SMART Study: A Study of Re-treatment With MabThera (Rituximab) in Patients With Rheumatoid Arthritis Who Have Failed on Anti-TNF Alfa Therapy

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01126541
• Collaborator: (none)
• Enrollment: 224
• Locations: 53
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will compare the efficacy and safety of re-treatment with 2 doses of MabThera (rituximab) in patients with active rheumatoid arthritis (RA) who have previously experienced an inadequate response or intolerance to anti-tumor necrosis factor (anti-TNF) therapies etanercept, infliximab or adalimumab therapy. All patients will receive infusions of 1000 mg intravenous (IV) MabThera on Days 1 and 15; at Week 24 patients who have demonstrated a moderate or good response will be randomized to receive re-treatment with either 1 or 2 additional infusions of 1000 mg IV MabThera. The anticipated time on study treatment is 2+ years, and the target sample size is 100-500 individuals.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: rituximab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Comparative Study to Assess the Effect of Retreatment With 2 Doses of MabThera on Disease Activity Score in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response or Intolerance to antiTNF-alfa Therapy.(SMART)
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A 1000 mg IV rituximab	Drug: rituximab; Arm A: 1000 mg IV (one infusion) every 2 months \nArm B: 2 x 1000 mg IV (2 infusions) every 2 months; Other Names: MabThera/Rituxan
Experimental: B 2 x 1000 mg IV rituximab	Drug: rituximab; Arm A: 1000 mg IV (one infusion) every 2 months \nArm B: 2 x 1000 mg IV (2 infusions) every 2 months; Other Names: MabThera/Rituxan

Outcome Measures

Primary Outcome Measures

1. Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (DAS28-CRP) Area Under the Curve (AUC) at Week 104 [Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and serum CRP levels (measured in milligrams per liter [mg/L]) at each visit. Joint counts included swollen joint count (SJC) and tender joint count (TJC). Total score range was 0 to 9.4; a higher score indicated more disease activity. DAS28-CRP less than or equal to (≤)3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and less than (<)2.6 equals (=) remission. The AUC of all DAS28-CRP values between Day 1 and Week 104 (15 values of protocol visits) was calculated using the trapeze method (AUC between t1 and t2=(t2-t1)*((DAS28-CRP at t1 + DAS28-CRP at t2)/2). The true visit dates were used to calculate the time between 2 DAS28-CRP evaluations. All the AUC were censored at Week 104 (linear extrapolation using the 2 last DAS28-CRP values (Weeks 96 and 104) to obtain the "true" DAS28-CRP value at the "true" Week 104).

Secondary Outcome Measures

1. DAS28-CRP During the Initial Treatment [Days 1 and 15, and Weeks 6, 12, and 24]

   Mean DAS28-CRP at Week 24 of the Initial Treatment study. DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP ≤3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and <2.6=remission.

2. DAS28-CRP and Changes From Baseline to Week 24 in DAS28-CRP by Retreatment Course [Day 1, 24 weeks following each infusion up to 72 Weeks]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and <2.6=remission.

3. Percentage of Participants Achieving Clinical Remission (DAS28-CRP <2.6) or Low Disease Activity (DAS28-CRP ≤3.2) [Week 24 of the Initial Treatment, 24 weeks after first retreatment, and 24 weeks after second retreatment]

   Percentage of participants with clinical remission and low disease activity as measured by DAS28-CRP for Arm A and Arm B at Week 24 of the Initial Treatment, at 24 weeks after first re-treatment, and at 24 weeks after second retreatment. DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity and <2.6 = remission.

4. DAS28-CRP AUC Weighted Time [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and <2.6=remission.

5. Time to Achieve DAS28-CRP Remission After the First Course [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.

6. Time to Achieve DAS28-CRP Remission After Retreatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.

7. Time to Achieve DAS28-CRP ≤3.2 After the First Course of Treatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

8. Time to Achieve DAS28-CRP ≤3.2 After Retreatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

9. Duration of DAS28-CRP Remission After the First Course of Treatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

   DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.

10. Duration of DAS28-CRP Remission After Retreatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

    DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.

