte	North Carolina	United States	28203
10	Cleveland Clinic Foundation /ID# 1142-0739	Cleveland	Ohio	United States	44195
11	University of Pennsylvania /ID# 1142-0069	Philadelphia	Pennsylvania	United States	19104
12	Tennessee Oncology - Chattanooga /ID# 1142-0123	Chattanooga	Tennessee	United States	37404-1108
13	MD Anderson Cancer Center /ID# 1142-0032	Houston	Texas	United States	77030
14	Swedish Cancer Institute /ID# 1142-0114	Seattle	Washington	United States	98104
15	St George Hospital /ID# 1142-0654	Kogarah	New South Wales	Australia	2217
16	Flinders Medical Centre /ID# 1142-0163	Bedford Park	South Australia	Australia	5042
17	Monash Medical Centre /ID# 1142-0556	Clayton	Victoria	Australia	3168
18	Peter MacCallum Cancer Centre-East Melbourne /ID# 1142-0633	East Melbourne	Victoria	Australia	3002
19	St Vincent's Hospital Melbourne /ID# 1142-0501	Fitzroy	Victoria	Australia	3065
20	Frankston Hospital /ID# 1142-0715	Frankston	Victoria	Australia	3199
21	Austin Health /ID# 1142-0170	Heidelberg	Victoria	Australia	3084
22	Ospedale San Raffaele IRCCS /ID# 1142-0523	Milan	Lombardia	Italy	20132
23	Ospedale Policlinico San Martino /ID# 1142-0903	Genova		Italy	16132
24	ASST Grande Ospedale Metropolitano Niguarda /ID# 1142-0581	Milano		Italy	20162
25	Azienda Ospedaliero-Universitaria di Modena /ID# 1142-0524	Modena		Italy	41124
26	Azienda Ospedaliero Universitaria Maggiore della Carita di Novara /ID# 1142-0582	Novara		Italy	28100
27	Azienda Ospedaliera di Padova /ID# 1142-1175	Padova		Italy	35128
28	Azienda USL di Piacenza - Ospedale Guglielmo da Saliceto /ID# 1142-1182	Piacenza		Italy	29121
29	Middlemore Hospital /ID# 1142-0662	Otahuhu	Auckland	New Zealand	2025
30	Christchurch Hospital /ID# 1142-0589	Christchurch	Canterbury	New Zealand	8011
31	Palmerston North Hospital /ID# 1142-0585	Palmerston North	Manawatu-Wanganui	New Zealand	4414
32	North Shore Hospital /ID# 1142-0663	Auckland		New Zealand	0622
33	Duplicate_Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie /ID# 1142-0590	Lublin	Lubelskie	Poland	20-081
34	Malopolskie Centrum Medyczne /ID# 1142-0364	Krakow	Malopolskie	Poland	30-510
35	Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. ks. B. /ID# 1142-0592	Brzozow	Podkarpackie	Poland	36-200
36	Samodzielny Publiczny Szpital Klinczny Nr-1- Akademickie Cenrum Klinic /ID# 1142-0529	Gdańsk	Pomorskie	Poland	80-952
37	Medical Univ. of Lodz and Copernicus Memorial Hospital /ID# 1142-0531	Lodz		Poland	93-510
38	Hospital Duran i Reynals /ID# 1142-0604	Hospitalet de Llobregat	Barcelona	Spain	08907
39	Hospital Universitario Puerta de Hierro, Majadahonda /ID# 1142-0536	Majadahonda	Madrid	Spain	28222
40	Complejo Hospitalario de Navarra /ID# 1142-1197	Pamplona	Navarra	Spain	31008
41	Hospital Clinic de Barcelona /ID# 1142-0533	Barcelona		Spain	08036
42	Hospital Santa Creu i Sant Pau /ID# 1142-0535	Barcelona		Spain	08041
43	Hospital Universitario Virgen de las Nieves /ID# 1142-1196	Granada		Spain	18014
44	Hospital Universitario Ramon y Cajal /ID# 1142-0874	Madrid		Spain	28034
45	Hospital Universitario 12 de Octubre /ID# 1142-0864	Madrid		Spain	28041
46	Hospital Clinico Universitario de Salamanca /ID# 1142-0790	Salamanca		Spain	37007

Sponsors and Collaborators

Pharmacyclics LLC.
Janssen Research & Development, LLC

Investigators

Study Director: ABBVIE INC., AbbVie

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Pharmacyclics LLC.

ClinicalTrials.gov Identifier:

NCT02910583

Other Study ID Numbers:

PCYC-1142-CA
2016-002293-12

First Posted:

Sep 22, 2016

Last Update Posted:

Feb 18, 2022

Last Verified:

Jan 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Lymphoma

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Venetoclax

Study Results

Participant Flow

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 Detail	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
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	15
MRD Cohort/ Confirmed uMRD: Randomized to Ibrutinib (Blinded)	0	43
MRD Cohort/ Confirmed uMRD: Randomized Placebo (Blinded)	0	43
MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label)	0	31
MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label)	0	32
COMPLETED	152	157
NOT COMPLETED	7	7

Baseline Characteristics

Arm/Group Title	FD Cohort: All Treated	MRD Cohort: All Treated	Total
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 Participants	159	164	323
Age, Customized (Count of Participants)
< 65 years	114 71.7%	123 75%	237 73.4%
>= 65 years	45 28.3%	41 25%	86 26.6%
Sex: Female, Male (Count of Participants)
Female	53 33.3%	61 37.2%	114 35.3%
Male	106 66.7%	103 62.8%	209 64.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 3.1%	11 6.7%	16 5%
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) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.6%	1 0.3%
Asian	3 1.9%	5 3%	8 2.5%
Native Hawaiian or Other Pacific Islander	1 0.6%	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%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	7 4.4%	9 5.5%	16 5%

Outcome Measures

1. Primary Outcome

Title	MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants
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

Outcome Measure Data

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)
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.
Measure Participants	43	43
Number (95% Confidence Interval) [percentage of participants]	100.0 62.9%	95.3 58.1%

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
	Type of Statistical Test	Superiority
	Comments

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

Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95% -1.6 to 10.9
	Parameter Dispersion	Type: Value:
	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
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.

Outcome Measure Data

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
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.
Measure Participants	136	159
Number (95% Confidence Interval) [percentage of participants]	55.9 35.2%	55.3 33.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MRD Cohort/Confirmed uMRD: Randomized to Ibrutinib (Blinded)
	Comments
	Type of Statistical Test	Superiority
	Comments

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

3. Secondary Outcome

Title	MRD Cohort: CRR (CR/CRi Rate)
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).

Outcome Measure Data

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
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.
Measure Participants	164	43	43	31	32
Number (95% Confidence Interval) [percentage of participants]	62.8 39.5%	72.1 44%	60.5 18.7%	74.2 NaN	56.3 NaN

4. Secondary Outcome

Title	MRD Cohort: Overall Response Rate (ORR)
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).

Outcome Measure Data

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
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.
Measure Participants	164	43	43	31	32
Number (95% Confidence Interval) [percentage of participants]	97.0 61%	100.0 61%	100.0 31%	100.0 NaN	100.0 NaN

5. Secondary Outcome

Title	MRD Cohort: Duration of Response (DOR)
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).

Outcome Measure Data

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
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.
Measure Participants	159	43	43	31	32
Number (95% Confidence Interval) [percentage of participants]	94.7 59.6%	100.0 61%	95.3 29.5%	96.7 NaN	96.7 NaN

6. Secondary Outcome

Title	MRD Cohort: MRD-Negativity Rate (MRR)
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).

Outcome Measure Data

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
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.
Measure Participants	164	63	31	32
PB or BM	81.1 51%	63.5 38.7%	51.6 16%	75.0 NaN
BM	76.8 48.3%	54.0 32.9%	41.9 13%	65.6 NaN
PB	79.3 49.9%	58.7 35.8%	48.4 15%	68.8 NaN

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)
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).

Outcome Measure Data

Analysis Population Description
MRD Cohort: All Treated Population with baseline TLS high risk

Arm/Group Title	MRD Cohort: All Treated
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.
Measure Participants	40
Number [percentage of participants]	90.0 56.6%

8. Secondary Outcome

Title	MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 36 Months Landmark Time
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).

Outcome Measure Data

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
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 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.
Measure Participants	164	43	43	31	32
Number (95% Confidence Interval) [percentage of participants]	95.6 60.1%	100.0 61%	95.3 29.5%	96.7 NaN	96.7 NaN

9. Secondary Outcome

Title	MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 36 Months Landmark Time
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).

Outcome Measure Data

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
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 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.
Measure Participants	164	43	43	31	32
Number (95% Confidence Interval) [percentage of participants]	99.4 62.5%	100.0 61%	100.0 31%	96.7 NaN	100.0 NaN

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
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.

