Ibrutinib in Combination With Corticosteroids vs Placebo in Combination With Corticosteroids in Participants With New Onset Chronic Graft Versus Host Disease (cGVHD)

Chronic Graft Versus Host Disease Clinical Trial

— iNTEGRATE  

Official title:

A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids Versus Placebo in Combination With Corticosteroids in Subjects With New Onset Chronic Graft Versus Host Disease (cGVHD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02959944
• Other study ID #: PCYC-1140-IM
• Status: Completed
• Phase: Phase 3
• Start date: May 11, 2017
• Est. completion date: July 12, 2021

Study information

• Verified date: March 2023
• Source: Pharmacyclics LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 193
• Est. completion date: July 12, 2021
• Est. primary completion date: March 27, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Key Inclusion Criteria:

• New onset moderate or severe cGVHD as defined by the 2014 National Institutes of Health (NIH) Consensus Development Project Criteria
• Need for systemic treatment with corticosteroids for cGVHD
• No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP])
• Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d
• Age =12 years old
• Karnofsky or Lansky (subjects <16 years) performance status =60

Key Exclusion Criteria:

• Received any previous systemic treatment for cGVHD with the exception of corticosteroids administered for cGVHD within the 72 hours prior to signing the informed consent form.
• Inability to begin a prednisone dose =0.5 mg/kg/d for the treatment of cGVHD
• Any uncontrolled infection or active infection requiring ongoing systemic treatment
• Progressive underlying malignant disease or any post-transplant lymphoproliferative disease
• Known bleeding disorders
• Active hepatitis C virus (HCV) or hepatitis B virus (HBV)

Related Conditions & MeSH terms

• Chronic Graft Versus Host Disease
• Graft vs Host Disease

Intervention

Drug:
• ibrutinib
Ibrutinib capsules administered orally daily
• Placebo
Placebo capsules administered orally daily
• Prednisone
Prednisone administered daily

