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

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02959944
• Collaborator: Janssen Research & Development, LLC (Industry)
• Enrollment: 193
• Locations: 102
• Arms: 2
• Actual Duration (Months): 50
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Chronic Graft Versus Host Disease	Drug: ibrutinib; Drug: Placebo; Drug: Prednisone	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 193 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: May 11, 2017
• Actual Primary Completion Date: Mar 27, 2020
• Actual Study Completion Date: Jul 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibrutinib + Prednisone Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Drug: ibrutinib; Ibrutinib capsules administered orally daily; Other Names: IMBRUVICA® PCI-32765 ; Drug: Prednisone; Prednisone administered daily
Placebo Comparator: Placebo + Prednisone Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Drug: Placebo; Placebo capsules administered orally daily; Drug: Prednisone; Prednisone administered daily

Outcome Measures

Primary Outcome Measures

1. Primary Analysis: Response Rate at 48 Weeks [48 weeks (Cumulatively up to 30 March 2020)]

   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.

2. Final Analysis: Response Rate at 48 Weeks [48 weeks (Cumulatively up to 12 July 2021)]

   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.

Secondary Outcome Measures

1. Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD [Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020)]

   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.

2. Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD [Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)]

   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.

3. Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants [Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020)]

   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.

4. Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants [Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)]

   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.

5. Primary Analysis: Response Rate at 24 Weeks [24 weeks (Cumulatively up to 30 March 2020)]

   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.

6. Final Analysis: Response Rate at 24 Weeks [24 weeks (Cumulatively up to 12 July 2021)]

   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.

7. Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits [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)]

   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.

8. Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits [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)]

   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.

9. 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)]

10. 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)]

11. Primary Analysis: Overall Survival (OS) [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.]

    OS was defined as the time of randomization until the time of death due to any cause, in months.

12. Final Analysis: OS [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.]

    OS was defined as the time of randomization until the time of death due to any cause, in months.

13. Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time [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)]

    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.

14. Final Analysis: DOR for Participants Who Had PR or CR at Any Time [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)]

    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.

15. Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone [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.]

    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.

16. Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone [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.]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology - Scottsdale - Cancer Transplant Institute Location /ID# 1140-1120	Scottsdale	Arizona	United States	85258-4547
2	LPCH Stanford /ID# 1140-1128	Palo Alto	California	United States	94304
3	Ucsf /Id# 1140-0003	San Francisco	California	United States	94143
4	Stanford University/Stanford Cancer Center, Pasteur Drive /ID# 1140-0400	Stanford	California	United States	94305
5	UCHSC Anschultz Cancer Pavilion /ID# 1140-0068	Aurora	Colorado	United States	80010
6	Children's National Medical Center /ID# 1140-1122	Washington	District of Columbia	United States	20010
7	Jackson Memorial Hospital, University of Miami /ID# 1140-0647	Miami	Florida	United States	33136-1096
8	Florida Hospital Cancer Institute/Adventist Health System/Sunbelt, Inc /ID# 1140-1121	Orlando	Florida	United States	32804
9	Emory University, Winship Cancer Institute /ID# 1140-0033	Atlanta	Georgia	United States	30322
10	Emory University/Winship Cancer Institute /ID# 1140-1179	Atlanta	Georgia	United States	30322
11	University of Chicago /ID# 1140-0126	Chicago	Illinois	United States	60637
12	Loyola University /ID# 1140-0713	Maywood	Illinois	United States	60153
13	Indiana University Melvin and Bren Simon Cancer Center /ID# 1140-0010	Indianapolis	Indiana	United States	46202-5112
14	University of Kentucky /ID# 1140-1140	Lexington	Kentucky	United States	40508-2678
15	University of Louisville Hospital /ID# 1140-1131	Louisville	Kentucky	United States	40202
16	University of Maryland /ID# 1140-0205	Baltimore	Maryland	United States	21201
17	Massachusetts General Hospital Cancer Center /ID# 1140-0020	Boston	Massachusetts	United States	02114
18	Boston Childrens Hospital /ID# 1140-1615	Boston	Massachusetts	United States	02115
19	Dana-Farber Cancer Institute /ID# 1140-0349	Boston	Massachusetts	United States	02215
20	Barbara Ann Karmanos Cancer In /ID# 1140-0130	Detroit	Michigan	United States	48201
21	University of Minnesota /ID# 1140-0807	Minneapolis	Minnesota	United States	55455
22	Mayo Clinic, Rochester, MN /ID# 1140-0240	Rochester	Minnesota	United States	55905
23	Hackensack University Medical Center/ John Theurer Cancer Center /ID# 1140-0343	Hackensack	New Jersey	United States	07601
24	Rutgers Cancer Institute of NJ /ID# 1140-0803	New Brunswick	New Jersey	United States	08903
25	Montefiore Medical Center - Moses Campus /ID# 1140-0120	Bronx	New York	United States	10467
26	New York Presbyterian Hospital/Weill Cornell Med College /ID# 1140-0200	New York	New York	United States	10021
27	Stony Brook University Medical Center /ID# 1140-0719	New York	New York	United States	10021
28	Columbia University Medical Center, MS-CHONY /ID# 1140-1124	New York	New York	United States	10032-1559
29	Weill Cornell Physicians - Hematologic Malignancies & Bone Marrow Transplant /ID# 1140-0019	New York	New York	United States	10065
30	University of Rochester Cancer Center /ID# 1140-0127	Rochester	New York	United States	14642-0001
31	University of North Carolina - Lineberger Comprehensive Cancer Center /ID# 1140-1133	Chapel Hill	North Carolina	United States	27516
32	Univ Hosp Cleveland /ID# 1140-0941	Cleveland	Ohio	United States	44106
33	University of Pittsburgh - UPMC (Hillman Cancer Center) /ID# 1140-0050	Pittsburgh	Pennsylvania	United States	15232
34	Medical University of South Carolina, MUSC /ID# 1140-0738	Charleston	South Carolina	United States	29425
35	Vanderbilt University Medical Center Vanderbilt Ingram Cancer Center /ID# 1140-0024	Nashville	Tennessee	United States	37232-5280
36	Methodist San Antonio /ID# 1140-1118	San Antonio	Texas	United States	78229-3710
37	Fred Hutchinson Cancer Research Center /ID# 1140-0404	Seattle	Washington	United States	98109
38	West Virginia University /ID# 1140-1090	Morgantown	West Virginia	United States	26506
39	The Kinghorn Cancer Centre /ID# 1140-1165	Darlinghurst	New South Wales	Australia	2010
40	Westmead Hospital /ID# 1140-0848	Westmead	New South Wales	Australia	2145
41	Royal Brisbane and Women's Hospital /ID# 1140-0190	Herston	Queensland	Australia	4029
42	Royal Children's Hospital/ID# 1140-1154	Parkville	Victoria	Australia	3052
43	Royal Melbourne Hospital (RMH) /ID# 1140-0633	Parkville	Victoria	Australia	3052
44	Fiona Stanley Hospital /ID# 1140-0880	Perth	Western Australia	Australia	6000
45	Univ. Klinik for Innere Medizin, Klinische Abteilung for Hematologie, Graz /ID# 1140-0373	Graz		Austria	8036
46	Krankenhaus der Elisabethinen Linz /ID# 1140-0849	Linz		Austria	4020
47	University of British Columbia (UBC) - Vancouver General Hospital (VGH) /ID# 1140-1166	Vancouver	British Columbia	Canada	V5Z 1M9
48	The Ottawa Hospital Regional Cancer Center /ID# 1140-0159	Ottawa	Ontario	Canada	K1H 8L6
49	Princess Margaret Cancer Centre /ID# 1140-0043	Toronto	Ontario	Canada	M5G 2M9
50	CHU Sainte-Justine /ID# 1140-1143	Montreal	Quebec	Canada	H3T 1C5
51	The First Affiliated Hospital of Soochow University /ID# 1140-1208	Suzhou	Jiangsu	China	215006
52	Chinese PLA General Hospital /ID# 1140-1198	Beijing		China	100853
53	Nanfang Hospital /ID# 1140-1379	Guangzhou Shi		China	510000
54	UHC Zagreb /ID# 1140-1169	Zagreb		Croatia	10000
55	Hopital Saint-Louis - Institut Hematologie Centre Hayem CHU /ID# 1140-0735	Paris	Ile-de-France	France	75010
56	Hopital de Brabois /ID# 1140-0775	Vandoeuvre-lès-nancy	Meurthe-et-Moselle	France	54511
57	CHU Amiens Groupe hospitalier Sud /ID# 1140-1205	Amiens		France	80054
58	CHU de GRENOBLE Alpes /ID# 1140-1058	Grenoble		France	38043
59	Centre Hospitalier Regional Universitaire de Lille /ID# 1140-0750	Lille		France	59037
60	CHU de Nantes /ID# 1140-0520	Nantes		France	44093
61	Groupe Hospitalier Pitie-Salpetriere /ID# 1140-0918	Paris		France	33000
62	Robert Bosch Hospital /ID# 1140-1160	Stuttgart	Baden-Wuerttemberg	Germany	70376
63	Universitatsklinikum Munster /ID# 1140-1195	Munster	Niedersachsen	Germany	48149
64	Universitaetsklinikum Dresden /ID# 1140-1367	Dresden		Germany	01307
65	Hannover Medical School /ID# 1140-1141	Hannover		Germany	30625
66	Dr. Haunerschen Kinderspital /ID# 1140-1142	Munich		Germany	80337
67	University Hospital of Regensburg /ID# 1140-1446	Regensburg		Germany	93053
68	St. Laszlo Hospital /ID# 1140-1164	Budapest		Hungary	1097
69	IRCCS Ospedale Pediatrico Bambino Gesu /ID# 1140-1150	Rome	Lazio	Italy	00165
70	A.O. Univ. Ospedali Riuniti /ID# 1140-0932	Ancona	Marche	Italy	60126
71	ASST Papa Giovanni XXIII /ID# 1140-1231	Bergamo		Italy	24127
72	Ospedale San Raffaele IRCCS /ID# 1140-0523	Milan		Italy	20132
73	University of Torino /ID# 1140-1268	Torino		Italy	10124
74	Centro Trapianti Cellule Staminali, Ospedale Infantile Regina Margherita /ID# 1140-1156	Turin		Italy	10126
75	Anjou Kousei Hospital /ID# 1140-1435	Anjo	Aichi	Japan	446-8602
76	Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital /ID# 1140-1437	Hiroshima-shi	Hiroshima	Japan	730-8619
77	Kobe City Medical Center General Hospital /ID# 1140-1438	Kobe-shi	Hyogo	Japan	650-0047
78	Hyogo College of Medicine College Hospital /Id# 1140-1434	Nishinomiya-shi	Hyogo	Japan	663-8501
79	Duplicate_University of Tsukuba Hospital /ID# 1140-1445	Tsukuba-shi	Ibaraki	Japan	305-8576
80	Tokai University Hospital /ID# 1140-1444	Isehara-shi	Kanagawa	Japan	259-1193
81	Duplicate_Kurashiki Central Hospital /ID# 1140-1442	Kurishiki-shi	Okayama	Japan	710-8602
82	Okayama University Hospital /ID# 1140-1430	Okayama-shi	Okayama	Japan	700-8558
83	Osaka Women's and Children's Hospital /ID# 1140-1440	Izumi-Shi	Osaka	Japan	594-1101
84	Osaka City University Hospital /ID# 1140-1157	Osaka-shi	Osaka	Japan	545-8586
85	Dup_Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital /ID# 1140-1439	Bunkyo-ku	Tokyo	Japan	113-8677
86	National Center for Child Health and Development /ID# 1140-1443	Setagaya-ku	Tokyo	Japan	157-8535
87	Kumamoto Medical Center /ID# 1140-1431	Kumamoto		Japan	860-0008
88	Hokkaido University Hospital /ID# 1140-1436	Sapporo		Japan	060-8648
89	Kyungpook National Univ Hosp /ID# 1140-1153	Daegu	Daegu Gwang Yeogsi	Korea, Republic of	41944
90	Yonsei University Health System, Severance Hospital /ID# 1140-0927	Seodaemun-gu	Seoul Teugbyeolsi	Korea, Republic of	03722
91	Samsung Medical Center /ID# 1140-0925	Seoul	Seoul Teugbyeolsi	Korea, Republic of	06351
92	Cath Univ Seoul St Mary's Hosp /ID# 1140-0928	Seoul	Seoul Teugbyeolsi	Korea, Republic of	06591
93	SoonChunHyang University Seoul /ID# 1140-1163	Seoul		Korea, Republic of	04401
94	Asan Medical Center /ID# 1140-0963	Seoul		Korea, Republic of	05505
95	National University Cancer Institute - National University Health System /ID# 1140-1155	Singapore		Singapore	119228
96	Singapore General Hospital /ID# 1140-1162	Singapore		Singapore	169608
97	Hospital Clinic /ID# 1140-0533	Barcelona		Spain	08036
98	Hospital Santa Creu i Sant Pau /ID# 1140-0535	Barcelona		Spain	08041
99	Hospital Universitario Virgen del Rocio /ID# 1140-0863	Sevilla		Spain	41013
100	Hospital Clinico Universitario de Valencia /ID# 1140-1145	Valencia		Spain	46010
101	China Medical University Hosp /ID# 1140-1199	Taichung City	Taichung	Taiwan	40447
102	National Taiwan Univ Hosp /ID# 1140-1184	Taipei City	Taipei	Taiwan	10002