Outcome Measure Data

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
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.
Measure Participants	164	43	43	31	32
Any TEAE	100.0 62.9%	100.0 61%	100.0 31%	100.0 NaN	100.0 NaN
Any Grade >=3 TEAE	73.8 46.4%	79.1 48.2%	65.1 20.2%	71.0 NaN	75.0 NaN
Any Ibrutinib (Ibr)-Related TEAE	94.5 59.4%	93.0 56.7%	93.0 28.8%	96.8 NaN	93.8 NaN
Any Grade >=3 Ibrutinib-Related TEAE	57.9 36.4%	55.8 34%	48.8 15.1%	61.3 NaN	62.5 NaN
Any Venetoclax (Ven)-Related TEAE	80.5 50.6%	86.0 52.4%	76.7 23.7%	80.6 NaN	96.9 NaN
Any Grade >=3 Venetoclax-Related TEAE	44.5 28%	51.2 31.2%	34.9 10.8%	45.2 NaN	56.3 NaN
Any TEAE Leading to Ibr or Ven Discontinuation	12.8 8.1%	4.7 2.9%	0 0%	9.7 NaN	12.5 NaN
Any TEAE Leading to Ibr or Ven Discontinuation: Ibr Only	7.3 4.6%	2.3 1.4%	0 0%	9.7 NaN	3.1 NaN
Any TEAE Leading to Ibr or Ven Discontinuation: Ven Only	1.2 0.8%	2.3 1.4%	0 0%	0 NaN	0 NaN
Any TEAE Leading to Ibr or Ven Discontinuation: Both Ibr and Ven	4.3 2.7%	0 0%	0 0%	0 NaN	9.4 NaN
Any TEAE Leading to Ibr or Ven Dose Reduction	24.4 15.3%	20.9 12.7%	23.3 7.2%	22.6 NaN	31.3 NaN
Any TEAE Leading to Ibr Only Dose Reduction	14.6 9.2%	14.0 8.5%	9.3 2.9%	16.1 NaN	21.9 NaN
Any TEAE Leading to Ven Only Dose Reduction	5.5 3.5%	4.7 2.9%	11.6 3.6%	0 NaN	3.1 NaN
Any TEAE Leading to Both Ibr and Ven Dose Reduction	4.3 2.7%	2.3 1.4%	2.3 0.7%	6.5 NaN	6.3 NaN
Any SAE	31.1 19.6%	27.9 17%	18.6 5.8%	35.5 NaN	37.5 NaN
Any Grade >= 3 SAE	26.2 16.5%	25.6 15.6%	16.3 5%	29.0 NaN	28.1 NaN
Any SAE Related to Ibr or Ven	18.3 11.5%	16.3 9.9%	11.6 3.6%	22.6 NaN	18.8 NaN
Any Ibr-related SAE	15.9 10%	11.6 7.1%	9.3 2.9%	19.4 NaN	18.8 NaN
Any Ven-related SAE	5.5 3.5%	4.7 2.9%	7.0 2.2%	9.7 NaN	3.1 NaN
Fatal TEAE	0.6 0.4%	0 0%	0 0%	3.2 NaN	0 NaN
Major Hemorrhage TEAE	2.4 1.5%	2.3 1.4%	0 0%	3.2 NaN	6.3 NaN
Grade >= 3 Major Hemorrhage TEAE	1.8 1.1%	2.3 1.4%	0 0%	3.2 NaN	3.1 NaN
Major Hemorrhage SAE	2.4 1.5%	2.3 1.4%	0 0%	3.2 NaN	6.3 NaN

11. Secondary Outcome

Title	FD Cohort: ORR
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.

Outcome Measure Data

Analysis Population Description
FD Cohort: All Treated Population

Arm/Group Title	FD Cohort, Non-Del 17p Population: All Treated	FD Cohort: All Treated
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.
Measure Participants	136	159
Number (95% Confidence Interval) [percentage of participants]	95.6 60.1%	96.2 58.7%

12. Secondary Outcome

Title	FD Cohort: DOR
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).

Outcome Measure Data

Analysis Population Description
FD Cohort: Participants who achieved PR or better.

Arm/Group Title	FD Cohort, Non-Del 17p Population: All Treated	FD Cohort: All Treated
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.
Measure Participants	130	153
Number (95% Confidence Interval) [percentage of participants]	96.1 60.4%	94.7 57.7%

13. Secondary Outcome

Title	FD Cohort: MRR
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).

Outcome Measure Data

Analysis Population Description
FD Cohort - All Treated Population

Arm/Group Title	FD Cohort, Non-Del 17p Population: All Treated	FD Cohort: All Treated
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.
Measure Participants	136	159
BM or PB	78.7 49.5%	78.6 47.9%
BM	61.8 38.9%	59.7 36.4%
PB	76.5 48.1%	76.7 46.8%

14. Secondary Outcome

Title	FD Cohort: Kaplan-Meier Estimate of PFS Rate at 24 Months Landmark Time
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).

Outcome Measure Data

Analysis Population Description
FD Cohort - All Treated Population

Arm/Group Title	FD Cohort, Non-Del 17p Population: All Treated	FD Cohort: All Treated
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.
Measure Participants	136	159
Median (95% Confidence Interval) [percentage of participants]	96.2 60.5%	94.8 57.8%

15. Secondary Outcome

Title	FD Cohort: Kaplan-Meier Estimate of OS Rate at 24 Months Landmark Time
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).

Outcome Measure Data

Analysis Population Description
FD Cohort - All Treated Population

Arm/Group Title	FD Cohort, Non-Del 17p Population: All Treated	FD Cohort: All Treated
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.
Measure Participants	136	159
Number (95% Confidence Interval) [percentage of participants]	97.7 61.4%	98.1 59.8%

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)
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).

Outcome Measure Data

Analysis Population Description
FD Cohort: All Treated Population with baseline TLS high risk

Arm/Group Title	FD Cohort: All Treated
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.
Measure Participants	34
Number [percentage of participants]	94.1 59.2%

17. Secondary Outcome

Title	FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs
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.

Outcome Measure Data

Analysis Population Description
FD Cohort: All Treated Population

Arm/Group Title	FD Cohort: All Treated
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.
Measure Participants	159
Any TEAE	99.4 62.5%
Any Grade >=3 TEAE	62.3 39.2%
Any Ibrutinib (Ibr)-Related TEAE	92.5 58.2%
Any Grade >=3 Ibrutinib-Related TEAE	44.7 28.1%
Any Venetoclax (Ven)-Related TEAE	84.3 53%
Any Grade >=3 Venetoclax-Related TEAE	44.7 28.1%
Any TEAE Leading to Ibr or Ven Discontinuation	5.0 3.1%
Any TEAE Leading to Ibr or Ven Discontinuation: Ibr Only	3.1 1.9%
Any TEAE Leading to Ibr or Ven Discontinuation: Ven Only	0 0%
Any TEAE Leading to Ibr or Ven Discontinuation: Both Ibr and Ven	1.9 1.2%
Any TEAE Leading to Ibr or Ven Dose Reduction	20.8 13.1%
Any TEAE Leading to Ibr Only Dose Reduction	5.7 3.6%
Any TEAE Leading to Ven Only Dose Reduction	11.3 7.1%
Any TEAE Leading to Both Ibr and Ven Dose Reduction	3.8 2.4%
Any SAE	22.6 14.2%
Any Grade >= 3 SAE	19.5 12.3%
Any SAE Related to Ibr or Ven	13.2 8.3%
Any Ibr-related SAE	11.3 7.1%
Any Ven-related SAE	8.2 5.2%
Fatal TEAE	0.6 0.4%
Major Hemorrhage TEAE	1.9 1.2%
Grade >= 3 Major Hemorrhage TEAE	1.3 0.8%
Major Hemorrhage SAE	1.3 0.8%

18. Secondary Outcome

Title	MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax)
Description
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)

Outcome Measure Data

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
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.
Measure Participants	130
Geometric Mean (Geometric Coefficient of Variation) [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)
Description
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)

Outcome Measure Data

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
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.
Measure Participants	130
tmax	2.00
tlast	24.0
t1/2term	5.30

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)
Description
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)

Outcome Measure Data

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
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.
Measure Participants	128
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)
Description
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)

Outcome Measure Data

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
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.
Measure Participants	91
Geometric Mean (Geometric Coefficient of Variation) [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)
Description
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)

Outcome Measure Data

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
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.
Measure Participants	128
Geometric Mean (Geometric Coefficient of Variation) [L/h]	833 (90.9)

23. Secondary Outcome

Title	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Cmax
Description
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)

Outcome Measure Data

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
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.
Measure Participants	131
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3034 (56.3)

24. Secondary Outcome

Title	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Tmax
Description
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)

Outcome Measure Data

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
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.
Measure Participants	131
Median (Full Range) [hours]	6.00

25. Secondary Outcome

Title	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: AUC0-24h
Description
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)

Outcome Measure Data

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
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.
Measure Participants	131
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	48993 (66.2)

26. Secondary Outcome

Title	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: CLss/F
Description
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)

Outcome Measure Data

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
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.
Measure Participants	131
Geometric Mean (Geometric Coefficient of Variation) [L/h]	8.16 (69.7)

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
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

