Trial Outcomes & Findings for A Study to Evaluate the Safety of Rituximab Retreatment in Subjects With Systemic Lupus Erythematosus (NCT NCT00137969)

Last Updated: 2019-08-20

Results Overview

The BILAG Index measures clinical disease activity in Systemic Lupus Erythematosus (SLE). A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24; PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

262 participants

Primary outcome timeframe

From baseline to 52 weeks

Results posted on

2019-08-20

Participant Flow

Participant milestones

Participant milestones
Measure	Rituximab 1000 mg + Prednisone Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Overall Study STARTED	174	88
Overall Study Received Study Drug	169	88
Overall Study COMPLETED	107	67
Overall Study NOT COMPLETED	67	21

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Evaluate the Safety of Rituximab Retreatment in Subjects With Systemic Lupus Erythematosus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Total n=257 Participants Total of all reporting groups
Age, Continuous	40.2 years STANDARD_DEVIATION 11.4 • n=5 Participants	40.5 years STANDARD_DEVIATION 12.8 • n=7 Participants	40.3 years STANDARD_DEVIATION 11.9 • n=5 Participants
Age, Customized < 20 years	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Age, Customized 20 to 64 years	166 participants n=5 Participants	83 participants n=7 Participants	249 participants n=5 Participants
Age, Customized > 64 years	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Sex: Female, Male Female	152 Participants n=5 Participants	82 Participants n=7 Participants	234 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	6 Participants n=7 Participants	23 Participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline to 52 weeks

Population: Intent-to-treat (ITT) population

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period MCR (excluding PCR)	21 Participants	14 Participants
Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period PCR	29 Participants	11 Participants
Number of Participants Who Achieved a Major Clinical Response (MCR), Partial Clinical Response (PCR), or Nonclinical Response (NCR) Defined by British Isles Lupus Assessment Group (BILAG) Scores Over The 52-week Treatment Period Nonclinical Response (NCR)	119 Participants	63 Participants

SECONDARY outcome

Timeframe: From baseline to 52 weeks

Population: ITT population

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Time-adjusted Area Under The Curve Minus Baseline (AUCMB) of BILAG Score Over The 52-week Treatment Period	-5.8 BILAG score unit Standard Deviation 4.0	-5.9 BILAG score unit Standard Deviation 4.5

SECONDARY outcome

Timeframe: From baseline to 52 weeks

Population: ITT population

The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. MCR = participants who achieved BILAG C scores or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Number of Participants Who Achieved an MCR (Excluding PCR)	21 participants	14 participants

SECONDARY outcome

Timeframe: From baseline to 52 Weeks

Population: ITT population

The BILAG Index measures clinical disease activity in SLE. A single alphabetic score (A through E) is used to denote disease severity for each of the 8 domains. The global BILAG score is the sum of a converted numerical score (A=9, B=3, C=1, D=0, E=0) over 8 domains. PCR = participants who achieved BILAG C score or better at 24 wks and maintained response without a flare for 16 consecutive weeks, or maximum of one BILAG B score at 24 weeks and maintained response without a flare to 52 wks, or maximum of 2 BILAG B scores at 24 wks without development of BILAG scores of A or B until Week 52 if the baseline BILAG score was 1A+\>=2Bs, or\>=2 As, or\>=4 Bs, or participants who enrolled with scores of severe disease and did not achieve a single BILAG B at Month 6. MCR = participants who achieved BILAG C or better at 24 weeks, maintained this response without developing a flare to 52 weeks, and did not experience a severe flare from Day 1 to Week 24.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Number of Participants Who Achieved a PCR (Including MCR)	50 participants	25 participants

SECONDARY outcome

Timeframe: 24 weeks

Population: ITT population

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Number of Participants Who Achieved a BILAG C or Better in All Domains	42 participants	24 participants

SECONDARY outcome

Timeframe: 52 weeks

Population: Number of participants who ever reached C/D/E for all 8 BILAG domains before Day 364 visit. If a participant reached C/D/E at the last visit, then this participant was excluded from the analysis.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=127 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=58 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Time to First Moderate or Severe Flare	112.0 days Interval 84.0 to 146.0	126.0 days Interval 56.0 to 225.0

SECONDARY outcome

Timeframe: From baseline to 52 weeks

Population: ITT population

Short Form (36) with additional questions specific to lupus (scale = 0-100; with 100 representing the highest level of functioning possible) to measure the ability of rituximab to improve quality of life. A positive value for this outcome measure indicates that symptoms have improved.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Change in SLE Expanded Health Survey Physical Function Score From Baseline	8.2 score on a scale Standard Deviation 22.8	4.1 score on a scale Standard Deviation 17.9

SECONDARY outcome

Timeframe: From Weeks 24 to 52

Population: ITT population

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg + Prednisone n=169 Participants Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 Participants Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Number of Participants Who Achieved an MCR in The ITT Population	14 participants	9 participants

