Trial Outcomes & Findings for A Study of the Safety and Efficacy of Rituximab in Patients With Moderate to Severe Rheumatoid Arthritis Receiving Methotrexate (NCT NCT00243412)

Last Updated: 2011-10-07

Results Overview

A Grade III Adverse Event (AE) is severe; defined as considerable interference with the subject's daily activities, medical intervention/therapy required and hospitalization possible. A Grade IV AE is life-threatening; defined as extreme limitation in activity, significant medical intervention/therapy required, hospitalization probable. Because of the small sample size and the small number of subjects who completed Week 104, the analysis were limited to descriptive statistics only.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

42 participants

Primary outcome timeframe

24 months

Results posted on

2011-10-07

Participant Flow

Approximately 40 subjects with moderately to severely active rheumatoid arthritis were to be enrolled at six to eight study centers in the United States and were randomly assigned in a 1:1 ratio to Arm A or B. Starting 15 August 2005 to 4 February 2009 (first subject enrolled to database lock).

All subjects were to receive rituximab 1000 mg \* 2 on Days 1 and 15. Subsequently, subjects in Arm A received rituximab 500 mg \* 2 every 6 months (Months 6, 12, and 18) and those in Arm B received rituximab 1000 mg \* 2 at 12 months. To maintain the blind, subjects in Arm B received placebo infusions at Months 6 and 18.

Participant milestones

Participant milestones
Measure	Arm A: 500 mg Rituximab Rituximab: 1000 mg intravenous (IV) on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion, For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Overall Study STARTED	21	21
Overall Study Safety Evaluable	21	20
Overall Study COMPLETED	11	10
Overall Study NOT COMPLETED	10	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: 500 mg Rituximab Rituximab: 1000 mg intravenous (IV) on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion, For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Overall Study Death	0	1
Overall Study Adverse Event	4	2
Overall Study Lost to Follow-up	0	1
Overall Study Physician Decision	1	1
Overall Study Withdrawal by Subject	4	5
Overall Study Other	1	1

Baseline Characteristics

A Study of the Safety and Efficacy of Rituximab in Patients With Moderate to Severe Rheumatoid Arthritis Receiving Methotrexate

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: 500 mg Rituximab n=21 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=21 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Total n=42 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	21 Participants n=5 Participants	20 Participants n=7 Participants	41 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Age Continuous	46.9 years STANDARD_DEVIATION 9.6 • n=5 Participants	47.4 years STANDARD_DEVIATION 11.1 • n=7 Participants	47.2 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	18 Participants n=7 Participants	37 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: 24 months

Population: Safety-Evaluable Population

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=21 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=20 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Number of Participants With Either an Infection or a Grade III or IV Adverse Event (National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE], Version 3.0) Infections	14 Participants	11 Participants
Number of Participants With Either an Infection or a Grade III or IV Adverse Event (National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE], Version 3.0) Adverse Events (Grade 3 or 4)	5 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, 24 months

Population: Participants from the Intent-to-Treat (ITT) population for whom data was available at baseline and month 24.

The DAS28-4(CRP) score is a measure of the subject's disease activity. DAS28-4(CRP) is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and CRP. DAS28 provides a number on a scale (0 to 10) indicating current disease activity. A score above 5.1 means high disease activity and a score below 3.2 indicates low disease activity. Change from baseline at 24 months was analyzed for DAS28-4 (CRP).

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Change From Baseline in Disease Activity Score 28-4 C-reactive Protein (DAS28-4(CRP)) Baseline	6.53 Scores on a scale Standard Deviation 0.70	6.33 Scores on a scale Standard Deviation 0.85
Change From Baseline in Disease Activity Score 28-4 C-reactive Protein (DAS28-4(CRP)) Month 24	4.03 Scores on a scale Standard Deviation 1.75	3.77 Scores on a scale Standard Deviation 1.42
Change From Baseline in Disease Activity Score 28-4 C-reactive Protein (DAS28-4(CRP)) Change from baseline	-2.49 Scores on a scale Standard Deviation 1.85	-2.56 Scores on a scale Standard Deviation 1.23

SECONDARY outcome

Timeframe: Baseline, 24 months

Population: Intent-to-Treat (ITT)