Sponsors and Collaborators

• Pharmacyclics LLC.
• Janssen Research & Development, LLC

Investigators

• Study Director: Justin Wahlstrom, MD, Pharmacyclics LLC.

Study Documents (Full-Text)

• Study Protocol - Feb 6, 2019
• Statistical Analysis Plan - Jan 28, 2020

More Information

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT02959944
• Other Study ID Numbers: PCYC-1140-IM
• First Posted: Nov 9, 2016
• Last Update Posted: Feb 22, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pharmacyclics LLC.: chronic graft versus host disease; PCYC1140; PCYC1140IM; 1140; Ibrutinib; GVHD; Steroid dependent; refractory; chronic; PCI32765; IMBRUVICA; Pharmacyclics; PCYC; graft versus host disease; immunology; new onset graft versus host disease; INTEGRATE; Corticosteroids; prednisone
• Additional relevant MeSH terms: Graft vs Host Disease; Prednisone

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 66 sites overall: 24 sites in North America, and 42 sites in the rest of the world.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Period Title: Overall Study
STARTED	95	98
Received at Least 1 Dose of Study Drug	94	96
COMPLETED	95	98
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone	Total
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Total of all reporting groups
Overall Participants	95	98	193
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.0 (14.48)	51.1 (14.99)	50.6 (14.71)
Sex: Female, Male (Count of Participants)
Female	34 35.8%	33 33.7%	67 34.7%
Male	61 64.2%	65 66.3%	126 65.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 5.3%	2 2%	7 3.6%
Not Hispanic or Latino	78 82.1%	78 79.6%	156 80.8%
Unknown or Not Reported	12 12.6%	18 18.4%	30 15.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.1%	0 0%	1 0.5%
Asian	27 28.4%	19 19.4%	46 23.8%
Native Hawaiian or Other Pacific Islander	1 1.1%	0 0%	1 0.5%
Black or African American	6 6.3%	4 4.1%	10 5.2%
White	47 49.5%	58 59.2%	105 54.4%
More than one race	1 1.1%	1 1%	2 1%
Unknown or Not Reported	12 12.6%	16 16.3%	28 14.5%

Outcome Measures

1. Primary Outcome

Title	Primary Analysis: Response Rate at 48 Weeks
Description	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.
Time Frame	48 weeks (Cumulatively up to 30 March 2020)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	41.1 43.3%	36.7 37.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5384
	Comments	P-value is computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.094 to 0.181
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval is computed using normal approximation.

2. Primary Outcome

Title	Final Analysis: Response Rate at 48 Weeks
Description	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.
Time Frame	48 weeks (Cumulatively up to 12 July 2021)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	41.1 43.3%	36.7 37.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5384
	Comments	P-value is computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.094 to 0.181
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval is computed using normal approximation.