11. Duration of DAS28-CRP ≤3.2 After the First Course of Treatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

    DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

12. Duration of DAS28-CRP ≤3.2 After Retreatment [Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104]

    DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

13. Percentage of Participants Achieving American College of Rheumatology 20%, 50%, and 70% Improvement (ACR20/ACR50/ACR70) [Week 24 of the initial treatment, 24 weeks after first retreatment, and 24 weeks after second retreatment]

    ACR20/50/70 response defined as ≥20%, 50%, or 70% improvement, respectively, in TJC and SJC, and ≥20%, 50%, or 70% improvement, respectively, in at least 3 of 5 remaining ACR core measures: Patient Global Assessment of Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity (on a visual analog scale [VAS]); Health Assessment Questionnaire-Disability Index (HAQ-DI); and CRP.

14. Percentage of Participants Achieving a Response During Initial Treatment by European League Against Rheumatism (EULAR) Category [Day 15, Weeks 6, 12, and 24]

    DAS28-based EULAR response criteria were used to measure individual response as no response, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders = change from baseline >1.2 with a DAS28 score of ≤3.2; moderate responders = change from baseline >1.2 with a DAS28 score of >3.2 to ≤ 5.1 or change from baseline >0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders = change from baseline ≤0.6 or change from baseline >0.6 and ≤ 1.2 with a DAS28 score of >5.1.

15. Percentage of Participants Achieving a Response During Retreatment by EULAR Category [Week 24, 24 weeks after 1st retreatment, 24 weeks after 2nd retreatment]

    DAS28-based EULAR response criteria were used to measure individual response as no response, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders = change from baseline >1.2 with a DAS28 score of ≤3.2; moderate responders = change from baseline >1.2 with a DAS28 score of >3.2 to ≤ 5.1 or change from baseline >0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders = change from baseline ≤0.6 or change from baseline >0.6 and ≤ 1.2 with a DAS28 score of >5.1.

16. Percentage of Participants With Rheumatoid Factor (RF) at 24 Weeks After Treatment [Week 24 of the initial treatment, 24 weeks after first re-treatment, and 24 weeks after second retreatment]

    RF is the auto antibody directed against immunoglobulin G (IgG) and its concentration is observed in human serum or plasma. RF value higher than 20 international units per milliliter (IU/mL) is considered positive.

17. Percentage of Participants With Anti-cyclic Citrullinated Protein (Anti-CCP) Antibodies at 24 Weeks After Treatment [Week 24 of the initial treatment, 24 weeks after first re-treatment, and 24 weeks after second retreatment]

    Anti-CCP antibodies are auto antibodies (antibodies directed against 1 or more of an individual's own proteins) that are frequently detected in the blood of rheumatoid arthritis participants. Anti-CCP antibodies value higher than 10 U/mL is considered positive.

18. Physician's Global Assessment of Disease Activity [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    The Physician's Global Assessment of disease activity is assessed on a 0 to 100 millimeter (mm) horizontal VAS by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Physicians were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high disease activity).

19. Patient Global Assessment of Disease Activity [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    The Patient's Global Assessment of Disease Activity is assessed on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).

20. Patient's Global Assessment of Pain [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    The participants assessed their pain over the past 24 hours on a 0 to 100 mm horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high pain levels).

21. Participant Assessment of Fatigue [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    Participants were asked to rate their level of fatigue over the last 7 days on a 100-mm VAS. The left-hand extreme of the line equals 0 mm, and is described as "no fatigue" and the right-hand extreme equals 100 mm as "extreme fatigue". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high levels of fatigue).

22. Cortisone Intake AUC (Time- and Weight-Weighted) [Day 1 (each infusion), Week 24, Week 104]

    All cortisone intakes (in mg) were taken into account (oral, IV [including the cortisone administration before the rituximab infusion], intramuscular, and intra-articular).

23. Total Mean Dose of Cortisone Between Week 24 and Week 104 [Week 24 to Week 104]

    All cortisone intakes were taken into account, including oral, IV (including the cortisone administration before the rituximab infusion), intramuscular and intra-articular.

24. HAQ-DI Scores [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0=least difficulty and 3 extreme difficulty.

25. Short Form 12 (SF-12) Physical Health Composite Score [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    Physical and Mental Health Composite Scores of SF-12 were computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.

26. SF-12 Mental Health Composite Score [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    Mental Health Composite Scores of SF-12 were computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.