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
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
	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	3/159 (1.9%)		0/164 (0%)		1/164 (0.6%)		0/43 (0%)		0/43 (0%)		0/43 (0%)		0/43 (0%)		0/31 (0%)		1/31 (3.2%)		0/32 (0%)		0/32 (0%)
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 (22.6%)		34/164 (20.7%)		51/164 (31.1%)		7/43 (16.3%)		12/43 (27.9%)		8/43 (18.6%)		8/43 (18.6%)		8/31 (25.8%)		11/31 (35.5%)		3/32 (9.4%)		12/32 (37.5%)
Blood and lymphatic system disorders
ANAEMIA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
FEBRILE NEUTROPENIA	1/159 (0.6%)	1	3/164 (1.8%)	3	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	3/43 (7%)	3	3/43 (7%)	3	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
HAEMOLYSIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
NEUTROPENIA	1/159 (0.6%)	1	1/164 (0.6%)	1	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
Cardiac disorders
ATRIAL FIBRILLATION	2/159 (1.3%)	2	4/164 (2.4%)	6	5/164 (3%)	7	1/43 (2.3%)	1	2/43 (4.7%)	2	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	3	1/31 (3.2%)	3	0/32 (0%)	0	0/32 (0%)	0
BRADYCARDIA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CARDIAC ARREST	0/159 (0%)	0	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CARDIAC FAILURE	1/159 (0.6%)	1	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
CONGESTIVE CARDIOMYOPATHY	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
CORONARY ARTERY STENOSIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
PALPITATIONS	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
PERICARDITIS	1/159 (0.6%)	1	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
SINUS BRADYCARDIA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
VENTRICULAR TACHYARRHYTHMIA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Congenital, familial and genetic disorders
MALFORMATION VENOUS	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Ear and labyrinth disorders
VERTIGO	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
VERTIGO POSITIONAL	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Eye disorders
EYE HAEMORRHAGE	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
MACULAR OEDEMA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
RETINAL HAEMORRHAGE	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Gastrointestinal disorders
ABDOMINAL PAIN	0/159 (0%)	0	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
COLITIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
DIARRHOEA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
NAUSEA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
RETROPERITONEAL HAEMORRHAGE	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
VOMITING	2/159 (1.3%)	2	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
General disorders
NON-CARDIAC CHEST PAIN	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
PAIN	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
PYREXIA	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	2
SUDDEN CARDIAC DEATH	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
SUDDEN DEATH	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Hepatobiliary disorders
BILE DUCT STONE	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CHOLELITHIASIS	1/159 (0.6%)	1	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
HEPATITIS	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Immune system disorders
ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY POSITIVE VASCULITIS	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Infections and infestations
ABDOMINAL ABSCESS	0/159 (0%)	0	0/164 (0%)	0	2/164 (1.2%)	2	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
APPENDICEAL ABSCESS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
APPENDICITIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
BRONCHITIS	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CAMPYLOBACTER INFECTION	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CELLULITIS	4/159 (2.5%)	4	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
COVID-19	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
DISSEMINATED VARICELLA ZOSTER VIRUS INFECTION	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
EMPYEMA	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
ESCHERICHIA BACTERAEMIA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
GASTROENTERITIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
INFLUENZA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
LOWER RESPIRATORY TRACT INFECTION BACTERIAL	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
LYMPHADENITIS BACTERIAL	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
PHARYNGITIS	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
PILONIDAL CYST	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
PNEUMONIA	3/159 (1.9%)	4	3/164 (1.8%)	3	7/164 (4.3%)	7	1/43 (2.3%)	1	3/43 (7%)	3	0/43 (0%)	0	1/43 (2.3%)	1	2/31 (6.5%)	2	2/31 (6.5%)	2	0/32 (0%)	0	2/32 (6.3%)	2
PYELONEPHRITIS	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
SALMONELLOSIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
SKIN INFECTION	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
STAPHYLOCOCCAL BACTERAEMIA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
VIRAL INFECTION	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
VIRAL UPPER RESPIRATORY TRACT INFECTION	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
WEST NILE VIRAL INFECTION	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Injury, poisoning and procedural complications
FEMUR FRACTURE	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
SPINAL COMPRESSION FRACTURE	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Investigations
BLOOD PRESSURE DECREASED	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
INFLUENZA B VIRUS TEST POSITIVE	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
Metabolism and nutrition disorders
HYPERPHOSPHATAEMIA	1/159 (0.6%)	1	1/164 (0.6%)	1	1/164 (0.6%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
HYPONATRAEMIA	2/159 (1.3%)	2	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
ARTHRITIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
BACK PAIN	1/159 (0.6%)	2	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
OSTEOPOROSIS	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
SPINAL SYNOVIAL CYST	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