ACR20 response was defined as satisfying the following 3 criteria improvement from baseline: ≥ 20% in tender joint count; ≥ 20% in swollen joint count; ≥ 20% improvement from baseline in 3 of the following 5 criteria: Subject's Global Assessment of Pain Subject's Global Assessment of Disease Activity Physician's Global Assessment Subject's Self-Assessment Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) Note: The definitions of ACR50 and ACR70 are the same as ACR20, except that the 20% value in the above definition is replaced by 50% and 70% values, respectively.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=21 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=21 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Number of Participants With American College of Rheumatology Responses (ACR20, ACR50, and ACR70) ACR20 Responders	7 Participants	6 Participants
Number of Participants With American College of Rheumatology Responses (ACR20, ACR50, and ACR70) ACR50 Responders	4 Participants	5 Participants
Number of Participants With American College of Rheumatology Responses (ACR20, ACR50, and ACR70) ACR70 Responders	4 Participants	3 Participants

SECONDARY outcome

Timeframe: 24 months

Population: Intent-to-Treat (ITT)

Major clinical response is an ACR70 response defined as improvement from baseline: ≥70% in tender joint count; ≥70% in swollen joint count; ≥70% in 3 of the following: Patient Pain Assessment, Patient Global Assessment, Physician Global Assessment, Patient Self-Assessed Disability, ESR or CRP for ≥169 consecutive days. Remission: ≥5 requirements fulfilled for ≥2 consecutive months: Duration of morning stiffness \<15 minutes, No fatigue, No joint pain, No joint tenderness or pain on motion, No soft tissue swelling in joints or tendon sheaths, ESR \<30 mm/hour for women and \<20 mm/hour for men.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=21 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=20 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Number of Participants With American College of Rheumatology (ACR) Major Clinical Response and/or Remission	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, 24 months

Population: Participants from the Intent-to-Treat (ITT) population for whom data was available at baseline and month 24.

EULAR remission = DAS28-4(CRP) \< 2.6 (Fransen et al. 2004. EULAR response categories (van Gestel et al. 1999): Good response = final DAS28-4(CRP) \< 3.2 and decreased \> 1.2 points from baseline Moderate response = final DAS28-4(CRP) ≥ 3.2 but ≤ 5.1 and decreased \> 0.6 points from baseline or final DAS28-4(CRP) \> 5.1 and decreased \> 1.2 from baseline.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Number of Participants With European League Against Rheumatism (EULAR) Response and Remission Using Disease Activity Score 28-4 (DAS28-4)C-reactive Protein (CRP) No Response	0 Participants	0 Participants
Number of Participants With European League Against Rheumatism (EULAR) Response and Remission Using Disease Activity Score 28-4 (DAS28-4)C-reactive Protein (CRP) Moderate Response	2 Participants	6 Participants
Number of Participants With European League Against Rheumatism (EULAR) Response and Remission Using Disease Activity Score 28-4 (DAS28-4)C-reactive Protein (CRP) Good Response	5 Participants	4 Participants
Number of Participants With European League Against Rheumatism (EULAR) Response and Remission Using Disease Activity Score 28-4 (DAS28-4)C-reactive Protein (CRP) Eular Remission	3 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline, 24 Months

Population: Participants from the Intent-to-Treat (ITT) for whom data was available at baseline and month 24.

The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning (PF), Role Physical (RP), Bodily Pain(BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE),Mental Health (MH). Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Summary Score: Mental Component Score	7.69 Units on a Scale Standard Deviation 16.10	2.28 Units on a Scale Standard Deviation 10.42
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Summary Score: Physical Component Score	9.88 Units on a Scale Standard Deviation 12.31	4.93 Units on a Scale Standard Deviation 9.83
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Bodily Pain	26.64 Units on a Scale Standard Deviation 26.64	8.00 Units on a Scale Standard Deviation 22.55
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: General Health	13.86 Units on a Scale Standard Deviation 18.78	18.40 Units on a Scale Standard Deviation 23.55
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Mental Health	20.00 Units on a Scale Standard Deviation 18.17	2.50 Units on a Scale Standard Deviation 26.48
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Physical Function	21.62 Units on a Scale Standard Deviation 35.45	15.72 Units on a Scale Standard Deviation 17.54
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Role Emotional	16.67 Units on a Scale Standard Deviation 45.95	8.33 Units on a Scale Standard Deviation 24.85
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Role Physical	34.09 Units on a Scale Standard Deviation 31.17	-1.25 Units on a Scale Standard Deviation 23.90
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Social Functioning	21.59 Units on a Scale Standard Deviation 35.83	7.50 Units on a Scale Standard Deviation 25.14
Change From Baseline in Short Form 36 (SF 36) Summary and Subscale Scores Subscale: Vitality	10.61 Units on a Scale Standard Deviation 26.03	8.13 Units on a Scale Standard Deviation 12.86

SECONDARY outcome

Timeframe: Baseline, 24 Months

Population: Participants from the Intent-to-Treat (ITT) population for whom data was available at baseline and month 24.

