A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03462719
Collaborator
Pharmacyclics LLC. (Industry)
211
86
2
71.6
2.5
0

Study Details

Study Description

Brief Summary

The purpose of this study is to assess progression-free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

The hypothesis is treatment with combination of I+VEN will result in longer PFS compared with G-Clb in participants with previously untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who meet International Workshop on CLL (iwCLL) treatment criteria. The study includes screening (30 days), treatment (from randomization until treatment discontinuation) and follow-up phase (from treatment discontinuation until Subsequent Therapy Phase [if applicable], death, lost to follow up, consent withdrawal, or study end, whichever occurs first). Participants without progression will continue disease evaluations until disease progression or death. Participants from either treatment arm that develop progressive disease may be eligible to receive single-agent ibrutinib until disease progression or unacceptable toxicity (Subsequent Therapy Phase). Participation in this phase of the study is not mandatory and is based on investigator's discretion. Study duration is approximately 6 years. Safety includes review of adverse events and laboratory tests performed over time.

Study Design

Study Type:
Interventional
Actual Enrollment :
211 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
Actual Study Start Date :
Apr 17, 2018
Actual Primary Completion Date :
Feb 26, 2021
Anticipated Study Completion Date :
Apr 5, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)

Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.

Drug: Ibrutinib
Participants will receive ibrutinib 420 mg orally once daily up to 15 cycles.

Drug: Venetoclax
Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 to 400 mg.

Drug: Ibrutinib (as Subsequent Therapy)
Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.

Active Comparator: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)

Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.

Drug: Chlorambucil
Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.

Drug: Obinutuzumab
Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.

Drug: Ibrutinib (as Subsequent Therapy)
Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.

Outcome Measures

Primary Outcome Measures

  1. Progression Free Survival (PFS) [Up to 2 years 10 months]

    PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes >15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; >=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi >15 mm) or >=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi >15 mm); >=50% increase from nadir in enlargement of liver/spleen; >=50% increase from baseline in lymphocyte count (ALC; to >=5*10^9/L); or >=50% increase from nadir in ALC in >=2 serial assessments if ALC is >=30000*10^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.

Secondary Outcome Measures

  1. Minimal Residual Disease (MRD) Negative Rate [Up to 2 years 10 months]

    MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than [<] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or <0.01 percentage [%]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive.

  2. Complete Response Rate (CRR) [Up to 2 years 10 months]

    Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 gram per deciliter (g/dL), absolute lymphocyte count <4000/microliter (mcL) and normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow.

  3. Overall Response Rate (ORR) [Up to 2 years 10 months]

    ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 g/dL and ALC <4000/mcL, normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum of products of multiple nodes, >=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly.

  4. Overall Survival (OS) [Up to 3 years 4 months]

    OS is defined as the time from date of randomization to date of death from any cause.

  5. Duration of Response (DOR) [Up to 2 years 10 months]

    DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; >= 50% increase from nadir in existing lymph node or >=50% increase from nadir in sum of product of diameters of multiple nodes; >=50% increase from nadir in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.

  6. Time-to-Next Treatment [Up to 2 years 10 months]

    Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.

  7. Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) [Up to 2 years 10 months]

    Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of >= 7 points (on a 0-100 scale). EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of >=0.08 points (on a 0-1 scale).

  8. Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) [Up to 2 years 10 months]

    Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of >=10 points (on 0-100 scale) and in symptom scores=increase of >=10 points (on 0-100 scale).

  9. Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score [Up to 2 years 10 months]

    Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease >= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase >=3 points (on a 0-52 scale).

  10. Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability [Up to 3 years 4 months]

    An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.

  11. Number of Participants With Abnormal Clinical Laboratory Findings [Up to 2 years 10 months]

    Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.

  12. Percentage of Participants With Sustained Hemoglobin Improvement [Up to 2 years 10 months]

    Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by >= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors.

  13. Percentage of Participants With Sustained Platelet Improvement [Up to 2 years 10 months]

    Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by >= 50% and lasts for at least 56 days without blood transfusion or growth factors.

