Trial Outcomes & Findings for A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (NCT NCT00087529)

Last Updated: 2015-09-09

Results Overview

Disease progression was assessed using the Expanded Disability Status Scale (EDSS), a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of greater than or equal to (≥) 1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score greater than (\>) 5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. Those who did not meet criteria for CDP, completed treatment with only initial progression, or received an exclusionary therapy were censored at last EDSS assessment. Time to CDP was the time from randomization to initial disease progression, estimated using Kaplan-Meier (KM) analysis.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

439 participants

Primary outcome timeframe

96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)

Results posted on

2015-09-09

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Overall Study STARTED	147	292
Overall Study COMPLETED	116	224
Overall Study NOT COMPLETED	31	68

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Overall Study Death	1	0
Overall Study Adverse Event	0	8
Overall Study Pregnancy	0	1
Overall Study Lost to Follow-up	2	3
Overall Study Participant Decision	14	37
Overall Study Physician Decision	4	8
Overall Study Initiation of Excluded Therapy	0	1
Overall Study Participant Noncompliance	0	1
Overall Study Disease Progression	5	4
Overall Study Did Not Continue to Safety Follow-Up	5	5

Baseline Characteristics

A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=147 Participants Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=292 Participants Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Total n=439 Participants Total of all reporting groups
Age, Continuous	49.6 years STANDARD_DEVIATION 8.69 • n=5 Participants	50.1 years STANDARD_DEVIATION 9.02 • n=7 Participants	49.9 years STANDARD_DEVIATION 8.90 • n=5 Participants
Sex: Female, Male Female	81 Participants n=5 Participants	140 Participants n=7 Participants	221 Participants n=5 Participants
Sex: Female, Male Male	66 Participants n=5 Participants	152 Participants n=7 Participants	218 Participants n=5 Participants

PRIMARY outcome

Timeframe: 96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)

Population: ITT Population.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=292 Participants Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Time to Confirmed Disease Progression (CDP)	NA weeks Stratified log rank test was used to test treatment effect. Hazard ratio and CDP rate (from KM) were used to describe treatment effect. Median time to CDP was not available because less than (\<) 50 percent (%) had a CDP event by end of Week 96.	NA weeks Stratified log rank test was used to test treatment effect. Hazard ratio and CDP rate (from KM) were used to describe treatment effect. Median time to CDP was not available because less than (\<) 50 percent (%) had a CDP event by end of Week 96.

PRIMARY outcome

Timeframe: 96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)

Population: ITT Population.

Disease progression was assessed using the EDSS, a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of ≥1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score \>5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. The percentage of participants with CDP was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=292 Participants Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Percentage of Participants With CDP	36.1 percentage of participants	28.4 percentage of participants

SECONDARY outcome

Timeframe: At Baseline and Week 96

Population: ITT Population. Participants with missing Baseline values were excluded.

Scheduled T2-weighted MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total volume of T2 (ie, hyperintense) brain lesions at each visit was documented. Missing Week 96 values were imputed using a last observation carried forward (LOCF) approach, while participants with missing Baseline values were excluded. The change in T2 lesion volume was calculated as \[volume at Week 96 minus volume at Baseline\] and expressed in cubic millimeters (mm\^3).

Outcome measures

Outcome measures
Measure	Placebo n=147 Participants Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=290 Participants Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan	809.50 mm^3 Interval -8557.0 to 26367.0	301.95 mm^3 Interval -4031.0 to 24076.0

SECONDARY outcome

Timeframe: At Baseline and Week 96

Population: ITT Population. Participants with missing Baseline values were excluded.

Scheduled MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total brain volume was documented at Baseline and at visits occurring during Weeks 48 and 96. Missing Week 96 values were imputed using a LOCF approach, while participants with missing Baseline values were excluded. The change in brain volume was calculated as \[volume at Week 96 minus volume at Baseline\] and expressed in cubic centimeters (cm\^3).

Outcome measures

Outcome measures
Measure	Placebo n=130 Participants Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=237 Participants Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Change From Baseline to Week 96 in Brain Volume on MRI Scan	-14.00 cm^3 Interval -76.0 to 323.7	-13.10 cm^3 Interval -91.0 to 346.4

Adverse Events

Placebo

Serious events: 20 serious events

Other events: 147 other events

Deaths: 0 deaths

Rituximab

Serious events: 47 serious events

Other events: 289 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-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