27. Medical Outcomes Study Sleep Scale (MOS-Sleep) Composite Sleep Problems 6 (SLP6) Index [Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment]

    The MOS Sleep Scale measures most constructs of sleep. The scale has a battery of questions to measure specific aspects of sleep in participants with co-morbidities. The SLP6 index is comprised of 6 items: provides a summary of sleep problems and contains questions from the sleep disturbance, sleep adequacy, respiratory impairment, and somnolence domains. The SLP6 index score ranges between 0 and 100, with higher values corresponding to more sleep problems.

28. Percentage of Participants Reporting Acceptable Disease Activity Symptom State Assessed Using Patient Acceptable and Unacceptable Symptom State (PASS) [Week 24, 12 and 24 weeks after 1st retreatment]

    Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of disease activity they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".

29. Patient Global Assessment of Disease Activity in Participants Reporting Acceptable Symptoms Using PASS [Week 24, 12 and 24 weeks after 1st retreatment]

    The Patient's Global Assessment of Disease Activity assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours) on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).

30. Percentage of Participants With Minimum Clinically Important Improvement (MCII) in Disease Activity [Week 24, 12 and 24 weeks after 1st retreatment]

    Participants were asked how their disease activity had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse-more disease activity.

31. Change From Baseline in Patient Global Assessment of Disease Activity in Participants With MCII [Baseline, Week 24, 12 and 24 weeks after 1st retreatment]

    The Patient's Global Assessment of Disease Activity was assessed in participants reporting MCII on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).

32. Percentage of Participants Reporting Acceptable Symptom State in Functioning Assessed Using PASS [Week 24, 12 and 24 weeks after 1st retreatment]

    Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of function they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of function they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".

33. HAQ-DI Scores in Participants Reporting Acceptable Function Using PASS [Week 24, 12 and 24 weeks after 1st retreatment]

    HAQ-DI was assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours). HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0=least difficulty and 3 extreme difficulty.

34. Percentage of Participants With MCII in Functioning [Week 24, 12 and 24 weeks after 1st retreatment]

    Participants were asked how their functioning had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse.

35. Change From Baseline in HAQ-DI in Participants With MCII [Baseline, Week 24, 12 and 24 weeks after 1st retreatment]

    HAQ-DI was assessed in participants with MCII. HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0=least difficulty and 3 extreme difficulty.

36. Percentage of Participants With Acceptable Symptom State in Pain Assessed Using PASS [Week 24, 12 and 24 weeks after 1st retreatment]

    Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of pain they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".

37. Patient Global Assessment of Pain in Participants Reporting Acceptable Symptoms Using PASS [Week 24, 12 and 24 weeks after 1st retreatment]

    Patient Global Assessment of Pain assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours) on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Higher values correspond to worst state of participant (high pain levels).

38. Percentage of Participants With MCII in Pain [Week 24, 12 and 24 weeks after 1st retreatment]

    Participants were asked how their pain had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse pain.

39. Change From Baseline in Patient Global Assessment of Pain in Participants With MCII [Baseline, Week 24, 12 and 24 weeks after 1st retreatment]

    The participants assessed their pain over the past 24 hours on a 0 to 100 mm horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high pain levels).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients >18 years of age

• RA for >=6 months

• Receiving outpatient treatment

• Ongoing treatment with methotrexate for >=3 months, stable for >=1 month

• Inadequate response or intolerance to etanercept, infliximab or adalimumab

Exclusion Criteria:

• Previous treatment with MabThera

• Concurrent treatment with any anti TNF-alfa therapy or biologic therapy

• Previous treatment with any investigational cell-depleting therapies

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Abbeville		France	80142
2		Agen		France	47923
3		Aix En Provence		France	13616
4		Aix Les Bains		France	73106
5		Amiens		France	80054
6		Belfort		France	90016
7		Berck		France	62600
8		Bobigny		France	93009
9		Bois-guillaume		France	76233
10		Boulogne-billancourt		France	92104
11		Brest		France	29609
12		Caen		France	14033
13		Cahors		France	46005
14		Clermont-ferrand		France	63003
15		Corbeil-essonnes		France	91106
16		Echirolles		France	38434
17		La Roche Sur Yon		France	85925
18		Le Kremlin Bicetre		France	94275
19		Libourne		France	33505
20		Lievin		France	62800
21		Lille		France	59037
22		Limoges		France	87042
23		Lomme		France	59462
24		Lyon		France	69365
25		Marseille		France	13013
26		Montivilliers		France	76290
27		Montpellier		France	34295
28		Nantes		France	44035
29		Narbonne		France	11108
30		Nice		France	06202
31		Paris		France	75019
32		Paris		France	75475
33		Paris		France	75571
34		Paris		France	75651
35		Paris		France	75674
36		Paris		France	75679
37		Paris		France	75877
38		PAU		France	64046
39		Perpignan		France	66046
40		Pessac		France	33600
41		Pierre Benite		France	69495
42		Poitiers		France	86021
43		Reims		France	51100
44		Rennes		France	35203
45		Saint-etienne		France	4200
46		Strasbourg		France	67098
47		Toulon		France	83100
48		Toulouse		France	31054
49		Toulouse		France	31059
50		Valence		France	26000
51		Valenciennes		France	59322
52		Vandoeuvre-les-nancy		France	54511
53		Vannes		France	56017