  14. Plasma Concentration of Ibrutinib and Venetoclax [Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6]

    Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Adult participants who are: (a) greater than or equal to (>=) 65 years old or, (b) 18 to 64 years old and have at least 1 of the following:
  1. Cumulative Illness Rating Scale (CIRS) score > 6

  2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using Cockcroft-Gault equation

  • Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria

  • Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter

  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or equal to (<=) 2

  • Active CLL/SLL requiring treatment per the iwCLL criteria

Exclusion Criteria:
  • Prior anti-leukemic therapy for CLL or SLL

  • Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of >10 percent (%) variable allele frequency (VAF)

  • Major surgery within 4 weeks of first dose of study treatment

  • Known bleeding disorders (example, von Willebrand's disease or hemophilia)

  • Central nervous system (CNS) involvement or suspected Richter's syndrome

Contacts and Locations

Locations

Site City State Country Postal Code
1 Norton Cancer Institute Louisville Kentucky United States 40207
2 John Theurer Cancer Center Hackensack New Jersey United States 07601
3 Novant Health Charlotte North Carolina United States 28204
4 Institut - Jules Bordet Anderlecht Belgium 1070
5 ZNA Stuivenberg Antwerpen Belgium 2060
6 Universitair Ziekenhuis Gent Gent Belgium 9000
7 Virga Jessa Ziekenhuis Hasselt Belgium 3500
8 UZ Leuven Gasthuisberg Leuven Belgium 3000
9 Tom Baker Cancer Centre Calgary Alberta Canada T2N 4N2
10 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
11 Juravinski Cancer Centre Hamilton Ontario Canada L8V 5C2
12 The Ottawa Hospital - General Campus Ottawa Ontario Canada K1H 8L6
13 CIUSSS de l'Est-de-l'Île-de-Montréal Installation Hôpital Maisonneuve-Rosemont Montreal Quebec Canada H1T 2M4
14 Jewish General Hospital Montreal Quebec Canada H3T 1E2
15 Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinika Brno Czechia 625 00
16 Fakultni nemocnice Hradec Kralove Hradec Kralove Czechia 500 05
17 Fakultni nemocnice Ostrava Ostrava Czechia 708 52
18 Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni Plzen Czechia 323 00
19 Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie Praha 2 Czechia 128 08
20 Aalborg University Hospital Aalborg Denmark 9000
21 Aarhus Universitetshospital Aarhus Denmark 8200
22 Rigshospitalet Copenhagen Denmark 2100
23 Odense Universitetshospital Odense C Denmark 5000
24 Roskilde Sygehus Roskilde Denmark DK- 4000
25 CHU de Clermont-Ferrand Clermont Ferrand France 63000
26 Hopital Claude Huriez Lille France 59000
27 CHU Montpellier Montpellier France 34295
28 Hopital Haut Leveque Service Maladie Du Sang Pessac France 33604
29 Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré Reims France 51100
30 Institut Universitaire du Cancer Toulouse Oncopole Toulouse Cedex 9 France 31059
31 CHU Bretonneau Tours Cedex 9 France 37044
32 CHU-Nancy Vandoeuvre les Nancy France 54511
33 Institut Gustave Roussy Villejuif France 94805
34 Bnai Zion Medical Center Haifa Israel 31048
35 Carmel Medical Center Haifa Israel 34362
36 Hadassah Medical Center Jerusalem Israel 9112001
37 Western Galilee Medical Center Nahariya Israel 22100
38 Sheba Medical Center Ramat Gan Israel 52621
39 Tel Aviv Sourasky Medical Center Tel Aviv Israel 64239
40 Flevoziekenhuis Almere Netherlands 1315RA
41 OLVG Amsterdam Netherlands 1091AC
42 Academic Medical Center Amsterdam Netherlands 1105 AZ
43 Reinier de Graaf Gasthuis Delft Netherlands 2625 AD
44 MC Haaglanden Den Haag Netherlands 2512 VA
45 Albert Schweitzer Ziekenhuis Dordrecht Netherlands 3318 AT
46 Catharinaziekenhuis Eindhoven Netherlands 5623 EJ
47 Spaarne Gasthuis Hoofddorp Netherlands 2134 TM
48 Zuyderland Medical Center Sittard-Geleen Netherlands 6162 BG
49 Antonius hospital Sneek Netherlands 8601 ZK
50 Elisabeth zkh Tilburg Netherlands 5022 GC
51 Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich Chorzów Poland 41-500
52 Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi Lodz Poland 93-510
53 Samodzielny Publiczny Szpital Kliniczny Nr 1 Lublin Poland 20-081
54 Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka, Slupsk Poland 76-200
55 Instytut Hematologii i Transfuzjologii Warszawa Poland 02-776
56 S.P. Botkin Moscow City Clinical Hospital Moscow Russian Federation 125284
57 Nizhniy Novgorod Region Clinical Hospital Nizhny Novgorod Russian Federation 603126
58 Ryazan Regional Clinical Hospital Ryazan Russian Federation 390039
59 FSBIFederal Centre of Heart, Blood and Endocrinology named after V.A.Almazov MoH of the RF Saint Petersburg Russian Federation 197341
60 St.-Petersburg Clinical Research Institute of Hematology and Transfusiology St. Petersburg Russian Federation 193024
61 Hosp. Univ. Vall D Hebron Barcelona Spain 08035
62 Hosp. Clinic I Provincial de Barcelona Barcelona Spain 08036
63 Hosp. de La Santa Creu I Sant Pau Barcelona Spain 8041
64 Hosp. Univ. de La Princesa Madrid Spain 28006
65 Hosp. Gral. Univ. Gregorio Marañon Madrid Spain 28007
66 Hosp. Univ. Infanta Leonor Madrid Spain 28031
67 Hospital Ramon y Cajal Madrid Spain 28034
68 Hosp. Univ. Fund. Jimenez Diaz Madrid Spain 28040
69 Clinica Univ. de Navarra Pamplona Spain 31008
70 Hospital Clinico Universitario Salamanca Salamanca Spain 37007
71 Hosp. Virgen Del Rocio Sevilla Spain 41013
72 Sunderby Sjukhus Medicinkliniken Luelå Sweden 97180
73 Karolinska Universitetssjukhuset Solna, Centrum för Hematologi, Stockholm Stockholm Sweden 171 76
74 Gazi Universitesi Tip FalKultesi Ankara Turkey 06500
75 Ankara Universitesi Tip Fakültesi Ibn-i Sina Hastanesi Ankara Turkey 6590
76 Ondokuz Mayis Universitesi Tip Fakultesi Atakum Turkey 55270
77 V.K.V. Amerikan Hastanesi Istanbul Turkey 34365
78 Dokuz Eylul Universitesi Tip Fakultesi Izmir Turkey 35340
79 Birmingham Heartlands Hospital Birmingham United Kingdom B9 5ST
80 Addenbrookes Hospital Cambridge United Kingdom CB2 0QQ
81 Queen Mary University of London Charterhouse Square United Kingdom EC1M 6BQ
82 New Victoria Hospital Glasgow United Kingdom G42 9LF
83 St James's Hospital Leeds United Kingdom LS9 7T
84 Derriford Hospital Plymouth United Kingdom PL6 8DH
85 Barking Havering and Redbridge University Hospitals NHS Trust Romford United Kingdom RM7 0AG
86 Royal Hallamshire Hospital Sheffield United Kingdom S10 2JF