INVASIVE DUCTAL BREAST CARCINOMA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
LUNG ADENOCARCINOMA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
MYELODYSPLASTIC SYNDROME	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
PROSTATE CANCER	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
RENAL CANCER	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
RENAL ONCOCYTOMA	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Nervous system disorders
ALTERED STATE OF CONSCIOUSNESS	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
AMNESIA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CEREBRAL HAEMORRHAGE	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
CEREBRAL VENOUS SINUS THROMBOSIS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
EPILEPSY	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
HEADACHE	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
HEPATIC ENCEPHALOPATHY	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
ISCHAEMIC STROKE	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
SUBARACHNOID HAEMORRHAGE	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
TRANSIENT ISCHAEMIC ATTACK	0/159 (0%)	0	0/164 (0%)	0	2/164 (1.2%)	2	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
Psychiatric disorders
ANXIETY	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
SCHIZOPHRENIA	1/159 (0.6%)	2	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY	1/159 (0.6%)	1	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
RENAL COLIC	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Reproductive system and breast disorders
MENORRHAGIA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Respiratory, thoracic and mediastinal disorders
BRONCHOSPASM	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
DYSPNOEA	2/159 (1.3%)	2	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
EMPHYSEMA	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
PULMONARY EMBOLISM	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
RESPIRATORY DISTRESS	0/159 (0%)	0	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Skin and subcutaneous tissue disorders
DERMATITIS BULLOUS	0/159 (0%)	0	1/164 (0.6%)	1	1/164 (0.6%)	1	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
Vascular disorders
CIRCULATORY COLLAPSE	1/159 (0.6%)	1	0/164 (0%)	0	0/164 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
HYPERTENSION	1/159 (0.6%)	1	0/164 (0%)	0	1/164 (0.6%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Other (Not Including 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	156/159 (98.1%)		162/164 (98.8%)		162/164 (98.8%)		43/43 (100%)		43/43 (100%)		42/43 (97.7%)		43/43 (100%)		31/31 (100%)		31/31 (100%)		32/32 (100%)		32/32 (100%)
Blood and lymphatic system disorders
ANAEMIA	10/159 (6.3%)	16	10/164 (6.1%)	22	12/164 (7.3%)	25	3/43 (7%)	7	4/43 (9.3%)	9	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	7	3/31 (9.7%)	8	4/32 (12.5%)	6	4/32 (12.5%)	6
INCREASED TENDENCY TO BRUISE	35/159 (22%)	44	35/164 (21.3%)	47	40/164 (24.4%)	57	11/43 (25.6%)	15	12/43 (27.9%)	17	6/43 (14%)	7	7/43 (16.3%)	9	9/31 (29%)	13	11/31 (35.5%)	18	6/32 (18.8%)	8	8/32 (25%)	11
NEUTROPENIA	65/159 (40.9%)	169	68/164 (41.5%)	223	72/164 (43.9%)	241	24/43 (55.8%)	102	24/43 (55.8%)	105	16/43 (37.2%)	35	16/43 (37.2%)	36	10/31 (32.3%)	26	12/31 (38.7%)	29	12/32 (37.5%)	40	14/32 (43.8%)	52
SPONTANEOUS HAEMATOMA	2/159 (1.3%)	4	4/164 (2.4%)	8	4/164 (2.4%)	12	1/43 (2.3%)	2	1/43 (2.3%)	3	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	4	1/32 (3.1%)	4	1/32 (3.1%)	5
THROMBOCYTOPENIA	21/159 (13.2%)	38	30/164 (18.3%)	59	32/164 (19.5%)	68	7/43 (16.3%)	13	8/43 (18.6%)	19	5/43 (11.6%)	9	6/43 (14%)	10	4/31 (12.9%)	10	5/31 (16.1%)	12	10/32 (31.3%)	20	10/32 (31.3%)	21
Cardiac disorders
ATRIAL FIBRILLATION	5/159 (3.1%)	7	8/164 (4.9%)	10	12/164 (7.3%)	17	2/43 (4.7%)	2	2/43 (4.7%)	2	3/43 (7%)	3	3/43 (7%)	3	2/31 (6.5%)	2	3/31 (9.7%)	3	0/32 (0%)	0	3/32 (9.4%)	5
PALPITATIONS	15/159 (9.4%)	17	21/164 (12.8%)	25	23/164 (14%)	32	10/43 (23.3%)	13	10/43 (23.3%)	16	6/43 (14%)	6	7/43 (16.3%)	9	0/31 (0%)	0	1/31 (3.2%)	1	4/32 (12.5%)	5	5/32 (15.6%)	7
SINUS TACHYCARDIA	2/159 (1.3%)	4	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
Ear and labyrinth disorders
VERTIGO	3/159 (1.9%)	3	7/164 (4.3%)	9	7/164 (4.3%)	9	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	2	1/43 (2.3%)	3	2/31 (6.5%)	2	2/31 (6.5%)	2	3/32 (9.4%)	4	3/32 (9.4%)	4
Endocrine disorders
HYPOTHYROIDISM	1/159 (0.6%)	1	1/164 (0.6%)	1	3/164 (1.8%)	3	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	2/32 (6.3%)	2
Eye disorders
DRY EYE	3/159 (1.9%)	3	6/164 (3.7%)	6	7/164 (4.3%)	7	2/43 (4.7%)	2	2/43 (4.7%)	2	1/43 (2.3%)	1	2/43 (4.7%)	2	1/31 (3.2%)	1	1/31 (3.2%)	1	2/32 (6.3%)	2	2/32 (6.3%)	2
VISION BLURRED	2/159 (1.3%)	2	9/164 (5.5%)	10	12/164 (7.3%)	14	2/43 (4.7%)	3	4/43 (9.3%)	6	0/43 (0%)	0	0/43 (0%)	0	3/31 (9.7%)	3	3/31 (9.7%)	3	3/32 (9.4%)	3	4/32 (12.5%)	4
Gastrointestinal disorders
ABDOMINAL DISCOMFORT	4/159 (2.5%)	5	10/164 (6.1%)	12	10/164 (6.1%)	12	5/43 (11.6%)	5	5/43 (11.6%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	2	1/31 (3.2%)	2	2/32 (6.3%)	3	2/32 (6.3%)	3
ABDOMINAL DISTENSION	10/159 (6.3%)	11	10/164 (6.1%)	15	12/164 (7.3%)	17	3/43 (7%)	5	4/43 (9.3%)	6	2/43 (4.7%)	5	3/43 (7%)	6	3/31 (9.7%)	3	4/31 (12.9%)	4	0/32 (0%)	0	0/32 (0%)	0
ABDOMINAL PAIN	13/159 (8.2%)	16	25/164 (15.2%)	29	26/164 (15.9%)	31	7/43 (16.3%)	7	7/43 (16.3%)	7	9/43 (20.9%)	10	9/43 (20.9%)	10	2/31 (6.5%)	2	2/31 (6.5%)	2	5/32 (15.6%)	6	6/32 (18.8%)	8
ABDOMINAL PAIN UPPER	13/159 (8.2%)	14	16/164 (9.8%)	21	20/164 (12.2%)	25	3/43 (7%)	3	4/43 (9.3%)	4	3/43 (7%)	3	3/43 (7%)	4	5/31 (16.1%)	10	7/31 (22.6%)	12	4/32 (12.5%)	4	5/32 (15.6%)	5
APHTHOUS ULCER	8/159 (5%)	10	8/164 (4.9%)	11	8/164 (4.9%)	11	2/43 (4.7%)	3	2/43 (4.7%)	3	5/43 (11.6%)	7	5/43 (11.6%)	7	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
CONSTIPATION	25/159 (15.7%)	31	27/164 (16.5%)	36	31/164 (18.9%)	42	7/43 (16.3%)	10	10/43 (23.3%)	13	7/43 (16.3%)	8	8/43 (18.6%)	10	7/31 (22.6%)	9	8/31 (25.8%)	11	6/32 (18.8%)	9	6/32 (18.8%)	10
DIARRHOEA	99/159 (62.3%)	201	115/164 (70.1%)	290	117/164 (71.3%)	406	33/43 (76.7%)	83	33/43 (76.7%)	85	27/43 (62.8%)	51	27/43 (62.8%)	60	23/31 (74.2%)	48	23/31 (74.2%)	56	26/32 (81.3%)	93	28/32 (87.5%)	199