Locations

Country	Name	City	State
Australia	The Kinghorn Cancer Centre /ID# 1140-1165	Darlinghurst	New South Wales
Australia	Royal Brisbane and Women's Hospital /ID# 1140-0190	Herston	Queensland
Australia	Royal Children's Hospital/ID# 1140-1154	Parkville	Victoria
Australia	Royal Melbourne Hospital (RMH) /ID# 1140-0633	Parkville	Victoria
Australia	Fiona Stanley Hospital /ID# 1140-0880	Perth	Western Australia
Australia	Westmead Hospital /ID# 1140-0848	Westmead	New South Wales
Austria	Univ. Klinik for Innere Medizin, Klinische Abteilung for Hematologie, Graz /ID# 1140-0373	Graz
Austria	Krankenhaus der Elisabethinen Linz /ID# 1140-0849	Linz
Canada	CHU Sainte-Justine /ID# 1140-1143	Montreal	Quebec
Canada	The Ottawa Hospital Regional Cancer Center /ID# 1140-0159	Ottawa	Ontario
Canada	Princess Margaret Cancer Centre /ID# 1140-0043	Toronto	Ontario
Canada	University of British Columbia (UBC) - Vancouver General Hospital (VGH) /ID# 1140-1166	Vancouver	British Columbia
China	Chinese PLA General Hospital /ID# 1140-1198	Beijing
China	Nanfang Hospital /ID# 1140-1379	Guangzhou Shi
China	The First Affiliated Hospital of Soochow University /ID# 1140-1208	Suzhou	Jiangsu
Croatia	UHC Zagreb /ID# 1140-1169	Zagreb
France	CHU Amiens Groupe hospitalier Sud /ID# 1140-1205	Amiens
France	CHU de GRENOBLE Alpes /ID# 1140-1058	Grenoble
France	Centre Hospitalier Regional Universitaire de Lille /ID# 1140-0750	Lille
France	CHU de Nantes /ID# 1140-0520	Nantes
France	Groupe Hospitalier Pitie-Salpetriere /ID# 1140-0918	Paris
France	Hopital Saint-Louis - Institut Hematologie Centre Hayem CHU /ID# 1140-0735	Paris	Ile-de-France
France	Hopital de Brabois /ID# 1140-0775	Vandoeuvre-lès-nancy	Meurthe-et-Moselle
Germany	Universitaetsklinikum Dresden /ID# 1140-1367	Dresden
Germany	Hannover Medical School /ID# 1140-1141	Hannover
Germany	Dr. Haunerschen Kinderspital /ID# 1140-1142	Munich
Germany	Universitatsklinikum Munster /ID# 1140-1195	Munster	Niedersachsen
Germany	University Hospital of Regensburg /ID# 1140-1446	Regensburg
Germany	Robert Bosch Hospital /ID# 1140-1160	Stuttgart	Baden-Wuerttemberg
Hungary	St. Laszlo Hospital /ID# 1140-1164	Budapest
Italy	A.O. Univ. Ospedali Riuniti /ID# 1140-0932	Ancona	Marche
Italy	ASST Papa Giovanni XXIII /ID# 1140-1231	Bergamo
Italy	Ospedale San Raffaele IRCCS /ID# 1140-0523	Milan
Italy	IRCCS Ospedale Pediatrico Bambino Gesu /ID# 1140-1150	Rome	Lazio
Italy	University of Torino /ID# 1140-1268	Torino
Italy	Centro Trapianti Cellule Staminali, Ospedale Infantile Regina Margherita /ID# 1140-1156	Turin
Japan	Anjou Kousei Hospital /ID# 1140-1435	Anjo	Aichi
Japan	Dup_Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital /ID# 1140-1439	Bunkyo-ku	Tokyo
Japan	Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital /ID# 1140-1437	Hiroshima-shi	Hiroshima
Japan	Tokai University Hospital /ID# 1140-1444	Isehara-shi	Kanagawa
Japan	Osaka Women's and Children's Hospital /ID# 1140-1440	Izumi-Shi	Osaka
Japan	Kobe City Medical Center General Hospital /ID# 1140-1438	Kobe-shi	Hyogo
Japan	Kumamoto Medical Center /ID# 1140-1431	Kumamoto
Japan	Duplicate_Kurashiki Central Hospital /ID# 1140-1442	Kurishiki-shi	Okayama
Japan	Hyogo College of Medicine College Hospital /Id# 1140-1434	Nishinomiya-shi	Hyogo
Japan	Okayama University Hospital /ID# 1140-1430	Okayama-shi	Okayama
Japan	Osaka City University Hospital /ID# 1140-1157	Osaka-shi	Osaka
Japan	Hokkaido University Hospital /ID# 1140-1436	Sapporo
Japan	National Center for Child Health and Development /ID# 1140-1443	Setagaya-ku	Tokyo
Japan	Duplicate_University of Tsukuba Hospital /ID# 1140-1445	Tsukuba-shi	Ibaraki
Korea, Republic of	Kyungpook National Univ Hosp /ID# 1140-1153	Daegu	Daegu Gwang Yeogsi
Korea, Republic of	Yonsei University Health System, Severance Hospital /ID# 1140-0927	Seodaemun-gu	Seoul Teugbyeolsi
Korea, Republic of	Asan Medical Center /ID# 1140-0963	Seoul
Korea, Republic of	Cath Univ Seoul St Mary's Hosp /ID# 1140-0928	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Samsung Medical Center /ID# 1140-0925	Seoul	Seoul Teugbyeolsi
Korea, Republic of	SoonChunHyang University Seoul /ID# 1140-1163	Seoul
Singapore	National University Cancer Institute - National University Health System /ID# 1140-1155	Singapore
Singapore	Singapore General Hospital /ID# 1140-1162	Singapore
Spain	Hospital Clinic /ID# 1140-0533	Barcelona
Spain	Hospital Santa Creu i Sant Pau /ID# 1140-0535	Barcelona
Spain	Hospital Universitario Virgen del Rocio /ID# 1140-0863	Sevilla
Spain	Hospital Clinico Universitario de Valencia /ID# 1140-1145	Valencia
Taiwan	China Medical University Hosp /ID# 1140-1199	Taichung City	Taichung
Taiwan	National Taiwan Univ Hosp /ID# 1140-1184	Taipei City	Taipei
United States	Emory University, Winship Cancer Institute /ID# 1140-0033	Atlanta	Georgia
United States	Emory University/Winship Cancer Institute /ID# 1140-1179	Atlanta	Georgia
United States	UCHSC Anschultz Cancer Pavilion /ID# 1140-0068	Aurora	Colorado
United States	University of Maryland /ID# 1140-0205	Baltimore	Maryland
United States	Boston Childrens Hospital /ID# 1140-1615	Boston	Massachusetts
United States	Dana-Farber Cancer Institute /ID# 1140-0349	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center /ID# 1140-0020	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus /ID# 1140-0120	Bronx	New York
United States	University of North Carolina - Lineberger Comprehensive Cancer Center /ID# 1140-1133	Chapel Hill	North Carolina
United States	Medical University of South Carolina, MUSC /ID# 1140-0738	Charleston	South Carolina
United States	University of Chicago /ID# 1140-0126	Chicago	Illinois
United States	Univ Hosp Cleveland /ID# 1140-0941	Cleveland	Ohio
United States	Barbara Ann Karmanos Cancer In /ID# 1140-0130	Detroit	Michigan
United States	Hackensack University Medical Center/ John Theurer Cancer Center /ID# 1140-0343	Hackensack	New Jersey
United States	Indiana University Melvin and Bren Simon Cancer Center /ID# 1140-0010	Indianapolis	Indiana