Sponsors and Collaborators

  • Janssen Research & Development, LLC
  • Pharmacyclics LLC.

Investigators

  • Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT03462719
Other Study ID Numbers:
  • CR108428
  • 2017-004699-77
  • 54179060CLL3011
First Posted:
Mar 12, 2018
Last Update Posted:
Aug 15, 2022
Last Verified:
Aug 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED 106 105
COMPLETED 11 11
NOT COMPLETED 95 94

Baseline Characteristics

Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab) Total
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Total of all reporting groups
Overall Participants 106 105 211
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
71
(8.02)
72
(6.16)
71.5
(7.01)
Sex: Female, Male (Count of Participants)
Female
47
44.3%
42
40%
89
42.2%
Male
59
55.7%
63
60%
122
57.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
1
0.9%
3
2.9%
4
1.9%
Not Hispanic or Latino
101
95.3%
99
94.3%
200
94.8%
Unknown or Not Reported
4
3.8%
3
2.9%
7
3.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
0
0%
1
1%
1
0.5%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
0
0%
White
101
95.3%
101
96.2%
202
95.7%
More than one race
1
0.9%
0
0%
1
0.5%
Unknown or Not Reported
4
3.8%
3
2.9%
7
3.3%
Region of Enrollment (Count of Participants)
BELGIUM
7
6.6%
2
1.9%
9
4.3%
CANADA
7
6.6%
10
9.5%
17
8.1%
CZECH REPUBLIC
9
8.5%
13
12.4%
22
10.4%
DENMARK
7
6.6%
5
4.8%
12
5.7%
FRANCE
4
3.8%
3
2.9%
7
3.3%
ISRAEL
6
5.7%
12
11.4%
18
8.5%
NETHERLANDS
1
0.9%
6
5.7%
7
3.3%
POLAND
12
11.3%
10
9.5%
22
10.4%
RUSSIAN FEDERATION
23
21.7%
16
15.2%
39
18.5%
SPAIN
10
9.4%
9
8.6%
19
9%
SWEDEN
2
1.9%
0
0%
2
0.9%
TURKEY
8
7.5%
13
12.4%
21
10%
UNITED KINGDOM
8
7.5%
4
3.8%
12
5.7%
UNITED STATES
2
1.9%
2
1.9%
4
1.9%