DRY MOUTH	6/159 (3.8%)	6	7/164 (4.3%)	7	8/164 (4.9%)	8	4/43 (9.3%)	4	4/43 (9.3%)	4	2/43 (4.7%)	2	2/43 (4.7%)	2	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
DYSPEPSIA	29/159 (18.2%)	37	28/164 (17.1%)	32	30/164 (18.3%)	35	10/43 (23.3%)	10	10/43 (23.3%)	10	5/43 (11.6%)	5	5/43 (11.6%)	8	6/31 (19.4%)	10	7/31 (22.6%)	12	6/32 (18.8%)	6	7/32 (21.9%)	7
FLATULENCE	6/159 (3.8%)	6	6/164 (3.7%)	6	7/164 (4.3%)	7	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	2/43 (4.7%)	2	0/31 (0%)	0	1/31 (3.2%)	1	3/32 (9.4%)	3	3/32 (9.4%)	3
GASTROOESOPHAGEAL REFLUX DISEASE	15/159 (9.4%)	17	26/164 (15.9%)	30	27/164 (16.5%)	32	6/43 (14%)	7	7/43 (16.3%)	8	4/43 (9.3%)	6	4/43 (9.3%)	6	6/31 (19.4%)	7	6/31 (19.4%)	8	7/32 (21.9%)	7	7/32 (21.9%)	7
GINGIVAL BLEEDING	3/159 (1.9%)	3	5/164 (3%)	6	7/164 (4.3%)	8	1/43 (2.3%)	1	2/43 (4.7%)	2	1/43 (2.3%)	1	1/43 (2.3%)	1	3/31 (9.7%)	4	4/31 (12.9%)	5	0/32 (0%)	0	0/32 (0%)	0
GLOSSODYNIA	0/159 (0%)	0	1/164 (0.6%)	1	2/164 (1.2%)	3	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	2/31 (6.5%)	3	0/32 (0%)	0	0/32 (0%)	0
HAEMORRHOIDAL HAEMORRHAGE	0/159 (0%)	0	2/164 (1.2%)	2	4/164 (2.4%)	4	1/43 (2.3%)	1	2/43 (4.7%)	2	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	2/32 (6.3%)	2
HAEMORRHOIDS	1/159 (0.6%)	2	4/164 (2.4%)	4	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	3/43 (7%)	3	3/43 (7%)	3	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
MOUTH ULCERATION	24/159 (15.1%)	30	14/164 (8.5%)	18	16/164 (9.8%)	28	3/43 (7%)	3	5/43 (11.6%)	7	3/43 (7%)	3	4/43 (9.3%)	4	5/31 (16.1%)	7	5/31 (16.1%)	9	3/32 (9.4%)	5	3/32 (9.4%)	9
NAUSEA	68/159 (42.8%)	97	73/164 (44.5%)	103	78/164 (47.6%)	120	20/43 (46.5%)	29	20/43 (46.5%)	34	19/43 (44.2%)	24	19/43 (44.2%)	25	18/31 (58.1%)	31	20/31 (64.5%)	36	9/32 (28.1%)	11	12/32 (37.5%)	17
ORAL PAIN	1/159 (0.6%)	1	3/164 (1.8%)	3	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
RECTAL HAEMORRHAGE	2/159 (1.3%)	2	2/164 (1.2%)	2	4/164 (2.4%)	4	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	3/32 (9.4%)	3
STOMATITIS	21/159 (13.2%)	33	24/164 (14.6%)	47	27/164 (16.5%)	59	8/43 (18.6%)	10	8/43 (18.6%)	11	8/43 (18.6%)	13	8/43 (18.6%)	13	3/31 (9.7%)	6	6/31 (19.4%)	11	3/32 (9.4%)	15	3/32 (9.4%)	21
TOOTHACHE	2/159 (1.3%)	2	5/164 (3%)	5	6/164 (3.7%)	6	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	1	1/31 (3.2%)	1	2/32 (6.3%)	2	2/32 (6.3%)	2
VOMITING	33/159 (20.8%)	48	35/164 (21.3%)	53	41/164 (25%)	68	13/43 (30.2%)	20	13/43 (30.2%)	24	6/43 (14%)	10	6/43 (14%)	10	5/31 (16.1%)	9	7/31 (22.6%)	15	6/32 (18.8%)	8	10/32 (31.3%)	13
General disorders
ASTHENIA	7/159 (4.4%)	11	10/164 (6.1%)	13	11/164 (6.7%)	14	2/43 (4.7%)	2	2/43 (4.7%)	2	2/43 (4.7%)	3	3/43 (7%)	4	2/31 (6.5%)	4	2/31 (6.5%)	4	2/32 (6.3%)	2	3/32 (9.4%)	3
CHEST DISCOMFORT	3/159 (1.9%)	3	3/164 (1.8%)	3	5/164 (3%)	5	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	2/43 (4.7%)	2	2/31 (6.5%)	2	4/31 (12.9%)	4	0/32 (0%)	0	0/32 (0%)	0
CHEST PAIN	4/159 (2.5%)	4	4/164 (2.4%)	4	5/164 (3%)	5	2/43 (4.7%)	2	2/43 (4.7%)	2	0/43 (0%)	0	1/43 (2.3%)	1	1/31 (3.2%)	1	2/31 (6.5%)	2	1/32 (3.1%)	1	1/32 (3.1%)	1
CHILLS	5/159 (3.1%)	5	10/164 (6.1%)	12	13/164 (7.9%)	17	2/43 (4.7%)	2	4/43 (9.3%)	4	4/43 (9.3%)	5	5/43 (11.6%)	6	1/31 (3.2%)	1	1/31 (3.2%)	1	3/32 (9.4%)	4	4/32 (12.5%)	7
FATIGUE	39/159 (24.5%)	50	46/164 (28%)	67	48/164 (29.3%)	81	11/43 (25.6%)	15	13/43 (30.2%)	21	15/43 (34.9%)	23	18/43 (41.9%)	32	10/31 (32.3%)	16	10/31 (32.3%)	20	7/32 (21.9%)	9	7/32 (21.9%)	12
INFLUENZA LIKE ILLNESS	6/159 (3.8%)	6	5/164 (3%)	5	8/164 (4.9%)	8	1/43 (2.3%)	1	2/43 (4.7%)	2	0/43 (0%)	0	1/43 (2.3%)	1	3/31 (9.7%)	3	4/31 (12.9%)	4	0/32 (0%)	0	1/32 (3.1%)	1
INJECTION SITE BRUISING	0/159 (0%)	0	4/164 (2.4%)	4	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
NON-CARDIAC CHEST PAIN	1/159 (0.6%)	1	2/164 (1.2%)	2	4/164 (2.4%)	5	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	3/31 (9.7%)	4	1/32 (3.1%)	1	1/32 (3.1%)	1
OEDEMA PERIPHERAL	11/159 (6.9%)	12	13/164 (7.9%)	20	18/164 (11%)	26	3/43 (7%)	5	5/43 (11.6%)	7	5/43 (11.6%)	7	6/43 (14%)	8	1/31 (3.2%)	1	3/31 (9.7%)	4	3/32 (9.4%)	6	4/32 (12.5%)	7
PAIN	4/159 (2.5%)	7	6/164 (3.7%)	6	8/164 (4.9%)	8	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	2/43 (4.7%)	2	3/31 (9.7%)	3	5/31 (16.1%)	5	2/32 (6.3%)	2	2/32 (6.3%)	2
PERIPHERAL SWELLING	11/159 (6.9%)	11	4/164 (2.4%)	4	6/164 (3.7%)	6	0/43 (0%)	0	0/43 (0%)	0	2/43 (4.7%)	2	2/43 (4.7%)	2	1/31 (3.2%)	1	2/31 (6.5%)	2	1/32 (3.1%)	1	2/32 (6.3%)	2
PYREXIA	21/159 (13.2%)	36	21/164 (12.8%)	25	26/164 (15.9%)	33	3/43 (7%)	3	6/43 (14%)	6	4/43 (9.3%)	4	4/43 (9.3%)	4	2/31 (6.5%)	2	3/31 (9.7%)	4	8/32 (25%)	9	9/32 (28.1%)	12
Immune system disorders
SEASONAL ALLERGY	1/159 (0.6%)	1	5/164 (3%)	5	7/164 (4.3%)	7	1/43 (2.3%)	1	1/43 (2.3%)	1	2/43 (4.7%)	2	2/43 (4.7%)	2	0/31 (0%)	0	2/31 (6.5%)	2	2/32 (6.3%)	2	2/32 (6.3%)	2
Infections and infestations
BRONCHITIS	5/159 (3.1%)	6	4/164 (2.4%)	4	5/164 (3%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	1/43 (2.3%)	1	2/31 (6.5%)	2	3/31 (9.7%)	3	1/32 (3.1%)	1	1/32 (3.1%)	1
CELLULITIS	7/159 (4.4%)	7	10/164 (6.1%)	13	11/164 (6.7%)	15	2/43 (4.7%)	2	2/43 (4.7%)	2	5/43 (11.6%)	5	5/43 (11.6%)	5	0/31 (0%)	0	0/31 (0%)	0	3/32 (9.4%)	6	4/32 (12.5%)	8
CONJUNCTIVITIS	5/159 (3.1%)	6	4/164 (2.4%)	4	8/164 (4.9%)	8	0/43 (0%)	0	1/43 (2.3%)	1	2/43 (4.7%)	2	2/43 (4.7%)	2	0/31 (0%)	0	2/31 (6.5%)	2	1/32 (3.1%)	1	2/32 (6.3%)	2
FOLLICULITIS	3/159 (1.9%)	3	4/164 (2.4%)	8	6/164 (3.7%)	11	3/43 (7%)	7	4/43 (9.3%)	9	0/43 (0%)	0	2/43 (4.7%)	2	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
FUNGAL SKIN INFECTION	4/159 (2.5%)	4	5/164 (3%)	5	6/164 (3.7%)	6	3/43 (7%)	3	3/43 (7%)	3	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
FURUNCLE	0/159 (0%)	0	1/164 (0.6%)	1	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
GASTROENTERITIS	5/159 (3.1%)	6	6/164 (3.7%)	6	7/164 (4.3%)	7	4/43 (9.3%)	4	4/43 (9.3%)	4	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	2	0/32 (0%)	0	1/32 (3.1%)	1
HERPES ZOSTER	1/159 (0.6%)	1	3/164 (1.8%)	4	6/164 (3.7%)	7	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	1/32 (3.1%)	1	4/32 (12.5%)	4
INFLUENZA	9/159 (5.7%)	9	4/164 (2.4%)	5	7/164 (4.3%)	10	4/43 (9.3%)	5	6/43 (14%)	9	0/43 (0%)	0	1/43 (2.3%)	1	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
LOCALISED INFECTION	7/159 (4.4%)	8	3/164 (1.8%)	3	6/164 (3.7%)	9	1/43 (2.3%)	1	3/43 (7%)	4	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	2/31 (6.5%)	4	1/32 (3.1%)	1	1/32 (3.1%)	1