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01126541
• Other Study ID Numbers: ML19895
• First Posted: May 19, 2010
• Last Update Posted: Sep 15, 2014
• Last Verified: Sep 1, 2014

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Rituximab

Study Results

Participant Flow

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 Milligrams (mg)	Randomized Retreatment Arm B: Rituximab 1000 mg x 2	Nonrandomized: Rituximab 1000 mg
Arm/Group Description	Participants received rituximab 1000 mg intravenously (IV) on Days 1 and 15. After Week 24, if Disease Activity Score based on 28-Joint Count (DAS28) was greater than (>)3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and methotrexate (MTX) ≥10 milligrams per week (mg/week) by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15, methylprednisolone 100 mg IV at 30 minutes before each rituximab infusion, and MTX ≥10 mg/week by mouth or parenterally throughout treatment course.
Period Title: Overall Study
STARTED	70	73	81
COMPLETED	60	61	55
NOT COMPLETED	10	12	26

Baseline Characteristics

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2	Nonrandomized: Rituximab 1000 mg	Total
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15, methylprednisolone 100 mg IV at 30 minutes before each rituximab infusion, and MTX ≥10 mg/week by mouth or parenterally throughout treatment course.	Total of all reporting groups
Overall Participants	70	73	81	224
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.5 (11.5)	57.2 (10.4)	56.1 (11.2)	56.0 (11.0)
Sex: Female, Male (Count of Participants)
Female	55 78.6%	62 84.9%	70 86.4%	187 83.5%
Male	15 21.4%	11 15.1%	11 13.6%	37 16.5%

Outcome Measures

1. Secondary Outcome

Title	DAS28-CRP During the Initial Treatment
Description	Mean DAS28-CRP at Week 24 of the Initial Treatment study. DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP ≤3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and <2.6=remission.
Time Frame	Days 1 and 15, and Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

Overall population: all participants with at least one treatment intake.

Arm/Group Title	Randomized Group	Nonrandomized Group
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants were randomized to receive a single rituximab 1000 mg IV infusion (Retreatment Arm A) or 2 x rituximab 1000 mg IV infusions 15 days apart (Retreatment Arm B). All participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15, methylprednisolone 100 mg IV at 30 minutes before each rituximab infusion, and MTX ≥10 mg/week by mouth or parenterally throughout treatment course.
Measure Participants	143	81
First Course, Day 1	5.82 (0.85)	5.77 (0.90)
First Course, Day 15	5.33 (1.09)	5.42 (1.07)
Follow-up, Week 6	4.69 (0.95)	5.12 (1.05)
Follow-up, Week 12	4.13 (0.91)	5.00 (1.19)
Follow-up, Week 24	3.65 (0.85)	5.24 (1.08)

2. Secondary Outcome

Title	DAS28-CRP and Changes From Baseline to Week 24 in DAS28-CRP by Retreatment Course
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and <2.6=remission.
Time Frame	Day 1, 24 weeks following each infusion up to 72 Weeks