Outcome Measures

1. Primary Outcome
Title Progression Free Survival (PFS)
Description PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes >15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; >=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi >15 mm) or >=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi >15 mm); >=50% increase from nadir in enlargement of liver/spleen; >=50% increase from baseline in lymphocyte count (ALC; to >=5*10^9/L); or >=50% increase from nadir in ALC in >=2 serial assessments if ALC is >=30000*10^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The intent-to-treat (ITT) analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Median (95% Confidence Interval) [Months]
NA
20.96
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Arm A (Ibrutinib + Venetoclax), Treatment Arm B (Chlorambucil + Obinutuzumab)
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.216
Confidence Interval (2-Sided) 95%
0.131 to 0.357
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Minimal Residual Disease (MRD) Negative Rate
Description MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than [<] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or <0.01 percentage [%]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Number (95% Confidence Interval) [Percentage of participants]
55.7
52.5%
21.0
20%
3. Secondary Outcome
Title Complete Response Rate (CRR)
Description Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 gram per deciliter (g/dL), absolute lymphocyte count <4000/microliter (mcL) and normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Number (95% Confidence Interval) [Percentage of Participants]
38.7
36.5%
11.4
10.9%
4. Secondary Outcome
Title Overall Response Rate (ORR)
Description ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 g/dL and ALC <4000/mcL, normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum of products of multiple nodes, >=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received. Participants with missing post-randomization data were considered non-responders.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Number (95% Confidence Interval) [Percentage of participants]
86.8
81.9%
84.8
80.8%
5. Secondary Outcome
Title Overall Survival (OS)
Description OS is defined as the time from date of randomization to date of death from any cause.
Time Frame Up to 3 years 4 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 11 16
Median (95% Confidence Interval) [Months]
NA
NA
6. Secondary Outcome
Title Duration of Response (DOR)
Description DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; >= 50% increase from nadir in existing lymph node or >=50% increase from nadir in sum of product of diameters of multiple nodes; >=50% increase from nadir in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
Population analyzed included ITT amongst who were responders (PR or better).
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 92 89
Median (95% Confidence Interval) [Months]
28.85
21.13
7. Secondary Outcome
Title Time-to-Next Treatment
Description Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Median (95% Confidence Interval) [Months]
NA
NA
8. Secondary Outcome
Title Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L)
Description Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of >= 7 points (on a 0-100 scale). EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of >=0.08 points (on a 0-1 scale).
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
EQ-5D-5L: Visual Analogue Score
8.34
24.18
EQ-5D-5L: Utility Score
14.29
24.11
9. Secondary Outcome
Title Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30)
Description Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of >=10 points (on 0-100 scale) and in symptom scores=increase of >=10 points (on 0-100 scale).
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Global Health Status
14.95
24.18
Cognitive Functioning
11.07
14.03
Emotional Functioning
NA
25.00
Physical Functioning
NA
NA
Role Functioning
11.10
8.48
Social Functioning
11.10
17.87
Fatigue (Symptom Scale)
8.38
17.87
Nausea/Vomiting (Symptom Scale)
11.07
NA
Pain (Symptom Scale)
8.31
11.01
10. Secondary Outcome
Title Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score
Description Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease >= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase >=3 points (on a 0-52 scale).
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Time to Worsening
8.15
14.03
Time to Improvement
5.59
3.75
11. Secondary Outcome
Title Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability
Description An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Time Frame Up to 3 years 4 months