Measure	Placebo n=147 participants at risk Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=292 participants at risk Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Blood and lymphatic system disorders Idiopathic thrombocytopenic purpura	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Acute myocardial infarction	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.68% 2/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Myocardial infarction	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Acute coronary syndrome	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Myocardial ischaemia	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Coronary artery stenosis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.68% 2/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Atrial fibrillation	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Cardiac disorders Cardiopulmonary failure	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Colitis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Diarrhoea	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Diverticulum	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Appendicitis perforated	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Gastrointestinal haemorrhage	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Asthenia	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Abasia	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Gait disturbance	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Pyrexia	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Chest discomfort	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Chest pain	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Pneumonia	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	1.4% 4/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Bronchitis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Urinary tract infection	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.68% 2/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Pyelonephritis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Cellulitis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.68% 2/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Diverticulitis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Meningitis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Escherichia bacteraemia	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Escherichia urinary tract infection	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Influenza	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Gastroenteritis viral	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Fall	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.68% 2/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Drug toxicity	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Wrist fracture	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Investigations Heart rate irregular	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Metabolism and nutrition disorders Anorexia	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	1.4% 4/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Osteonecrosis	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Parathyroid tumour benign	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Balance disorder	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Cerebellar ataxia	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Multiple sclerosis	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Intracranial aneurysm	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Cerebral infarction	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Syncope	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Encephalopathy	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Amyotrophic lateral sclerosis	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Myelitis transverse	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Muscle spasticity	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Optic neuritis	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Status epilepticus	0.68% 1/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.00% 0/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Pregnancy, puerperium and perinatal conditions Intra-uterine death	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Psychiatric disorders Disorientation	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Psychiatric disorders Mental status changes	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Throat tightness	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Social circumstances Activities of daily living impaired	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Vascular disorders Aortic aneurysm	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Vascular disorders Hypotension	0.00% 0/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	0.34% 1/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)

Measure	Placebo n=147 participants at risk Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.	Rituximab n=292 participants at risk Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks.
Eye disorders Vision blurred	6.1% 9/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.1% 15/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Nausea	10.9% 16/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	18.8% 55/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Constipation	13.6% 20/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	9.9% 29/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Diarrhoea	8.8% 13/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.9% 23/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Vomiting	6.8% 10/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.8% 17/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Gastrointestinal disorders Dyspepsia	1.4% 2/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.1% 15/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Fatigue	31.3% 46/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	35.6% 104/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Gait disturbance	23.1% 34/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	20.5% 60/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Oedema peripheral	10.2% 15/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	15.4% 45/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Asthenia	11.6% 17/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	12.3% 36/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Pyrexia	6.1% 9/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	13.4% 39/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Chills	4.1% 6/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	12.0% 35/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Pain	5.4% 8/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.2% 21/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Influenza like illness	2.0% 3/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.5% 16/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
General disorders Chest pain	5.4% 8/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	2.7% 8/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Urinary tract infection	24.5% 36/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	23.3% 68/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Nasopharyngitis	25.9% 38/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	21.9% 64/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Upper respiratory tract infection	18.4% 27/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	15.4% 45/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Influenza	6.1% 9/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.5% 22/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Sinusitis	6.1% 9/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	6.5% 19/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Infections and infestations Bronchitis	2.0% 3/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.1% 15/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Fall	27.2% 40/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	32.9% 96/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Contusion	12.9% 19/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	14.0% 41/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Post lumbar puncture syndrome	12.2% 18/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	12.7% 37/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Procedural pain	7.5% 11/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	6.2% 18/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Injury, poisoning and procedural complications Excoriation	4.1% 6/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	6.8% 20/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Muscular weakness	28.6% 42/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	34.6% 101/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Pain in extremity	18.4% 27/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	22.6% 66/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Back pain	19.7% 29/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	20.2% 59/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Arthralgia	15.6% 23/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	19.2% 56/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	11.6% 17/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	15.1% 44/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Muscle spasms	15.0% 22/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	12.7% 37/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.8% 7/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	9.9% 29/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Myalgia	6.8% 10/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.9% 23/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Neck pain	5.4% 8/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.5% 22/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	2.7% 4/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.8% 17/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Headache	18.4% 27/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	26.4% 77/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Hypoaesthesia	21.8% 32/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	19.5% 57/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Muscle spasticity	21.8% 32/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	16.8% 49/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Paraesthesia	12.9% 19/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	14.0% 41/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Dizziness	10.2% 15/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	14.4% 42/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Balance disorder	14.3% 21/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	10.6% 31/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Tremor	8.2% 12/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	6.8% 20/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Burning sensation	4.8% 7/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	6.8% 20/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Nervous system disorders Ataxia	4.1% 6/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	6.2% 18/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Psychiatric disorders Depression	17.0% 25/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	11.6% 34/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Psychiatric disorders Insomnia	8.2% 12/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	13.7% 40/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Psychiatric disorders Anxiety	4.8% 7/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.1% 15/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Renal and urinary disorders Micturition urgency	6.8% 10/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.2% 21/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Renal and urinary disorders Pollakiuria	5.4% 8/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	3.8% 11/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	10.2% 15/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	11.6% 34/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Cough	6.8% 10/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	11.3% 33/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Nasal congestion	3.4% 5/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	8.2% 24/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Throat irritation	1.4% 2/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.5% 22/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.1% 6/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.8% 17/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	5.4% 8/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	3.8% 11/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Skin and subcutaneous tissue disorders Pruritus	4.1% 6/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	21.9% 64/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Skin and subcutaneous tissue disorders Rash	8.8% 13/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	16.8% 49/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Skin and subcutaneous tissue disorders Erythema	2.0% 3/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	7.2% 21/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Skin and subcutaneous tissue disorders Urticaria	1.4% 2/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	5.8% 17/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Vascular disorders Flushing	4.8% 7/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	13.4% 39/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Vascular disorders Hypotension	8.2% 12/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	10.3% 30/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)
Vascular disorders Hypertension	6.8% 10/147 • Up to 122 weeks (from start of first infusion until study completion or early termination)	8.2% 24/292 • Up to 122 weeks (from start of first infusion until study completion or early termination)