LOWER RESPIRATORY TRACT INFECTION	3/159 (1.9%)	4	4/164 (2.4%)	5	5/164 (3%)	6	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	3/31 (9.7%)	3	4/31 (12.9%)	4	0/32 (0%)	0	0/32 (0%)	0
NASOPHARYNGITIS	11/159 (6.9%)	15	11/164 (6.7%)	13	23/164 (14%)	27	3/43 (7%)	4	6/43 (14%)	8	4/43 (9.3%)	4	6/43 (14%)	6	1/31 (3.2%)	1	8/31 (25.8%)	9	3/32 (9.4%)	4	5/32 (15.6%)	6
ORAL HERPES	7/159 (4.4%)	8	7/164 (4.3%)	7	8/164 (4.9%)	10	2/43 (4.7%)	2	3/43 (7%)	5	1/43 (2.3%)	1	2/43 (4.7%)	2	1/31 (3.2%)	1	1/31 (3.2%)	1	3/32 (9.4%)	3	3/32 (9.4%)	3
PARONYCHIA	4/159 (2.5%)	5	8/164 (4.9%)	11	12/164 (7.3%)	18	2/43 (4.7%)	2	4/43 (9.3%)	6	2/43 (4.7%)	2	2/43 (4.7%)	2	2/31 (6.5%)	2	3/31 (9.7%)	3	2/32 (6.3%)	5	3/32 (9.4%)	7
PHARYNGITIS	3/159 (1.9%)	4	1/164 (0.6%)	1	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	1/32 (3.1%)	1	2/32 (6.3%)	2
RASH PUSTULAR	0/159 (0%)	0	3/164 (1.8%)	4	4/164 (2.4%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	2	1/31 (3.2%)	2	1/32 (3.1%)	1	2/32 (6.3%)	2
RESPIRATORY TRACT INFECTION	1/159 (0.6%)	1	5/164 (3%)	8	6/164 (3.7%)	9	1/43 (2.3%)	2	1/43 (2.3%)	2	4/43 (9.3%)	6	6/43 (14%)	8	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
RHINITIS	2/159 (1.3%)	2	3/164 (1.8%)	4	5/164 (3%)	7	2/43 (4.7%)	3	3/43 (7%)	5	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	1/31 (3.2%)	1	1/32 (3.1%)	1	1/32 (3.1%)	1
SINUSITIS	10/159 (6.3%)	16	10/164 (6.1%)	16	19/164 (11.6%)	30	1/43 (2.3%)	1	6/43 (14%)	9	3/43 (7%)	3	4/43 (9.3%)	5	3/31 (9.7%)	6	5/31 (16.1%)	9	3/32 (9.4%)	6	4/32 (12.5%)	8
SKIN INFECTION	4/159 (2.5%)	4	4/164 (2.4%)	5	6/164 (3.7%)	7	1/43 (2.3%)	1	1/43 (2.3%)	1	2/43 (4.7%)	3	2/43 (4.7%)	3	0/31 (0%)	0	1/31 (3.2%)	1	1/32 (3.1%)	1	2/32 (6.3%)	2
TINEA PEDIS	0/159 (0%)	0	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
TOOTH INFECTION	1/159 (0.6%)	1	5/164 (3%)	6	6/164 (3.7%)	7	1/43 (2.3%)	1	1/43 (2.3%)	1	2/43 (4.7%)	3	4/43 (9.3%)	5	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
UPPER RESPIRATORY TRACT INFECTION	37/159 (23.3%)	47	48/164 (29.3%)	63	64/164 (39%)	104	14/43 (32.6%)	19	18/43 (41.9%)	37	15/43 (34.9%)	20	20/43 (46.5%)	42	11/31 (35.5%)	13	14/31 (45.2%)	24	3/32 (9.4%)	4	11/32 (34.4%)	15
URINARY TRACT INFECTION	12/159 (7.5%)	16	11/164 (6.7%)	18	19/164 (11.6%)	29	3/43 (7%)	3	7/43 (16.3%)	9	3/43 (7%)	7	5/43 (11.6%)	10	3/31 (9.7%)	3	6/31 (19.4%)	7	2/32 (6.3%)	5	3/32 (9.4%)	6
VIRAL INFECTION	2/159 (1.3%)	2	5/164 (3%)	7	6/164 (3.7%)	8	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	2	1/31 (3.2%)	2	2/32 (6.3%)	3	3/32 (9.4%)	4
Injury, poisoning and procedural complications
ARTHROPOD BITE	5/159 (3.1%)	5	3/164 (1.8%)	3	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
CONTUSION	24/159 (15.1%)	25	31/164 (18.9%)	45	35/164 (21.3%)	54	8/43 (18.6%)	9	8/43 (18.6%)	11	8/43 (18.6%)	13	10/43 (23.3%)	16	7/31 (22.6%)	10	10/31 (32.3%)	14	6/32 (18.8%)	11	6/32 (18.8%)	13
EYE CONTUSION	0/159 (0%)	0	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
LIMB INJURY	3/159 (1.9%)	3	3/164 (1.8%)	3	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	2/43 (4.7%)	2	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
RIB FRACTURE	1/159 (0.6%)	1	2/164 (1.2%)	2	3/164 (1.8%)	3	0/43 (0%)	0	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
SCRATCH	1/159 (0.6%)	1	2/164 (1.2%)	2	4/164 (2.4%)	4	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	3/31 (9.7%)	3	1/32 (3.1%)	1	1/32 (3.1%)	1
SKIN ABRASION	4/159 (2.5%)	5	5/164 (3%)	5	9/164 (5.5%)	9	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	6/32 (18.8%)	6
SKIN LACERATION	3/159 (1.9%)	3	5/164 (3%)	5	6/164 (3.7%)	6	1/43 (2.3%)	1	2/43 (4.7%)	2	1/43 (2.3%)	1	1/43 (2.3%)	1	3/31 (9.7%)	3	3/31 (9.7%)	3	0/32 (0%)	0	0/32 (0%)	0
WOUND HAEMORRHAGE	0/159 (0%)	0	2/164 (1.2%)	2	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	3/32 (9.4%)	3
Investigations
ALANINE AMINOTRANSFERASE INCREASED	6/159 (3.8%)	6	10/164 (6.1%)	18	13/164 (7.9%)	26	1/43 (2.3%)	1	2/43 (4.7%)	4	3/43 (7%)	3	5/43 (11.6%)	7	2/31 (6.5%)	8	3/31 (9.7%)	9	3/32 (9.4%)	4	3/32 (9.4%)	5
ASPARTATE AMINOTRANSFERASE INCREASED	9/159 (5.7%)	16	13/164 (7.9%)	17	14/164 (8.5%)	19	3/43 (7%)	3	4/43 (9.3%)	4	5/43 (11.6%)	5	5/43 (11.6%)	6	2/31 (6.5%)	4	2/31 (6.5%)	4	2/32 (6.3%)	4	2/32 (6.3%)	5
BLOOD BILIRUBIN INCREASED	6/159 (3.8%)	15	5/164 (3%)	9	5/164 (3%)	15	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	3/31 (9.7%)	7	3/31 (9.7%)	12	1/32 (3.1%)	1	1/32 (3.1%)	2
BLOOD CREATININE INCREASED	7/159 (4.4%)	8	12/164 (7.3%)	12	13/164 (7.9%)	17	5/43 (11.6%)	5	5/43 (11.6%)	6	2/43 (4.7%)	2	4/43 (9.3%)	4	1/31 (3.2%)	1	2/31 (6.5%)	4	4/32 (12.5%)	4	4/32 (12.5%)	5
NEUTROPHIL COUNT DECREASED	16/159 (10.1%)	38	4/164 (2.4%)	5	5/164 (3%)	6	1/43 (2.3%)	1	2/43 (4.7%)	2	2/43 (4.7%)	2	2/43 (4.7%)	2	1/31 (3.2%)	2	1/31 (3.2%)	2	0/32 (0%)	0	0/32 (0%)	0
PLATELET COUNT DECREASED	7/159 (4.4%)	12	8/164 (4.9%)	11	8/164 (4.9%)	11	4/43 (9.3%)	7	4/43 (9.3%)	7	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
WEIGHT DECREASED	6/159 (3.8%)	6	6/164 (3.7%)	6	7/164 (4.3%)	7	3/43 (7%)	3	4/43 (9.3%)	4	2/43 (4.7%)	2	2/43 (4.7%)	2	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
WHITE BLOOD CELL COUNT DECREASED	6/159 (3.8%)	15	4/164 (2.4%)	5	4/164 (2.4%)	6	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	2	2/32 (6.3%)	3	2/32 (6.3%)	4
Metabolism and nutrition disorders
DECREASED APPETITE	7/159 (4.4%)	9	16/164 (9.8%)	18	17/164 (10.4%)	20	4/43 (9.3%)	4	5/43 (11.6%)	6	7/43 (16.3%)	7	7/43 (16.3%)	7	4/31 (12.9%)	5	4/31 (12.9%)	5	1/32 (3.1%)	2	1/32 (3.1%)	2
HYPERGLYCAEMIA	3/159 (1.9%)	4	2/164 (1.2%)	3	3/164 (1.8%)	4	1/43 (2.3%)	2	1/43 (2.3%)	2	1/43 (2.3%)	1	6/43 (14%)	6	0/31 (0%)	0	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
HYPERKALAEMIA	5/159 (3.1%)	5	12/164 (7.3%)	14	12/164 (7.3%)	14	3/43 (7%)	5	3/43 (7%)	5	2/43 (4.7%)	2	2/43 (4.7%)	2	4/31 (12.9%)	4	4/31 (12.9%)	4	3/32 (9.4%)	3	3/32 (9.4%)	3
HYPERPHOSPHATAEMIA	7/159 (4.4%)	9	8/164 (4.9%)	11	8/164 (4.9%)	11	4/43 (9.3%)	4	4/43 (9.3%)	4	3/43 (7%)	4	3/43 (7%)	4	1/31 (3.2%)	3	1/31 (3.2%)	3	0/32 (0%)	0	0/32 (0%)	0
HYPERURICAEMIA	12/159 (7.5%)	19	9/164 (5.5%)	14	14/164 (8.5%)	23	5/43 (11.6%)	7	5/43 (11.6%)	8	2/43 (4.7%)	2	2/43 (4.7%)	2	1/31 (3.2%)	2	2/31 (6.5%)	3	1/32 (3.1%)	3	4/32 (12.5%)	7
HYPOCALCAEMIA	1/159 (0.6%)	1	7/164 (4.3%)	7	7/164 (4.3%)	7	2/43 (4.7%)	2	2/43 (4.7%)	2	1/43 (2.3%)	1	1/43 (2.3%)	1	2/31 (6.5%)	2	2/31 (6.5%)	2	1/32 (3.1%)	1	1/32 (3.1%)	1