Outcome Measure Data

Analysis Population Description
The safety analysis set is defined as all randomized participants who received at least one dose of any one of the four study drugs (ibrutinib, venetoclax, chlorambucil, or obinutuzumab).
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Count of Participants [Participants]
105
99.1%
99
94.3%
12. Secondary Outcome
Title Number of Participants With Abnormal Clinical Laboratory Findings
Description Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The safety analysis set is defined as all randomized participants who received at least one dose of any one of the four study drugs (ibrutinib, venetoclax, chlorambucil, or obinutuzumab).
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Hematology: Absolute Neutrophils Counts (Decrease)
81
76.4%
95
90.5%
Hematology: Hemoglobin (Decrease)
38
35.8%
42
40%
Hematology: Platelets (Decrease)
52
49.1%
78
74.3%
Hematology: Any hemoglobin, platelet, or ANC decrease
94
88.7%
103
98.1%
Chemistry: Alanine Transaminase (ALT) (Increase)
22
20.8%
26
24.8%
Chemistry: Aspartate Aminotransferase (AST) (Increase)
23
21.7%
30
28.6%
Chemistry: Alkaline Phosphatase (Increase)
19
17.9%
21
20%
Chemistry: Bilirubin (Increase)
36
34%
25
23.8%
Chemistry: Creatinine (Increase)
33
31.1%
17
16.2%
Chemistry: Creatinine Clearance (Decrease)
40
37.7%
17
16.2%
Chemistry: Hypercalcemia
13
12.3%
3
2.9%
Chemistry: Hypoalbuminemia
36
34%
20
19%
Chemistry: Hypocalcemia
27
25.5%
30
28.6%
Chemistry: Phosphate (Decrease)
16
15.1%
6
5.7%
Chemistry: Potassium (Decrease)
25
23.6%
9
8.6%
Chemistry: Potassium (Increase)
31
29.2%
22
21%
Chemistry: Sodium (Decrease)
25
23.6%
26
24.8%
Chemistry: Sodium (Increase)
12
11.3%
8
7.6%
Chemistry: Uric Acid (Increase)
37
34.9%
19
18.1%
13. Secondary Outcome
Title Percentage of Participants With Sustained Hemoglobin Improvement
Description Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by >= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Number [Percentage of Participants]
44.3
41.8%
50.5
48.1%
14. Secondary Outcome
Title Percentage of Participants With Sustained Platelet Improvement
Description Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by >= 50% and lasts for at least 56 days without blood transfusion or growth factors.
Time Frame Up to 2 years 10 months

Outcome Measure Data

Analysis Population Description
The ITT analysis set included all randomized participants who were analyzed according to assigned treatment group, regardless of the actual treatment received.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 106 105
Number [Percentage of Participants]
24.5
23.1%
29.5
28.1%
15. Secondary Outcome
Title Plasma Concentration of Ibrutinib and Venetoclax
Description Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry.
Time Frame Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6

Outcome Measure Data

Analysis Population Description
The pharmacokinetics (PK) analysis set is defined as all randomized participants in Treatment Arm A who received at least one dose of ibrutinib and/or venetoclax and had at least one valid blood sample drawn for PK analysis. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this endpoint. Here, "n (number analyzed)" is defined as number of participants analyzed for specified category.
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
Measure Participants 79
Ibrutinib: Pre-dose Day 1 Cycle 2 (Ibrutinib Alone)
5.70
(5.58)
Ibrutinib: Pre-dose Day 1 Cycle 3 (Ibrutinib Alone)
6.20
(7.78)
Ibrutinib: Pre-dose Day 1 Cycle 5 (Ibrutinib and Venetoclax)
6.37
(6.71)
Ibrutinib: Pre-dose Day 1 Cycle 6 (Ibrutinib and Venetoclax)
5.90
(6.74)
Venetoclax: Pre-dose Day 1 Cycle 5 (Ibrutinib + Venetoclax)
1139
(959)
Venetoclax: Pre-dose Day 1 Cycle 6 (Ibrutinib + Venetoclax)
1765
(1573)