3. Secondary Outcome

Title	Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD
Description	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.
Time Frame	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants. Participants with withdrawal of all corticosteroids. No participants were on corticosteroids at 21 and 24 Months in the Ibrutinib + Prednisone Arm/Group.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	40	36
3 Months	0.042 0%	0.021 0%
6 Months	0.229 0.2%	0.216 0.2%
9 Months	0.318 0.3%	0.322 0.3%
12 Months	0.392 0.4%	0.356 0.4%
15 Months	0.419 0.4%	0.356 0.4%
18 Months	0.419 0.4%	0.356 0.4%
21 Months	0.425 0.4%
24 Months	0.425 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.324
	Comments	Gray's chi-square test (p-value) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD
Description	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.
Time Frame	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants. Participants with withdrawal of all corticosteroids. No participants were on corticosteroids at 21 and 24 Months in the Ibrutinib + Prednisone Arm/Group.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	45	38
3 Months	0.042 0%	0.021 0%
6 Months	0.218 0.2%	0.219 0.2%
9 Months	0.318 0.3%	0.326 0.3%
12 Months	0.406 0.4%	0.359 0.4%
15 Months	0.439 0.5%	0.359 0.4%
18 Months	0.450 0.5%	0.369 0.4%
21 Months	0.495 0.5%	0.391 0.4%
24 Months	0.495 0.5%	0.391 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.281
	Comments	Gray's chi-square test (p-value) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants
Description	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.
Time Frame	Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants. Participants with withdrawal of all immunosuppressants

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	29	24
3 Months	0.011 0%	0.000 0%
6 Months	0.142 0.1%	0.134 0.1%
9 Months	0.220 0.2%	0.207 0.2%
12 Months	0.256 0.3%	0.241 0.2%
15 Months	0.285 0.3%	0.241 0.2%
18 Months	0.313 0.3%	0.241 0.2%
21 Months	0.376 0.4%	0.268 0.3%
24 Months	0.421 0.4%	0.268 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.275
	Comments	Gray's chi-square test (p-value) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants
Description	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.
Time Frame	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants. Participants with withdrawal of all immunosuppressants

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	37	30
3 Months	0.011 0%	0.000 0%
6 Months	0.143 0.2%	0.136 0.1%
9 Months	0.222 0.2%	0.221 0.2%
12 Months	0.280 0.3%	0.264 0.3%
15 Months	0.314 0.3%	0.274 0.3%
18 Months	0.349 0.4%	0.285 0.3%
21 Months	0.372 0.4%	0.307 0.3%
24 Months	0.406 0.4%	0.307 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments	Gray's chi-square test (p-value) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Primary Analysis: Response Rate at 24 Weeks
Description	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.
Time Frame	24 weeks (Cumulatively up to 30 March 2020)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	47.4 49.9%	54.1 55.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3510
	Comments	P-value was computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	-0.067
	Confidence Interval	(2-Sided) 95%; -0.208 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval is computed using normal approximation.

8. Secondary Outcome

Title	Final Analysis: Response Rate at 24 Weeks
Description	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.
Time Frame	24 weeks (Cumulatively up to 12 July 2021)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	47.4 49.9%	54.1 55.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3510
	Comments	P-value was computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	-0.067
	Confidence Interval	(2-Sided) 95%; -0.208 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval is computed using normal approximation.

9. Secondary Outcome

Title	Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	38.9 40.9%	26.5 27%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0659
	Comments	P-value is computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	0.124
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.256
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval is computed using normal approximation.

10. Secondary Outcome

Title	Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	43.2 45.5%	30.6 31.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0708
	Comments	P-value is computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	0.125
	Confidence Interval	(2-Sided) 95%; -0.010 to 0.261
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	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
Time Frame	24 weeks (Cumulatively up to 30 March 2020)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	40.0 42.1%	45.9 46.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4064
	Comments	P-value was computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	-0.059
	Confidence Interval	(2-Sided) 95%; -0.199 to 0.080
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval was computed using normal approximation.

12. Secondary Outcome

Title	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
Time Frame	24 weeks (Cumulatively up to 12 July 2021)

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Number [percentage of participants]	41.1 43.3%	45.9 46.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4955
	Comments	P-value was computed using non-stratified Chi-Square test.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Rates
	Estimated Value	-0.049
	Confidence Interval	(2-Sided) 95%; -0.188 to 0.091
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval was computed using normal approximation.

13. Secondary Outcome

Title	Primary Analysis: Overall Survival (OS)
Description	OS was defined as the time of randomization until the time of death due to any cause, in months.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.994
	Confidence Interval	(2-Sided) 95%; 0.507 to 1.949
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is estimated using unstratified Cox regression model with treatment as the only covariate.

14. Secondary Outcome

Title	Final Analysis: OS
Description	OS was defined as the time of randomization until the time of death due to any cause, in months.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Intent to Treat Population: all randomized participants.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	95	98
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.061
	Confidence Interval	(2-Sided) 95%; 0.591 to 1.904
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is estimated using unstratified Cox regression model with treatment as the only covariate.

15. Secondary Outcome

Title	Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Participants in the Intent-to-Treat Population (all randomized participants) who had response of CR/PR at any time during the study and had not started any subsequent therapy for cGVHD or had evidence of relapse of their underlying disease that was indication for transplant at the time of response.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	74	80
Median (95% Confidence Interval) [months]	19.8	10.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1010
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.697
	Confidence Interval	(2-Sided) 95%; 0.451 to 1.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Final Analysis: DOR for Participants Who Had PR or CR at Any Time
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Participants in the Intent-to-Treat Population (all randomized participants) who had response of CR/PR at any time during the study and had not started any subsequent therapy for cGVHD or had evidence of relapse of their underlying disease that was indication for transplant at the time of response.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	74	80
Median (95% Confidence Interval) [months]	19.1	10.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibrutinib + Prednisone, Placebo + Prednisone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1004
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.717
	Confidence Interval	(2-Sided) 95%; 0.482 to 1.068
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least one dose of either ibrutinib or placebo, analyzed according to the actual treatment received.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	94	96
Any TEAE	93 97.9%	95 96.9%
Any Grade ≥ 3 TEAE	60 63.2%	64 65.3%
Any Ibrutinib-/Placebo-Related TEAE	66 69.5%	58 59.2%
Any Grade ≥ 3 Ibrutinib-/Placebo-Related TEAE	32 33.7%	28 28.6%
Any Corticosteroid-Related TEAE	71 74.7%	77 78.6%
Any Grade ≥ 3 Corticosteroid-Related TEAE	32 33.7%	36 36.7%
Any TEAE Leading to Discontinuation (DC) of Any Treatment	21 22.1%	24 24.5%
Any TEAE Leading to DC of Ibrutinib/Placebo	21 22.1%	23 23.5%
Any TEAE Leading to DC of Corticosteroid	8 8.4%	8 8.2%
Any Treatment Emergent SAE (TESAE)	46 48.4%	48 49%
Any Grade ≥ 3 TESAE	43 45.3%	46 46.9%
Any Treatment-Related TESAE	27 28.4%	28 28.6%
Any Ibrutinib/Placebo Treatment-Related TESAE	24 25.3%	19 19.4%
Any Corticosteroid Treatment-Related TESAE	24 25.3%	27 27.6%
Any Fatal TEAE	10 10.5%	7 7.1%