HYPOGLYCAEMIA	1/159 (0.6%)	1	4/164 (2.4%)	4	5/164 (3%)	5	2/43 (4.7%)	2	2/43 (4.7%)	2	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	2/31 (6.5%)	2	1/32 (3.1%)	1	1/32 (3.1%)	1
HYPOKALAEMIA	7/159 (4.4%)	8	11/164 (6.7%)	17	11/164 (6.7%)	20	3/43 (7%)	5	3/43 (7%)	8	3/43 (7%)	5	3/43 (7%)	5	2/31 (6.5%)	3	2/31 (6.5%)	3	2/32 (6.3%)	3	2/32 (6.3%)	3
HYPOMAGNESAEMIA	0/159 (0%)	0	7/164 (4.3%)	14	7/164 (4.3%)	15	3/43 (7%)	5	3/43 (7%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	2	1/31 (3.2%)	2	2/32 (6.3%)	6	2/32 (6.3%)	7
IRON DEFICIENCY	4/159 (2.5%)	4	8/164 (4.9%)	8	8/164 (4.9%)	9	2/43 (4.7%)	2	2/43 (4.7%)	2	3/43 (7%)	3	3/43 (7%)	3	1/31 (3.2%)	1	1/31 (3.2%)	1	2/32 (6.3%)	2	2/32 (6.3%)	3
VITAMIN B12 DEFICIENCY	0/159 (0%)	0	2/164 (1.2%)	2	3/164 (1.8%)	3	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	2/32 (6.3%)	2
Musculoskeletal and connective tissue disorders
ARTHRALGIA	52/159 (32.7%)	80	56/164 (34.1%)	99	67/164 (40.9%)	129	12/43 (27.9%)	23	17/43 (39.5%)	35	13/43 (30.2%)	24	19/43 (44.2%)	36	12/31 (38.7%)	20	16/31 (51.6%)	28	14/32 (43.8%)	21	15/32 (46.9%)	30
BACK PAIN	20/159 (12.6%)	22	26/164 (15.9%)	35	34/164 (20.7%)	46	7/43 (16.3%)	7	8/43 (18.6%)	8	4/43 (9.3%)	7	8/43 (18.6%)	12	4/31 (12.9%)	8	10/31 (32.3%)	17	8/32 (25%)	10	9/32 (28.1%)	11
BONE PAIN	4/159 (2.5%)	5	7/164 (4.3%)	9	7/164 (4.3%)	10	3/43 (7%)	5	3/43 (7%)	6	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	2/32 (6.3%)	2	2/32 (6.3%)	2
JOINT STIFFNESS	0/159 (0%)	0	1/164 (0.6%)	1	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	2/43 (4.7%)	2	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
MUSCLE SPASMS	47/159 (29.6%)	66	32/164 (19.5%)	40	36/164 (22%)	47	9/43 (20.9%)	11	11/43 (25.6%)	14	6/43 (14%)	9	8/43 (18.6%)	12	9/31 (29%)	10	10/31 (32.3%)	11	6/32 (18.8%)	8	7/32 (21.9%)	11
MUSCULOSKELETAL CHEST PAIN	3/159 (1.9%)	3	2/164 (1.2%)	2	4/164 (2.4%)	4	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	2/43 (4.7%)	2	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	4/32 (12.5%)	4
MUSCULOSKELETAL PAIN	0/159 (0%)	0	3/164 (1.8%)	4	5/164 (3%)	6	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/31 (0%)	0	1/31 (3.2%)	1	2/32 (6.3%)	3	2/32 (6.3%)	3
MYALGIA	23/159 (14.5%)	29	24/164 (14.6%)	35	27/164 (16.5%)	41	9/43 (20.9%)	15	9/43 (20.9%)	17	7/43 (16.3%)	9	7/43 (16.3%)	9	3/31 (9.7%)	3	5/31 (16.1%)	6	3/32 (9.4%)	3	3/32 (9.4%)	3
NECK PAIN	5/159 (3.1%)	7	5/164 (3%)	5	7/164 (4.3%)	7	2/43 (4.7%)	2	2/43 (4.7%)	2	0/43 (0%)	0	2/43 (4.7%)	2	2/31 (6.5%)	2	3/31 (9.7%)	3	0/32 (0%)	0	1/32 (3.1%)	1
OSTEOARTHRITIS	1/159 (0.6%)	1	2/164 (1.2%)	2	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	1/43 (2.3%)	1	1/31 (3.2%)	1	3/31 (9.7%)	3	0/32 (0%)	0	0/32 (0%)	0
PAIN IN EXTREMITY	21/159 (13.2%)	25	22/164 (13.4%)	27	27/164 (16.5%)	34	3/43 (7%)	3	4/43 (9.3%)	4	7/43 (16.3%)	9	7/43 (16.3%)	10	5/31 (16.1%)	5	8/31 (25.8%)	8	6/32 (18.8%)	9	7/32 (21.9%)	12
SPINAL PAIN	1/159 (0.6%)	1	1/164 (0.6%)	1	3/164 (1.8%)	4	0/43 (0%)	0	1/43 (2.3%)	2	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	2/32 (6.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	3/159 (1.9%)	4	6/164 (3.7%)	8	8/164 (4.9%)	12	1/43 (2.3%)	1	3/43 (7%)	3	3/43 (7%)	3	4/43 (9.3%)	4	1/31 (3.2%)	3	1/31 (3.2%)	5	1/32 (3.1%)	1	1/32 (3.1%)	1
Nervous system disorders
DIZZINESS	26/159 (16.4%)	33	26/164 (15.9%)	32	30/164 (18.3%)	41	6/43 (14%)	8	8/43 (18.6%)	12	9/43 (20.9%)	9	9/43 (20.9%)	11	3/31 (9.7%)	4	5/31 (16.1%)	9	6/32 (18.8%)	9	6/32 (18.8%)	9
HEADACHE	39/159 (24.5%)	55	46/164 (28%)	64	47/164 (28.7%)	74	13/43 (30.2%)	18	13/43 (30.2%)	21	16/43 (37.2%)	23	16/43 (37.2%)	26	8/31 (25.8%)	10	8/31 (25.8%)	15	7/32 (21.9%)	10	8/32 (25%)	12
HYPOAESTHESIA	1/159 (0.6%)	1	7/164 (4.3%)	8	11/164 (6.7%)	13	2/43 (4.7%)	2	3/43 (7%)	3	3/43 (7%)	3	4/43 (9.3%)	5	2/31 (6.5%)	3	4/31 (12.9%)	6	0/32 (0%)	0	1/32 (3.1%)	1
MEMORY IMPAIRMENT	1/159 (0.6%)	1	3/164 (1.8%)	3	4/164 (2.4%)	5	2/43 (4.7%)	2	3/43 (7%)	4	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
NEUROPATHY PERIPHERAL	0/159 (0%)	0	4/164 (2.4%)	4	4/164 (2.4%)	4	0/43 (0%)	0	0/43 (0%)	0	2/43 (4.7%)	2	2/43 (4.7%)	2	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
PARAESTHESIA	6/159 (3.8%)	7	10/164 (6.1%)	13	13/164 (7.9%)	16	4/43 (9.3%)	4	4/43 (9.3%)	4	3/43 (7%)	4	4/43 (9.3%)	6	2/31 (6.5%)	4	4/31 (12.9%)	6	1/32 (3.1%)	1	2/32 (6.3%)	2
SCIATICA	0/159 (0%)	0	2/164 (1.2%)	2	4/164 (2.4%)	4	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	1/43 (2.3%)	1	0/31 (0%)	0	1/31 (3.2%)	1	1/32 (3.1%)	1	2/32 (6.3%)	2
SYNCOPE	2/159 (1.3%)	2	2/164 (1.2%)	2	6/164 (3.7%)	6	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	2/31 (6.5%)	2	1/32 (3.1%)	1	3/32 (9.4%)	3
TREMOR	2/159 (1.3%)	2	1/164 (0.6%)	1	3/164 (1.8%)	4	1/43 (2.3%)	1	3/43 (7%)	4	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Psychiatric disorders
AGITATION	0/159 (0%)	0	4/164 (2.4%)	5	4/164 (2.4%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	3	2/31 (6.5%)	3	0/32 (0%)	0	0/32 (0%)	0
ANXIETY	1/159 (0.6%)	1	9/164 (5.5%)	9	12/164 (7.3%)	12	1/43 (2.3%)	1	4/43 (9.3%)	4	1/43 (2.3%)	1	2/43 (4.7%)	2	5/31 (16.1%)	5	5/31 (16.1%)	5	2/32 (6.3%)	2	2/32 (6.3%)	2
DEPRESSION	1/159 (0.6%)	1	6/164 (3.7%)	6	8/164 (4.9%)	9	2/43 (4.7%)	2	4/43 (9.3%)	4	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	3	1/32 (3.1%)	1	1/32 (3.1%)	1
INSOMNIA	6/159 (3.8%)	6	12/164 (7.3%)	12	15/164 (9.1%)	15	1/43 (2.3%)	1	1/43 (2.3%)	1	3/43 (7%)	3	5/43 (11.6%)	5	5/31 (16.1%)	5	7/31 (22.6%)	7	2/32 (6.3%)	2	3/32 (9.4%)	3
Renal and urinary disorders
HAEMATURIA	9/159 (5.7%)	9	12/164 (7.3%)	14	12/164 (7.3%)	14	3/43 (7%)	3	3/43 (7%)	3	2/43 (4.7%)	2	2/43 (4.7%)	2	3/31 (9.7%)	5	3/31 (9.7%)	5	4/32 (12.5%)	4	4/32 (12.5%)	4
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA	1/159 (0.6%)	1	3/164 (1.8%)	3	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	2/31 (6.5%)	2	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
ERECTILE DYSFUNCTION	2/159 (1.3%)	2	5/164 (3%)	5	5/164 (3%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	2	1/32 (3.1%)	1	1/32 (3.1%)	1
TESTICULAR SWELLING	2/159 (1.3%)	2	0/164 (0%)	0	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	2/32 (6.3%)	2
Respiratory, thoracic and mediastinal disorders
COUGH	27/159 (17%)	33	28/164 (17.1%)	33	36/164 (22%)	46	7/43 (16.3%)	9	13/43 (30.2%)	16	10/43 (23.3%)	12	15/43 (34.9%)	19	5/31 (16.1%)	5	7/31 (22.6%)	9	4/32 (12.5%)	4	4/32 (12.5%)	5
DYSPNOEA	9/159 (5.7%)	9	14/164 (8.5%)	16	18/164 (11%)	20	4/43 (9.3%)	4	7/43 (16.3%)	7	6/43 (14%)	6	6/43 (14%)	6	2/31 (6.5%)	3	3/31 (9.7%)	4	0/32 (0%)	0	0/32 (0%)	0