Adverse Events

Time Frame Up to 3 years 4 months
Adverse Event Reporting Description The safety analysis set is defined as all randomized participants who received at least one dose of any one of the four study drugs (ibrutinib, venetoclax, chlorambucil, or obinutuzumab).
Arm/Group Title Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Arm/Group Description Participants received ibrutinib 420 milligrams (mg) orally once daily for 3 cycles (each cycle is of 28 days) followed by the combination of ibrutinib 420 mg and venetoclax 400 mg orally once daily for 12 cycles (including a 5-week venetoclax dose ramp up starting in cycle 4). Participants who subsequently developed independent review committee (IRC)-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity. Participants received chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight orally once daily on Days 1 and 15 of Cycles 1 to 6 in combination with obinutuzumab 1000 mgs intravenously (IV) once daily on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2 to 6 (each cycle is of 28 days). Participants who subsequently developed IRC-confirmed progressive disease (PD) and had active disease requiring treatment were eligible to participate in the Subsequent Therapy Phase and received single-agent ibrutinib until disease progression or unacceptable toxicity.
All Cause Mortality
Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 11/106 (10.4%) 16/105 (15.2%)
Serious Adverse Events
Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 49/106 (46.2%) 30/105 (28.6%)
Blood and lymphatic system disorders
Anaemia 3/106 (2.8%) 2/105 (1.9%)
Febrile Neutropenia 1/106 (0.9%) 3/105 (2.9%)
Neutropenia 2/106 (1.9%) 1/105 (1%)
Cardiac disorders
Acute Myocardial Infarction 2/106 (1.9%) 1/105 (1%)
Angina Unstable 1/106 (0.9%) 0/105 (0%)
Atrial Fibrillation 7/106 (6.6%) 0/105 (0%)
Cardiac Arrest 1/106 (0.9%) 0/105 (0%)
Cardiac Failure 3/106 (2.8%) 0/105 (0%)
Cardiac Failure Congestive 0/106 (0%) 1/105 (1%)
Myocardial Infarction 1/106 (0.9%) 0/105 (0%)
Sinus Node Dysfunction 2/106 (1.9%) 0/105 (0%)
Supraventricular Tachycardia 0/106 (0%) 1/105 (1%)
Gastrointestinal disorders
Diarrhoea 3/106 (2.8%) 1/105 (1%)
Gastritis 1/106 (0.9%) 0/105 (0%)
Mesenteric Artery Thrombosis 1/106 (0.9%) 0/105 (0%)
Oesophagitis 0/106 (0%) 1/105 (1%)
General disorders
Asthenia 1/106 (0.9%) 0/105 (0%)
Oedema Peripheral 2/106 (1.9%) 0/105 (0%)
Pyrexia 1/106 (0.9%) 2/105 (1.9%)
Sudden Death 2/106 (1.9%) 0/105 (0%)
Hepatobiliary disorders
Cholecystitis Acute 1/106 (0.9%) 0/105 (0%)
Cholecystitis Chronic 1/106 (0.9%) 0/105 (0%)
Cholestasis 0/106 (0%) 1/105 (1%)
Gallbladder Rupture 0/106 (0%) 1/105 (1%)
Immune system disorders
Cytokine Release Syndrome 0/106 (0%) 1/105 (1%)
Infections and infestations
Bronchitis 1/106 (0.9%) 0/105 (0%)
Bronchopulmonary Aspergillosis 1/106 (0.9%) 0/105 (0%)
Cellulitis 1/106 (0.9%) 0/105 (0%)
Clostridium Colitis 1/106 (0.9%) 0/105 (0%)
Covid-19 Pneumonia 0/106 (0%) 0/105 (0%)
Erysipelas 1/106 (0.9%) 0/105 (0%)
Escherichia Urinary Tract Infection 0/106 (0%) 1/105 (1%)
Gastroenteritis 1/106 (0.9%) 0/105 (0%)