18. Secondary Outcome

Title	Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least one dose of either ibrutinib or placebo, analyzed according to the actual treatment received.

Arm/Group Title	Ibrutinib + Prednisone	Placebo + Prednisone
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
Measure Participants	94	96
Any TEAE	93 97.9%	95 96.9%
Any Grade ≥ 3 TEAE	64 67.4%	64 65.3%
Any Ibrutinib-/Placebo-Related TEAE	67 70.5%	57 58.2%
Any Grade ≥ 3 Ibrutinib-/Placebo-Related TEAE	35 36.8%	27 27.6%
Any Corticosteroid-Related TEAE	72 75.8%	76 77.6%
Any Grade ≥ 3 Corticosteroid-Related TEAE	34 35.8%	35 35.7%
Any TEAE Leading to Discontinuation (DC) of Any Treatment	23 24.2%	28 28.6%
Any TEAE Leading to DC of Ibrutinib/Placebo	22 23.2%	27 27.6%
Any TEAE Leading to DC of Corticosteroid	10 10.5%	9 9.2%
Any Treatment Emergent SAE (TESAE)	49 51.6%	47 48%
Any Grade ≥ 3 TESAE	46 48.4%	45 45.9%
Any Treatment-Related TESAE	29 30.5%	27 27.6%
Any Ibrutinib/Placebo Treatment-Related TESAE	26 27.4%	18 18.4%
Any Corticosteroid Treatment-Related TESAE	26 27.4%	26 26.5%
Any Fatal TEAE	12 12.6%	6 6.1%