Adverse Events

Rituximab 1000 mg + Prednisone

Serious events: 72 serious events

Other events: 164 other events

Deaths: 0 deaths

Placebo + Prednisone

Serious events: 32 serious events

Other events: 85 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Rituximab 1000 mg + Prednisone n=169 participants at risk Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 participants at risk Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Infections and infestations Acute Sinusitis	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Sinusitis	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Gastroentiritis Viral	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Cytomegalovirus Colitis	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Genital Infection Female	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Blood and lymphatic system disorders Neutropenia	3.6% 6/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Blood and lymphatic system disorders Pancytopenia	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Blood and lymphatic system disorders Haemolytic Anaemia	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Blood and lymphatic system disorders Lymphophenia	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Blood and lymphatic system disorders Thrombocythaemia	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Coronary Artery Disease	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Diastolic Dysfunction	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Cardiomyopathy	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Cardiac Failure	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Angina Pectoris	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Myocarditis	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Pericarditis	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Pericardial Effusion	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Right Ventricular Failure	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Supraventricular Extrasystoles	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Endocrine disorders Hypothyroidism	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Gastrointestinal Haemorrhage	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	2.3% 2/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Abdominal Pain	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Pancreatitis	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Pancreatitis Acute	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Gastric Ulcer	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Gastric Ulcer Perforation	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Diverticular Perforation	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Colitis	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Irritable Bowel Syndrome	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Intestinal Perforation	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Malabsorption	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Vomiting	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Peptic Ulcer	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Pyrexia	2.4% 4/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Chest Pain	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	3.4% 3/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Death	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Multi-Organ Failure	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Hepatobiliary disorders Cholecystitis	0.00% 0/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	1.1% 1/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Immune system disorders Serum Sickness	0.59% 1/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	0.00% 0/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).

Other adverse events
Measure	Rituximab 1000 mg + Prednisone n=169 participants at risk Participants received rituximab 1000 mg intravenously (IV) on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.	Placebo + Prednisone n=88 participants at risk Participants received placebo intravenously on Days 1, 15, 168, and 182. Participants also received an initial dose of prednisone (0.5, 0.75, or 1.0 mg/kg orally once a day) with tapering beginning at Day 16 for 10 weeks to a dose of ≤ 10 mg/day. Participants also received acetaminophen 1000 mg orally and diphenhydramine 50 mg orally prior to study drug infusion.
Metabolism and nutrition disorders Hypokalaemia	4.1% 7/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Metabolism and nutrition disorders Decreased appetite	7.1% 12/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	2.3% 2/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Musculoskeletal and connective tissue disorders Pain in Extremity	13.0% 22/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	17.0% 15/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Musculoskeletal and connective tissue disorders Back Pain	10.7% 18/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	14.8% 13/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	6.5% 11/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Musculoskeletal and connective tissue disorders Neck Pain	5.3% 9/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Ear Infection	1.2% 2/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Injury, poisoning and procedural complications Contusion	5.9% 10/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	6.8% 6/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Investigations Weight Increased	2.4% 4/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Blood and lymphatic system disorders Anaemia	3.6% 6/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Tachycardia	5.9% 10/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	3.4% 3/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Cardiac disorders Palpitations	5.3% 9/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	3.4% 3/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Endocrine disorders Cushingoid	4.1% 7/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	6.8% 6/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Eye disorders Vision Blurred	1.8% 3/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Eye disorders Conjunctivitis	2.4% 4/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	6.8% 6/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Eye disorders Dry Eye	3.6% 6/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Nausea	26.0% 44/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	27.3% 24/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Vomiting	14.2% 24/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	12.5% 11/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Diarrhoea	17.8% 30/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	13.6% 12/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Abdominal Pain	7.1% 12/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Abdominal Pain Upper	7.1% 12/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Constipation	8.9% 15/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	9.1% 8/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Gastrooesophageal Reflux Disease	7.7% 13/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Abdominal Discomfort	5.9% 10/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Dyspepsia	4.7% 8/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	8.0% 7/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Gastrointestinal disorders Toothache	4.1% 7/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Oedema Peripheral	14.8% 25/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	14.8% 13/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Chest Pain	5.9% 10/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	10.2% 9/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Pain	7.7% 13/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Fatigue	12.4% 21/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	17.0% 15/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
General disorders Pyrexia	10.1% 17/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	6.8% 6/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Upper Respiratory Tract Infection	32.0% 54/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	36.4% 32/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Sinusitis	16.6% 28/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	17.0% 15/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Nasopharyngitis	10.1% 17/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Urinary Tract Infection	28.4% 48/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	29.5% 26/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Candidiasis	7.1% 12/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	15.9% 14/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Oral Candidiasis	9.5% 16/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	10.2% 9/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Bronchitis	16.6% 28/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	13.6% 12/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Pneumonia	1.8% 3/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	5.7% 5/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).
Infections and infestations Herpes Zoster	9.5% 16/169 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).	4.5% 4/88 • From the beginning to the end of the study (Week 78 plus extended safety follow-up, with an average duration of 96 weeks).