Gastrointestinal Infection 1/106 (0.9%) 0/105 (0%)
Infection 1/106 (0.9%) 0/105 (0%)
Influenza 1/106 (0.9%) 0/105 (0%)
Pneumococcal Sepsis 0/106 (0%) 1/105 (1%)
Pneumonia 6/106 (5.7%) 6/105 (5.7%)
Pneumonia Cytomegaloviral 1/106 (0.9%) 0/105 (0%)
Respiratory Tract Infection 0/106 (0%) 1/105 (1%)
Septic Shock 1/106 (0.9%) 0/105 (0%)
Tonsillitis 1/106 (0.9%) 0/105 (0%)
Urinary Tract Infection 0/106 (0%) 1/105 (1%)
Injury, poisoning and procedural complications
Fall 1/106 (0.9%) 0/105 (0%)
Femoral Neck Fracture 1/106 (0.9%) 0/105 (0%)
Hip Fracture 1/106 (0.9%) 1/105 (1%)
Infusion Related Reaction 0/106 (0%) 3/105 (2.9%)
Multiple Injuries 0/106 (0%) 1/105 (1%)
Overdose 0/106 (0%) 2/105 (1.9%)
Spinal Compression Fracture 1/106 (0.9%) 0/105 (0%)
Wound Necrosis 1/106 (0.9%) 0/105 (0%)
Investigations
Alanine Aminotransferase Increased 0/106 (0%) 2/105 (1.9%)
Aspartate Aminotransferase Increased 0/106 (0%) 1/105 (1%)
Blood Phosphorus Increased 0/106 (0%) 1/105 (1%)
Neutrophil Count Decreased 1/106 (0.9%) 0/105 (0%)
Metabolism and nutrition disorders
Hyperkalaemia 1/106 (0.9%) 0/105 (0%)
Hyperphosphataemia 2/106 (1.9%) 0/105 (0%)
Iron Deficiency 0/106 (0%) 1/105 (1%)
Tumour Lysis Syndrome 0/106 (0%) 3/105 (2.9%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain 1/106 (0.9%) 0/105 (0%)
Polyarthritis 1/106 (0.9%) 0/105 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Gastric 0/106 (0%) 1/105 (1%)
Hepatocellular Carcinoma 1/106 (0.9%) 0/105 (0%)
Lung Neoplasm Malignant 1/106 (0.9%) 0/105 (0%)
Myelodysplastic Syndrome 0/106 (0%) 1/105 (1%)
Myeloproliferative Neoplasm 0/106 (0%) 1/105 (1%)
Neoplasm Malignant 1/106 (0.9%) 0/105 (0%)
Uterine Leiomyoma 1/106 (0.9%) 0/105 (0%)
Nervous system disorders
Cerebral Haemorrhage 1/106 (0.9%) 0/105 (0%)
Dizziness 1/106 (0.9%) 0/105 (0%)
Ischaemic Stroke 2/106 (1.9%) 0/105 (0%)
Spinal Cord Compression 1/106 (0.9%) 0/105 (0%)
Toxic Encephalopathy 1/106 (0.9%) 0/105 (0%)
Psychiatric disorders
Depression 1/106 (0.9%) 0/105 (0%)
Major Depression 1/106 (0.9%) 0/105 (0%)
Mental Disorder 1/106 (0.9%) 0/105 (0%)
Renal and urinary disorders
Acute Kidney Injury 1/106 (0.9%) 0/105 (0%)
Chronic Kidney Disease 1/106 (0.9%) 0/105 (0%)
Haematuria 2/106 (1.9%) 0/105 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease 1/106 (0.9%) 0/105 (0%)
Dyspnoea 1/106 (0.9%) 1/105 (1%)
Dyspnoea Exertional 1/106 (0.9%) 0/105 (0%)
Haemoptysis 1/106 (0.9%) 0/105 (0%)
Pneumothorax 1/106 (0.9%) 0/105 (0%)
Pulmonary Congestion 1/106 (0.9%) 0/105 (0%)
Skin and subcutaneous tissue disorders
Dermatitis Bullous 1/106 (0.9%) 0/105 (0%)
Ecchymosis 1/106 (0.9%) 0/105 (0%)
Pyoderma Gangrenosum 1/106 (0.9%) 0/105 (0%)
Rash 1/106 (0.9%) 0/105 (0%)
Urticaria 1/106 (0.9%) 0/105 (0%)
Vascular disorders
Hypertension 1/106 (0.9%) 0/105 (0%)
Hypertensive Urgency 1/106 (0.9%) 0/105 (0%)
Hypotension 1/106 (0.9%) 0/105 (0%)
Venous Thrombosis 1/106 (0.9%) 0/105 (0%)
Other (Not Including Serious) Adverse Events
Treatment Arm A (Ibrutinib + Venetoclax) Treatment Arm B (Chlorambucil + Obinutuzumab)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 98/106 (92.5%) 98/105 (93.3%)