Adverse Events

Time Frame	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.
Arm/Group Title	Ibrutinib		Placebo
Arm/Group Description	Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.		Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.
All Cause Mortality
	Ibrutinib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/94 (24.5%)		22/96 (22.9%)
Serious Adverse Events
	Ibrutinib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/94 (54.3%)		49/96 (51%)
Blood and lymphatic system disorders
ANAEMIA	0/94 (0%)	0	1/96 (1%)	1
COAGULOPATHY	0/94 (0%)	0	1/96 (1%)	1
NEUTROPENIA	1/94 (1.1%)	1	0/96 (0%)	0
THROMBOTIC MICROANGIOPATHY	0/94 (0%)	0	1/96 (1%)	1
Cardiac disorders
ACUTE CORONARY SYNDROME	0/94 (0%)	0	1/96 (1%)	1
ATRIAL FIBRILLATION	1/94 (1.1%)	1	2/96 (2.1%)	2
ATRIAL FLUTTER	1/94 (1.1%)	1	0/96 (0%)	0
CARDIAC ARREST	1/94 (1.1%)	1	1/96 (1%)	1
CARDIAC FAILURE	1/94 (1.1%)	1	1/96 (1%)	1
MYOCARDITIS	1/94 (1.1%)	1	0/96 (0%)	0
PERICARDIAL EFFUSION	2/94 (2.1%)	2	0/96 (0%)	0
Eye disorders
DIPLOPIA	1/94 (1.1%)	1	0/96 (0%)	0
Gastrointestinal disorders
COLITIS	0/94 (0%)	0	1/96 (1%)	1
DIARRHOEA	2/94 (2.1%)	2	1/96 (1%)	2
ENTERITIS	1/94 (1.1%)	1	0/96 (0%)	0
GASTROINTESTINAL HAEMORRHAGE	0/94 (0%)	0	2/96 (2.1%)	2
ILEUS	1/94 (1.1%)	1	0/96 (0%)	0
LARGE INTESTINE PERFORATION	1/94 (1.1%)	1	0/96 (0%)	0
LOWER GASTROINTESTINAL HAEMORRHAGE	0/94 (0%)	0	1/96 (1%)	1
MELAENA	1/94 (1.1%)	1	0/96 (0%)	0
PANCREATIC ENZYME ABNORMALITY	1/94 (1.1%)	1	0/96 (0%)	0
SMALL INTESTINAL OBSTRUCTION	0/94 (0%)	0	1/96 (1%)	1
VOMITING	1/94 (1.1%)	1	0/96 (0%)	0
General disorders
DEATH	2/94 (2.1%)	2	0/96 (0%)	0
MALAISE	1/94 (1.1%)	1	0/96 (0%)	0
OEDEMA PERIPHERAL	0/94 (0%)	0	1/96 (1%)	1
PYREXIA	1/94 (1.1%)	1	3/96 (3.1%)	3
Hepatobiliary disorders
CHOLECYSTITIS	1/94 (1.1%)	1	1/96 (1%)	1
HEPATIC CIRRHOSIS	1/94 (1.1%)	1	0/96 (0%)	0
Immune system disorders
GRAFT VERSUS HOST DISEASE	0/94 (0%)	0	3/96 (3.1%)	3
CHRONIC GRAFT VERSUS HOST DISEASE	3/94 (3.2%)	3	3/96 (3.1%)	3
HYPOGAMMAGLOBULINAEMIA	1/94 (1.1%)	1	0/96 (0%)	0
Infections and infestations
BACTERAEMIA	1/94 (1.1%)	1	1/96 (1%)	1
BRONCHITIS	1/94 (1.1%)	1	1/96 (1%)	1
COVID-19	2/94 (2.1%)	2	0/96 (0%)	0
CELLULITIS	3/94 (3.2%)	3	0/96 (0%)	0
CLOSTRIDIUM DIFFICILE INFECTION	0/94 (0%)	0	1/96 (1%)	2
CYTOMEGALOVIRUS COLITIS	0/94 (0%)	0	1/96 (1%)	1
CYTOMEGALOVIRUS INFECTION REACTIVATION	1/94 (1.1%)	1	1/96 (1%)	1
DACRYOCYSTITIS	1/94 (1.1%)	1	0/96 (0%)	0
DIVERTICULITIS	1/94 (1.1%)	1	0/96 (0%)	0
ENCEPHALITIS	1/94 (1.1%)	1	0/96 (0%)	0
EPSTEIN-BARR VIRUS INFECTION REACTIVATION	1/94 (1.1%)	1	0/96 (0%)	0
EYE INFECTION	0/94 (0%)	0	1/96 (1%)	1
HAEMOPHILUS INFECTION	0/94 (0%)	0	1/96 (1%)	1
INFLUENZA	4/94 (4.3%)	4	4/96 (4.2%)	4
KLEBSIELLA BACTERAEMIA	1/94 (1.1%)	1	0/96 (0%)	0
KLEBSIELLA SEPSIS	0/94 (0%)	0	1/96 (1%)	1
LOWER RESPIRATORY TRACT INFECTION	0/94 (0%)	0	1/96 (1%)	1
MASTOIDITIS	1/94 (1.1%)	1	0/96 (0%)	0
MEDIASTINITIS	1/94 (1.1%)	1	0/96 (0%)	0
METAPNEUMOVIRUS INFECTION	0/94 (0%)	0	1/96 (1%)	1
PARAINFLUENZAE VIRUS INFECTION	1/94 (1.1%)	1	1/96 (1%)	1
PAROTITIS	0/94 (0%)	0	1/96 (1%)	1
PERIORBITAL CELLULITIS	1/94 (1.1%)	1	0/96 (0%)	0
PERITONITIS	0/94 (0%)	0	1/96 (1%)	1
PNEUMOCYSTIS JIROVECII PNEUMONIA	1/94 (1.1%)	1	0/96 (0%)	0
PNEUMONIA	6/94 (6.4%)	8	9/96 (9.4%)	10
PNEUMONIA CYTOMEGALOVIRAL	1/94 (1.1%)	1	0/96 (0%)	0
PNEUMONIA FUNGAL	1/94 (1.1%)	2	0/96 (0%)	0
PNEUMONIA LEGIONELLA	1/94 (1.1%)	1	0/96 (0%)	0
PNEUMONIA PARAINFLUENZAE VIRAL	0/94 (0%)	0	1/96 (1%)	1
PNEUMONIA VIRAL	0/94 (0%)	0	1/96 (1%)	1
PNEUMONIA RESPIRATORY SYNCYTIAL VIRAL	0/94 (0%)	0	2/96 (2.1%)	2
RESPIRATORY SYNCYTIAL VIRUS INFECTION	0/94 (0%)	0	1/96 (1%)	1
RESPIRATORY TRACT INFECTION	1/94 (1.1%)	1	0/96 (0%)	0
SEPSIS	1/94 (1.1%)	1	2/96 (2.1%)	2