DYSPNOEA EXERTIONAL	1/159 (0.6%)	1	3/164 (1.8%)	3	4/164 (2.4%)	4	1/43 (2.3%)	1	2/43 (4.7%)	2	2/43 (4.7%)	2	3/43 (7%)	3	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
EPISTAXIS	18/159 (11.3%)	26	24/164 (14.6%)	33	30/164 (18.3%)	44	8/43 (18.6%)	11	10/43 (23.3%)	15	7/43 (16.3%)	12	8/43 (18.6%)	14	4/31 (12.9%)	5	5/31 (16.1%)	8	4/32 (12.5%)	4	6/32 (18.8%)	7
NASAL CONGESTION	4/159 (2.5%)	4	14/164 (8.5%)	17	15/164 (9.1%)	18	6/43 (14%)	7	7/43 (16.3%)	8	2/43 (4.7%)	3	2/43 (4.7%)	3	3/31 (9.7%)	3	3/31 (9.7%)	3	1/32 (3.1%)	1	1/32 (3.1%)	1
NASAL DRYNESS	1/159 (0.6%)	1	5/164 (3%)	5	5/164 (3%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	3/43 (7%)	3	3/43 (7%)	3	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	1/32 (3.1%)	1
OROPHARYNGEAL PAIN	17/159 (10.7%)	19	28/164 (17.1%)	37	36/164 (22%)	53	7/43 (16.3%)	11	10/43 (23.3%)	15	5/43 (11.6%)	7	7/43 (16.3%)	10	7/31 (22.6%)	8	9/31 (29%)	14	8/32 (25%)	9	10/32 (31.3%)	14
PRODUCTIVE COUGH	4/159 (2.5%)	4	5/164 (3%)	5	7/164 (4.3%)	7	3/43 (7%)	3	5/43 (11.6%)	5	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
RHINITIS ALLERGIC	2/159 (1.3%)	4	3/164 (1.8%)	3	6/164 (3.7%)	6	1/43 (2.3%)	1	2/43 (4.7%)	2	1/43 (2.3%)	1	1/43 (2.3%)	1	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	1/32 (3.1%)	1
SINUS CONGESTION	3/159 (1.9%)	3	5/164 (3%)	5	7/164 (4.3%)	7	2/43 (4.7%)	2	4/43 (9.3%)	4	2/43 (4.7%)	2	2/43 (4.7%)	2	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	0/32 (0%)	0
Skin and subcutaneous tissue disorders
ALOPECIA	6/159 (3.8%)	6	8/164 (4.9%)	8	8/164 (4.9%)	8	3/43 (7%)	3	3/43 (7%)	3	1/43 (2.3%)	1	2/43 (4.7%)	2	0/31 (0%)	0	0/31 (0%)	0	3/32 (9.4%)	3	3/32 (9.4%)	3
BLISTER	1/159 (0.6%)	4	4/164 (2.4%)	4	6/164 (3.7%)	6	1/43 (2.3%)	1	2/43 (4.7%)	2	2/43 (4.7%)	2	2/43 (4.7%)	2	1/31 (3.2%)	1	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
BLOOD BLISTER	6/159 (3.8%)	7	5/164 (3%)	5	5/164 (3%)	5	0/43 (0%)	0	0/43 (0%)	0	4/43 (9.3%)	4	4/43 (9.3%)	4	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
DERMATITIS ACNEIFORM	2/159 (1.3%)	2	4/164 (2.4%)	4	4/164 (2.4%)	4	2/43 (4.7%)	2	2/43 (4.7%)	2	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
DRY SKIN	16/159 (10.1%)	18	19/164 (11.6%)	19	24/164 (14.6%)	24	8/43 (18.6%)	8	10/43 (23.3%)	10	6/43 (14%)	6	7/43 (16.3%)	7	2/31 (6.5%)	2	3/31 (9.7%)	3	3/32 (9.4%)	3	5/32 (15.6%)	5
ECCHYMOSIS	4/159 (2.5%)	4	7/164 (4.3%)	7	11/164 (6.7%)	13	3/43 (7%)	3	6/43 (14%)	7	0/43 (0%)	0	0/43 (0%)	0	3/31 (9.7%)	3	3/31 (9.7%)	4	1/32 (3.1%)	1	2/32 (6.3%)	2
ECZEMA	4/159 (2.5%)	5	3/164 (1.8%)	3	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	1/43 (2.3%)	1	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2
ERYTHEMA	8/159 (5%)	8	9/164 (5.5%)	11	10/164 (6.1%)	14	1/43 (2.3%)	1	1/43 (2.3%)	1	2/43 (4.7%)	4	3/43 (7%)	5	2/31 (6.5%)	2	2/31 (6.5%)	3	4/32 (12.5%)	4	5/32 (15.6%)	6
HYPERHIDROSIS	4/159 (2.5%)	6	5/164 (3%)	6	5/164 (3%)	6	0/43 (0%)	0	0/43 (0%)	0	1/43 (2.3%)	1	2/43 (4.7%)	2	1/31 (3.2%)	1	1/31 (3.2%)	1	2/32 (6.3%)	3	2/32 (6.3%)	3
NAIL RIDGING	0/159 (0%)	0	3/164 (1.8%)	3	5/164 (3%)	5	0/43 (0%)	0	1/43 (2.3%)	1	3/43 (7%)	3	3/43 (7%)	3	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	1/32 (3.1%)	1
NIGHT SWEATS	5/159 (3.1%)	5	8/164 (4.9%)	9	13/164 (7.9%)	16	2/43 (4.7%)	2	4/43 (9.3%)	5	1/43 (2.3%)	1	3/43 (7%)	3	4/31 (12.9%)	4	5/31 (16.1%)	6	1/32 (3.1%)	2	3/32 (9.4%)	4
ONYCHOCLASIS	14/159 (8.8%)	14	17/164 (10.4%)	17	20/164 (12.2%)	20	4/43 (9.3%)	4	5/43 (11.6%)	5	5/43 (11.6%)	5	5/43 (11.6%)	6	3/31 (9.7%)	3	4/31 (12.9%)	4	4/32 (12.5%)	4	5/32 (15.6%)	5
PETECHIAE	17/159 (10.7%)	23	20/164 (12.2%)	29	24/164 (14.6%)	33	3/43 (7%)	3	4/43 (9.3%)	4	3/43 (7%)	6	3/43 (7%)	6	5/31 (16.1%)	8	6/31 (19.4%)	9	6/32 (18.8%)	9	8/32 (25%)	11
PRURITUS	17/159 (10.7%)	18	14/164 (8.5%)	17	19/164 (11.6%)	25	5/43 (11.6%)	5	6/43 (14%)	7	1/43 (2.3%)	1	2/43 (4.7%)	3	2/31 (6.5%)	2	3/31 (9.7%)	3	5/32 (15.6%)	8	7/32 (21.9%)	12
RASH	10/159 (6.3%)	12	14/164 (8.5%)	16	18/164 (11%)	21	2/43 (4.7%)	2	5/43 (11.6%)	5	3/43 (7%)	3	4/43 (9.3%)	5	3/31 (9.7%)	4	3/31 (9.7%)	5	5/32 (15.6%)	6	6/32 (18.8%)	7
RASH ERYTHEMATOUS	9/159 (5.7%)	11	10/164 (6.1%)	12	11/164 (6.7%)	14	2/43 (4.7%)	3	3/43 (7%)	5	4/43 (9.3%)	5	4/43 (9.3%)	5	1/31 (3.2%)	1	1/31 (3.2%)	1	2/32 (6.3%)	2	2/32 (6.3%)	2
RASH MACULO-PAPULAR	27/159 (17%)	32	23/164 (14%)	30	26/164 (15.9%)	34	6/43 (14%)	8	8/43 (18.6%)	11	8/43 (18.6%)	8	10/43 (23.3%)	11	4/31 (12.9%)	8	5/31 (16.1%)	9	5/32 (15.6%)	6	5/32 (15.6%)	6
SKIN ATROPHY	0/159 (0%)	0	1/164 (0.6%)	1	2/164 (1.2%)	3	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	1/32 (3.1%)	1	2/32 (6.3%)	3
SKIN DISCOLOURATION	4/159 (2.5%)	5	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	2/31 (6.5%)	2	2/31 (6.5%)	2	0/32 (0%)	0	0/32 (0%)	0
SKIN FISSURES	5/159 (3.1%)	6	7/164 (4.3%)	7	8/164 (4.9%)	8	2/43 (4.7%)	2	2/43 (4.7%)	2	3/43 (7%)	3	3/43 (7%)	3	0/31 (0%)	0	1/31 (3.2%)	1	2/32 (6.3%)	2	2/32 (6.3%)	2
SKIN FRAGILITY	0/159 (0%)	0	1/164 (0.6%)	1	3/164 (1.8%)	3	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	1/31 (3.2%)	1	1/31 (3.2%)	1	0/32 (0%)	0	2/32 (6.3%)	2
SKIN LESION	8/159 (5%)	8	8/164 (4.9%)	8	11/164 (6.7%)	13	2/43 (4.7%)	2	4/43 (9.3%)	6	1/43 (2.3%)	1	3/43 (7%)	3	1/31 (3.2%)	1	1/31 (3.2%)	1	3/32 (9.4%)	3	4/32 (12.5%)	4
SKIN MASS	2/159 (1.3%)	2	4/164 (2.4%)	5	4/164 (2.4%)	5	0/43 (0%)	0	0/43 (0%)	0	4/43 (9.3%)	5	4/43 (9.3%)	5	0/31 (0%)	0	0/31 (0%)	0	0/32 (0%)	0	0/32 (0%)	0
Vascular disorders
HYPERTENSION	24/159 (15.1%)	33	25/164 (15.2%)	31	34/164 (20.7%)	48	8/43 (18.6%)	10	10/43 (23.3%)	18	6/43 (14%)	7	8/43 (18.6%)	13	5/31 (16.1%)	6	9/31 (29%)	12	5/32 (15.6%)	7	7/32 (21.9%)	9
PHLEBITIS	0/159 (0%)	0	2/164 (1.2%)	2	2/164 (1.2%)	2	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/43 (0%)	0	0/31 (0%)	0	0/31 (0%)	0	2/32 (6.3%)	2	2/32 (6.3%)	2

Limitations/Caveats

[Not Specified]

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

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

Name/Title	Global Medical Services
Organization	AbbVie
Phone	800-633-9110
Email	abbvieclinicaltrials@abbvie.com

Responsible Party:

Pharmacyclics LLC.

ClinicalTrials.gov Identifier:

NCT02910583

Other Study ID Numbers:

PCYC-1142-CA
2016-002293-12

First Posted:

Sep 22, 2016

Last Update Posted:

Feb 18, 2022

Last Verified:

Jan 1, 2022

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

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