Blood and lymphatic system disorders
Anaemia 17/106 (16%) 18/105 (17.1%)
Leukopenia 1/106 (0.9%) 6/105 (5.7%)
Neutropenia 36/106 (34%) 56/105 (53.3%)
Thrombocytopenia 12/106 (11.3%) 28/105 (26.7%)
Cardiac disorders
Atrial Fibrillation 12/106 (11.3%) 2/105 (1.9%)
Palpitations 6/106 (5.7%) 3/105 (2.9%)
Ear and labyrinth disorders
Vertigo 8/106 (7.5%) 0/105 (0%)
Gastrointestinal disorders
Abdominal Pain 2/106 (1.9%) 5/105 (4.8%)
Constipation 11/106 (10.4%) 7/105 (6.7%)
Diarrhoea 53/106 (50%) 13/105 (12.4%)
Dyspepsia 10/106 (9.4%) 3/105 (2.9%)
Mouth Ulceration 8/106 (7.5%) 0/105 (0%)
Nausea 28/106 (26.4%) 27/105 (25.7%)
Vomiting 15/106 (14.2%) 14/105 (13.3%)
General disorders
Asthenia 9/106 (8.5%) 7/105 (6.7%)
Chills 2/106 (1.9%) 12/105 (11.4%)
Fatigue 16/106 (15.1%) 10/105 (9.5%)
Oedema Peripheral 15/106 (14.2%) 3/105 (2.9%)
Pyrexia 6/106 (5.7%) 18/105 (17.1%)
Infections and infestations
Bronchitis 7/106 (6.6%) 7/105 (6.7%)
Conjunctivitis 7/106 (6.6%) 2/105 (1.9%)
Nasopharyngitis 4/106 (3.8%) 7/105 (6.7%)
Pharyngitis 6/106 (5.7%) 1/105 (1%)
Pneumonia 5/106 (4.7%) 6/105 (5.7%)
Upper Respiratory Tract Infection 13/106 (12.3%) 14/105 (13.3%)
Urinary Tract Infection 17/106 (16%) 4/105 (3.8%)
Injury, poisoning and procedural complications
Contusion 5/106 (4.7%) 0/105 (0%)
Infusion Related Reaction 0/106 (0%) 28/105 (26.7%)
Investigations
Alanine Aminotransferase Increased 3/106 (2.8%) 5/105 (4.8%)
Aspartate Aminotransferase Increased 3/106 (2.8%) 6/105 (5.7%)
Neutrophil Count Decreased 10/106 (9.4%) 9/105 (8.6%)
Weight Decreased 8/106 (7.5%) 1/105 (1%)
Metabolism and nutrition disorders
Decreased Appetite 14/106 (13.2%) 6/105 (5.7%)
Hyperkalaemia 8/106 (7.5%) 5/105 (4.8%)
Hyperphosphataemia 9/106 (8.5%) 0/105 (0%)
Hyperuricaemia 6/106 (5.7%) 3/105 (2.9%)
Hyponatraemia 6/106 (5.7%) 1/105 (1%)
Musculoskeletal and connective tissue disorders
Arthralgia 12/106 (11.3%) 7/105 (6.7%)
Back Pain 10/106 (9.4%) 7/105 (6.7%)
Muscle Spasms 9/106 (8.5%) 2/105 (1.9%)
Myalgia 7/106 (6.6%) 1/105 (1%)
Pain in Extremity 6/106 (5.7%) 8/105 (7.6%)
Nervous system disorders
Dizziness Postural 4/106 (3.8%) 6/105 (5.7%)
Headache 7/106 (6.6%) 5/105 (4.8%)
Psychiatric disorders
Insomnia 9/106 (8.5%) 5/105 (4.8%)
Respiratory, thoracic and mediastinal disorders
Cough 9/106 (8.5%) 11/105 (10.5%)
Dyspnoea 6/106 (5.7%) 8/105 (7.6%)
Epistaxis 12/106 (11.3%) 3/105 (2.9%)
Skin and subcutaneous tissue disorders
Hyperhidrosis 1/106 (0.9%) 6/105 (5.7%)
Onychoclasis 7/106 (6.6%) 0/105 (0%)
Pruritus 8/106 (7.5%) 5/105 (4.8%)
Rash 17/106 (16%) 7/105 (6.7%)
Vascular disorders
Haematoma 8/106 (7.5%) 2/105 (1.9%)
Hypertension 13/106 (12.3%) 5/105 (4.8%)
Hypotension 3/106 (2.8%) 10/105 (9.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.

Results Point of Contact

Name/Title EXECUTIVE MEDICAL DIRECTOR
Organization Janssen Research & Development, LLC
Phone 844-434-4210
Email ClinicalTrialDisclosure@its.jnj.com
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT03462719
Other Study ID Numbers:
  • CR108428
  • 2017-004699-77
  • 54179060CLL3011
First Posted:
Mar 12, 2018
Last Update Posted:
Aug 15, 2022
Last Verified:
Aug 1, 2022