SEPTIC SHOCK	2/94 (2.1%)	2	1/96 (1%)	1
SINUSITIS	0/94 (0%)	0	1/96 (1%)	1
SINUSITIS FUNGAL	1/94 (1.1%)	1	0/96 (0%)	0
SKIN INFECTION	0/94 (0%)	0	1/96 (1%)	1
STAPHYLOCOCCAL BACTERAEMIA	0/94 (0%)	0	1/96 (1%)	1
STAPHYLOCOCCAL SEPSIS	1/94 (1.1%)	1	0/96 (0%)	0
URINARY TRACT INFECTION	1/94 (1.1%)	1	1/96 (1%)	1
URINARY TRACT INFECTION BACTERIAL	1/94 (1.1%)	1	0/96 (0%)	0
UROSEPSIS	1/94 (1.1%)	1	0/96 (0%)	0
WOUND INFECTION	1/94 (1.1%)	1	0/96 (0%)	0
Injury, poisoning and procedural complications
ANKLE FRACTURE	1/94 (1.1%)	1	0/96 (0%)	0
FALL	1/94 (1.1%)	1	0/96 (0%)	0
FEMORAL NECK FRACTURE	0/94 (0%)	0	1/96 (1%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/94 (0%)	0	1/96 (1%)	1
ASPARTATE AMINOTRANSFERASE INCREASED	0/94 (0%)	0	1/96 (1%)	1
WHITE BLOOD CELL COUNT DECREASED	1/94 (1.1%)	1	0/96 (0%)	0
Metabolism and nutrition disorders
DIABETES MELLITUS INADEQUATE CONTROL	0/94 (0%)	0	1/96 (1%)	1
HYPERGLYCAEMIA	2/94 (2.1%)	2	2/96 (2.1%)	2
HYPONATRAEMIA	0/94 (0%)	0	2/96 (2.1%)	2
STEROID DIABETES	0/94 (0%)	0	2/96 (2.1%)	2
Musculoskeletal and connective tissue disorders
MUSCLE ATROPHY	1/94 (1.1%)	1	0/96 (0%)	0
MYOPATHY	1/94 (1.1%)	1	0/96 (0%)	0
RHABDOMYOLYSIS	1/94 (1.1%)	1	0/96 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA	0/94 (0%)	0	1/96 (1%)	1
ACUTE MYELOID LEUKAEMIA RECURRENT	2/94 (2.1%)	2	4/96 (4.2%)	4
ACUTE PROMYELOCYTIC LEUKAEMIA	1/94 (1.1%)	1	0/96 (0%)	0
BENIGN NEOPLASM OF TESTIS	1/94 (1.1%)	1	0/96 (0%)	0
BLADDER CANCER	0/94 (0%)	0	1/96 (1%)	1
COLON CANCER	0/94 (0%)	0	1/96 (1%)	1
LEUKAEMIA RECURRENT	1/94 (1.1%)	1	2/96 (2.1%)	2
POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER	1/94 (1.1%)	2	0/96 (0%)	0
PRIMARY MYELOFIBROSIS	0/94 (0%)	0	1/96 (1%)	1
Nervous system disorders
ISCHAEMIC STROKE	1/94 (1.1%)	1	0/96 (0%)	0
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME	1/94 (1.1%)	1	0/96 (0%)	0
SEIZURE	1/94 (1.1%)	1	0/96 (0%)	0
SYNCOPE	2/94 (2.1%)	2	0/96 (0%)	0
Psychiatric disorders
DEPRESSION	0/94 (0%)	0	1/96 (1%)	1
MANIA	1/94 (1.1%)	1	0/96 (0%)	0
SUBSTANCE-INDUCED PSYCHOTIC DISORDER	0/94 (0%)	0	1/96 (1%)	1
Renal and urinary disorders
ACUTE KIDNEY INJURY	1/94 (1.1%)	2	2/96 (2.1%)	2
CYSTITIS HAEMORRHAGIC	0/94 (0%)	0	1/96 (1%)	1
HAEMATURIA	2/94 (2.1%)	2	0/96 (0%)	0
HYDRONEPHROSIS	1/94 (1.1%)	1	1/96 (1%)	1
NEPHROLITHIASIS	0/94 (0%)	0	1/96 (1%)	1
OBSTRUCTIVE NEPHROPATHY	1/94 (1.1%)	1	0/96 (0%)	0
RENAL FAILURE	0/94 (0%)	0	1/96 (1%)	1
URETEROLITHIASIS	1/94 (1.1%)	1	1/96 (1%)	1
URETHRAL STENOSIS	0/94 (0%)	0	1/96 (1%)	1
Reproductive system and breast disorders
INTERMENSTRUAL BLEEDING	0/94 (0%)	0	1/96 (1%)	1
SCROTAL OEDEMA	0/94 (0%)	0	1/96 (1%)	1
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE	0/94 (0%)	0	1/96 (1%)	1
BRONCHITIS CHRONIC	1/94 (1.1%)	1	0/96 (0%)	0
DYSPNOEA	0/94 (0%)	0	1/96 (1%)	1
HYPOXIA	0/94 (0%)	0	1/96 (1%)	1
PLEURAL EFFUSION	0/94 (0%)	0	1/96 (1%)	1
PULMONARY MASS	1/94 (1.1%)	1	0/96 (0%)	0
PULMONARY EMBOLISM	0/94 (0%)	0	4/96 (4.2%)	4
PULMONARY OEDEMA	1/94 (1.1%)	1	0/96 (0%)	0
RESPIRATORY FAILURE	2/94 (2.1%)	2	0/96 (0%)	0
Vascular disorders
DEEP VEIN THROMBOSIS	0/94 (0%)	0	2/96 (2.1%)	2
PHLEBITIS	0/94 (0%)	0	1/96 (1%)	1
Other (Not Including Serious) Adverse Events
	Ibrutinib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/94 (93.6%)		92/96 (95.8%)
Blood and lymphatic system disorders
INCREASED TENDENCY TO BRUISE	9/94 (9.6%)	10	8/96 (8.3%)	8
ANAEMIA	4/94 (4.3%)	17	11/96 (11.5%)	21
NEUTROPENIA	1/94 (1.1%)	1	6/96 (6.3%)	11
THROMBOCYTOPENIA	18/94 (19.1%)	30	15/96 (15.6%)	25
Cardiac disorders
PALPITATIONS	5/94 (5.3%)	5	3/96 (3.1%)	3
Endocrine disorders
CUSHINGOID	3/94 (3.2%)	3	6/96 (6.3%)	6
Eye disorders
CATARACT	2/94 (2.1%)	3	7/96 (7.3%)	8