The Stanford HAQ-DI is a patient-reported questionnaire specific for RA. It consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The questionnaire was provided in a certified translation of the local languages at the participating sites and was scored based on the instructions from the Stanford University Medical Center.The questions are evaluated on a 4-point scale: 0=without any difficulty, 1= with some difficulty, 2= with much difficulty, and 3= unable to do. Higher scores= greater dysfunction.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI)	-0.60 Scores on a scale Standard Deviation 0.87	-0.45 Scores on a scale Standard Deviation 0.72

SECONDARY outcome

Timeframe: Baseline, 24 Months

Population: Participants from the Intent-to-Treat (ITT) population for whom data was available at baseline and month 24.

FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Change From Baseline in Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F)	9.64 Scores on a scale Standard Deviation 15.54	8.80 Scores on a scale Standard Deviation 12.15

SECONDARY outcome

Timeframe: 24 Months

Population: Participants from the Intent-to-Treat (ITT) for whom data was available at baseline and month 24.

The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10, where a score of less than or equal to 3.2 implies well controlled disease and greater than or equal to 5.1 implies active disease In this trial, CRP rather than ESR was used, unless the CRP value was missing at both Day 1 and screening, in which case ESR value was used.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
DAS28-4 Erythrocyte Sedimentation Rate(ESR)	4.25 Scores on a scale Standard Deviation 1.98	4.32 Scores on a scale Standard Deviation 1.39

SECONDARY outcome

Timeframe: Baseline, 24 Months

Population: Participants from the Safety-Evaluable population for whom data was available at baseline and month 24.

Serum levels of rheumatoid factor at baseline, month 24 and change from baseline to month 24.

Outcome measures

Outcome measures
Measure	Arm A: 500 mg Rituximab n=11 Participants Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=10 Participants Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Change From Baseline in Rheumatoid Factor (RF) Month 24	43.0 IU/mL Standard Deviation 70.8	41.4 IU/mL Standard Deviation 34.3
Change From Baseline in Rheumatoid Factor (RF) Baseline	542.8 IU/mL Standard Deviation 1011.6	243.7 IU/mL Standard Deviation 280.2
Change From Baseline in Rheumatoid Factor (RF) Change from Baseline to Month 24	-499.8 IU/mL Standard Deviation 946.9	-202.3 IU/mL Standard Deviation 279.1

SECONDARY outcome

Timeframe: Baseline, 24 Months

Because of the different laboratory methods that were used to measure anti-CCP antibody levels, no summary statistics were calculated.

Outcome measures

Outcome data not reported

Adverse Events

Arm A: 500 mg Rituximab

Serious events: 3 serious events

Other events: 21 other events

Deaths: 0 deaths

Arm B: 1000 mg Rituximab

Serious events: 2 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm A: 500 mg Rituximab n=21 participants at risk Rituximab: 1000 mg IV on Days 1 and 15 of the first cycle; 500 mg IV on Days 1 and 15 of each subsequent 6-month cycle (Months 6, 12, and 18). Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).	Arm B: 1000 mg Rituximab n=20 participants at risk Rituximab: 1000 mg IV on Days 1 and 15 of each 12-month cycle (Rituximab cycles were administered at baseline and Month 12). For the Month 6 and 18 cycles, rituximab or placebo was administered. Corticosteroids: 100 mg IV methylprednisolone prior to each rituximab infusion. For the Months 6 and 18 cycles, IV saline was administered prior to each rituximab or placebo infusion. Methotrexate: 15-25 mg/wk oral or parenteral (10-14 mg/wk if intolerant). Folate: Minimum of 1 mg/day (or folinic acid 5 mg/wk).
Cardiac disorders DEATH	0.00% 0/21 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.	5.0% 1/20 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.
General disorders NON-CARDIAC CHEST PAIN	4.8% 1/21 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.	0.00% 0/20 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) MALIGNANT MELANOMA	0.00% 0/21 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.	5.0% 1/20 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) UTERINE LEIOMYOMA	4.8% 1/21 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.	0.00% 0/20 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.
Nervous system disorders INTRACRANIAL ANEURYSM	4.8% 1/21 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.	0.00% 0/20 • Duration includes safety-evaluable subjects during the 2-year treatment period; in addition Serious adverse events that occurred during safety follow-up. A total of 42 subjects were randomized into the trial, 21 in Group A (500 mg rituximab retreatment regimen) and 21 in Group B (1000 mg rituximab retreatment regimen). Twenty subjects in Group B were treated with study drug and included in the safety-evaluable population.

Other adverse events

Additional Information

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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