United States	University of Kentucky /ID# 1140-1140	Lexington	Kentucky
United States	University of Louisville Hospital /ID# 1140-1131	Louisville	Kentucky
United States	Loyola University /ID# 1140-0713	Maywood	Illinois
United States	Jackson Memorial Hospital, University of Miami /ID# 1140-0647	Miami	Florida
United States	University of Minnesota /ID# 1140-0807	Minneapolis	Minnesota
United States	West Virginia University /ID# 1140-1090	Morgantown	West Virginia
United States	Vanderbilt University Medical Center Vanderbilt Ingram Cancer Center /ID# 1140-0024	Nashville	Tennessee
United States	Rutgers Cancer Institute of NJ /ID# 1140-0803	New Brunswick	New Jersey
United States	Columbia University Medical Center, MS-CHONY /ID# 1140-1124	New York	New York
United States	New York Presbyterian Hospital/Weill Cornell Med College /ID# 1140-0200	New York	New York
United States	Stony Brook University Medical Center /ID# 1140-0719	New York	New York
United States	Weill Cornell Physicians - Hematologic Malignancies & Bone Marrow Transplant /ID# 1140-0019	New York	New York
United States	Florida Hospital Cancer Institute/Adventist Health System/Sunbelt, Inc /ID# 1140-1121	Orlando	Florida
United States	LPCH Stanford /ID# 1140-1128	Palo Alto	California
United States	University of Pittsburgh - UPMC (Hillman Cancer Center) /ID# 1140-0050	Pittsburgh	Pennsylvania
United States	Mayo Clinic, Rochester, MN /ID# 1140-0240	Rochester	Minnesota
United States	University of Rochester Cancer Center /ID# 1140-0127	Rochester	New York
United States	Methodist San Antonio /ID# 1140-1118	San Antonio	Texas
United States	Ucsf /Id# 1140-0003	San Francisco	California
United States	Arizona Oncology - Scottsdale - Cancer Transplant Institute Location /ID# 1140-1120	Scottsdale	Arizona
United States	Fred Hutchinson Cancer Research Center /ID# 1140-0404	Seattle	Washington
United States	Stanford University/Stanford Cancer Center, Pasteur Drive /ID# 1140-0400	Stanford	California
United States	Children's National Medical Center /ID# 1140-1122	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Pharmacyclics LLC.	Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  China,  Croatia,  France,  Germany,  Hungary,  Italy,  Japan,  Korea, Republic of,  Singapore,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary Analysis: Response Rate at 48 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks.; Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	48 weeks (Cumulatively up to 30 March 2020)
Primary	Final Analysis: Response Rate at 48 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks.; Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	48 weeks (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD	The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval [CI]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020)
Secondary	Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD	The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval [CI]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants	The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib.	Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020)
Secondary	Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants	The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib.	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Response Rate at 24 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks.; Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	24 weeks (Cumulatively up to 30 March 2020)
Secondary	Final Analysis: Response Rate at 24 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks.; Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	24 weeks (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits	Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment.; The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.	Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020)
Secondary	Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits	Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment.; The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.	Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days		24 weeks (Cumulatively up to 30 March 2020)
Secondary	Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days		24 weeks (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Overall Survival (OS)	OS was defined as the time of randomization until the time of death due to any cause, in months.	Median time on study (cumulatively up to 30 March 2020) was 19.8 months and 18.4 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.
Secondary	Final Analysis: OS	OS was defined as the time of randomization until the time of death due to any cause, in months.	Median time on study (cumulatively up to 12 July 2021) was 33.1 months and 32.5 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.
Secondary	Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time	Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology.	Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020)
Secondary	Final Analysis: DOR for Participants Who Had PR or CR at Any Time	Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology.	Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021)
Secondary	Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone	AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires 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 was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug.	From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 30 March 2020), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.
Secondary	Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone	AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires 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 was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug.	From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 12 July 2021), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.