DRY EYE	5/94 (5.3%)	6	4/96 (4.2%)	4
VISION BLURRED	7/94 (7.4%)	7	9/96 (9.4%)	10
Gastrointestinal disorders
ABDOMINAL PAIN	8/94 (8.5%)	10	6/96 (6.3%)	6
CONSTIPATION	7/94 (7.4%)	7	14/96 (14.6%)	15
DIARRHOEA	14/94 (14.9%)	20	13/96 (13.5%)	19
DYSPEPSIA	7/94 (7.4%)	7	4/96 (4.2%)	4
NAUSEA	13/94 (13.8%)	20	13/96 (13.5%)	15
VOMITING	15/94 (16%)	20	8/96 (8.3%)	8
General disorders
ASTHENIA	5/94 (5.3%)	7	6/96 (6.3%)	7
FATIGUE	17/94 (18.1%)	22	18/96 (18.8%)	30
INFLUENZA LIKE ILLNESS	5/94 (5.3%)	6	1/96 (1%)	1
OEDEMA PERIPHERAL	25/94 (26.6%)	37	13/96 (13.5%)	17
PYREXIA	7/94 (7.4%)	7	16/96 (16.7%)	22
Hepatobiliary disorders
HEPATIC FUNCTION ABNORMAL	6/94 (6.4%)	19	6/96 (6.3%)	10
Immune system disorders
HYPOGAMMAGLOBULINAEMIA	5/94 (5.3%)	5	3/96 (3.1%)	3
Infections and infestations
BRONCHITIS	2/94 (2.1%)	2	7/96 (7.3%)	8
CONJUNCTIVITIS	4/94 (4.3%)	5	5/96 (5.2%)	6
HERPES ZOSTER	5/94 (5.3%)	6	5/96 (5.2%)	5
INFLUENZA	5/94 (5.3%)	5	6/96 (6.3%)	7
NASOPHARYNGITIS	6/94 (6.4%)	6	8/96 (8.3%)	11
PARONYCHIA	5/94 (5.3%)	5	2/96 (2.1%)	2
RHINOVIRUS INFECTION	1/94 (1.1%)	1	7/96 (7.3%)	7
SINUSITIS	1/94 (1.1%)	1	5/96 (5.2%)	8
UPPER RESPIRATORY TRACT INFECTION	15/94 (16%)	24	15/96 (15.6%)	21
Injury, poisoning and procedural complications
CONTUSION	10/94 (10.6%)	11	4/96 (4.2%)	5
FALL	3/94 (3.2%)	4	7/96 (7.3%)	7
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/94 (7.4%)	11	16/96 (16.7%)	29
ASPARTATE AMINOTRANSFERASE INCREASED	1/94 (1.1%)	1	13/96 (13.5%)	17
BLOOD ALKALINE PHOSPHATASE INCREASED	3/94 (3.2%)	3	6/96 (6.3%)	12
BLOOD CREATININE INCREASED	5/94 (5.3%)	8	6/96 (6.3%)	7
PLATELET COUNT DECREASED	7/94 (7.4%)	13	6/96 (6.3%)	10
WEIGHT DECREASED	6/94 (6.4%)	6	4/96 (4.2%)	4
WEIGHT INCREASED	5/94 (5.3%)	7	6/96 (6.3%)	6
Metabolism and nutrition disorders
DECREASED APPETITE	7/94 (7.4%)	8	7/96 (7.3%)	8
HYPERKALAEMIA	3/94 (3.2%)	3	8/96 (8.3%)	10
HYPERGLYCAEMIA	4/94 (4.3%)	6	13/96 (13.5%)	23
HYPOKALAEMIA	11/94 (11.7%)	21	14/96 (14.6%)	21
HYPOMAGNESAEMIA	4/94 (4.3%)	10	8/96 (8.3%)	11
HYPONATRAEMIA	9/94 (9.6%)	10	6/96 (6.3%)	9
HYPOPHOSPHATAEMIA	3/94 (3.2%)	5	9/96 (9.4%)	11
Musculoskeletal and connective tissue disorders
ARTHRALGIA	12/94 (12.8%)	19	13/96 (13.5%)	16
BACK PAIN	6/94 (6.4%)	7	11/96 (11.5%)	12
MUSCULAR WEAKNESS	5/94 (5.3%)	7	9/96 (9.4%)	9
MUSCLE SPASMS	17/94 (18.1%)	20	16/96 (16.7%)	27
MYALGIA	1/94 (1.1%)	1	5/96 (5.2%)	6
PAIN IN EXTREMITY	5/94 (5.3%)	6	5/96 (5.2%)	5
Nervous system disorders
DIZZINESS	10/94 (10.6%)	10	11/96 (11.5%)	16
HEADACHE	13/94 (13.8%)	19	12/96 (12.5%)	17
PERIPHERAL SENSORY NEUROPATHY	6/94 (6.4%)	7	2/96 (2.1%)	5
TREMOR	5/94 (5.3%)	5	9/96 (9.4%)	10
Psychiatric disorders
ANXIETY	5/94 (5.3%)	5	7/96 (7.3%)	8
DEPRESSION	5/94 (5.3%)	6	2/96 (2.1%)	2
INSOMNIA	26/94 (27.7%)	28	18/96 (18.8%)	20
Renal and urinary disorders
ACUTE KIDNEY INJURY	3/94 (3.2%)	7	8/96 (8.3%)	9
Respiratory, thoracic and mediastinal disorders
COUGH	21/94 (22.3%)	24	29/96 (30.2%)	37
DYSPNOEA	9/94 (9.6%)	12	14/96 (14.6%)	16
DYSPNOEA EXERTIONAL	2/94 (2.1%)	2	5/96 (5.2%)	6
EPISTAXIS	7/94 (7.4%)	8	4/96 (4.2%)	5
OROPHARYNGEAL PAIN	5/94 (5.3%)	6	3/96 (3.1%)	3
PRODUCTIVE COUGH	5/94 (5.3%)	8	3/96 (3.1%)	3
RHINORRHOEA	3/94 (3.2%)	5	8/96 (8.3%)	8
Skin and subcutaneous tissue disorders
PRURITUS	6/94 (6.4%)	7	7/96 (7.3%)	10
Vascular disorders
HYPERTENSION	10/94 (10.6%)	16	13/96 (13.5%)	14

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Institution/Investigator will not publish without Sponsor prior review and approval Institution/Investigator will not publish until the earlier of (i) results of study are submitted for publication (ii) notification that submission of the multicenter results are no longer planned (iii) 18 months after study termination.