Outcome Measure Data

Analysis Population Description

ITT Population; number (n)=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Initial treatment, Day 1 (n=70,73)	5.79 (0.85)	5.84 (0.86)
Initial treatment, Week 24 (n=70,73)	3.57 (0.89)	3.73 (0.80)
Change at Week 24 (n=70,73)	-2.22 (0.96)	-2.11 (0.93)
1st retreatment, Day 1 (n=66,68)	4.33 (0.91)	4.45 (0.80)
1st retreatment, Week 24 (n=66,68)	3.67 (1.15)	3.69 (1.05)
1st retreatment, Change at Week 24 (n=66,68)	-0.67 (1.15)	-0.79 (1.13)
2nd retreatment, Day 1 (n=49,48)	4.60 (0.87)	4.55 (0.96)
2nd retreatment, Week 24 (n=41,39)	3.72 (1.10)	3.76 (1.12)
2nd retreatment, Change at Week 24 (n=41,39)	-0.94 (1.17)	-0.78 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Change from Day 1 to Week 24 (initial treatment)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Primary objective to demonstrate noninferiority of retreatment with one 1000 mg rituximab infusion. Mean ±SD of the DAS28-CRP AUC at 24 months = 2218 ±967 (based on EDWARDS, REFLEX and DANCER study data). H0 (null hypothesis): Arm B - Arm A >20%. H1: Arm B - Arm A ≤ 20%. Power = 80%; Larger difference clinically acceptable = 20% = 444; Significance level of 2.5% (one-sided).
Statistical Test of Hypothesis	p-Value	0.465
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Arm A vs. Arm B: Change from 1st retreatment to 24 weeks after
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Primary objective to demonstrate noninferiority of retreatment with one 1000 mg rituximab infusion. Mean ±SD of the DAS28-CRP AUC at 24 months = 2218 ±967 (based on EDWARDS, REFLEX and DANCER study data). H0 (null hypothesis): Arm B - Arm A >20%. H1: Arm B - Arm A ≤ 20%. Power = 80%; Larger difference clinically acceptable = 20% = 444; Significance level of 2.5% (one-sided)
Statistical Test of Hypothesis	p-Value	0.161
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Arm A vs. Arm B: Change from 2nd retreatment to 24 weeks after
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Primary objective to demonstrate noninferiority of retreatment with one 1000 mg rituximab infusion. Mean ±SD of the DAS28-CRP AUC at 24 months = 2218 ±967 (based on EDWARDS, REFLEX and DANCER study data). H0 (null hypothesis): Arm B - Arm A >20%. H1: Arm B - Arm A ≤ 20%. Power = 80%; Larger difference clinically acceptable = 20% = 444; Significance level of 2.5% (one-sided)
Statistical Test of Hypothesis	p-Value	0.524
	Comments
	Method	Student t-test
	Comments

3. Primary Outcome

Title	Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (DAS28-CRP) Area Under the Curve (AUC) at Week 104
Description	DAS28-CRP was based on joint counts, overall participant assessment, and serum CRP levels (measured in milligrams per liter [mg/L]) at each visit. Joint counts included swollen joint count (SJC) and tender joint count (TJC). Total score range was 0 to 9.4; a higher score indicated more disease activity. DAS28-CRP less than or equal to (≤)3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and less than (<)2.6 equals (=) remission. The AUC of all DAS28-CRP values between Day 1 and Week 104 (15 values of protocol visits) was calculated using the trapeze method (AUC between t1 and t2=(t2-t1)*((DAS28-CRP at t1 + DAS28-CRP at t2)/2). The true visit dates were used to calculate the time between 2 DAS28-CRP evaluations. All the AUC were censored at Week 104 (linear extrapolation using the 2 last DAS28-CRP values (Weeks 96 and 104) to obtain the "true" DAS28-CRP value at the "true" Week 104).
Time Frame	Week 104

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) population: all randomized participants in the Intent-to-Treat (ITT) population (defined as all randomized participants) without major protocol violations. Participants were grouped according to their initially assigned treatment arm irrespective of the treatment actually received.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	51	49
Mean (Standard Error) [score on a scale*week]	2761.4 (507.8)	2666.0 (490.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Primary objective to demonstrate noninferiority of retreatment with one 1000 mg rituximab infusion. Mean plus or minus (±)SD of the DAS28-CRP AUC at 24 months = 2218 ±967 (based on EDWARDS, REFLEX and DANCER study data). H0 (null hypothesis): Arm B - Arm A >20%. H1: Arm B - Arm A ≤ 20%. Power = 80%; Larger difference clinically acceptable = 20% = 444; Significance level of 2.5% (one-sided)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference
	Estimated Value	51.38
	Confidence Interval	(2-Sided) 95%; -131.22 to 233.98
	Parameter Dispersion	Type: Standard Deviation; Value: 92.00
	Estimation Comments	Covariate analysis with baseline DAS28-CRP value as covariate

4. Secondary Outcome

Title	Percentage of Participants Achieving Clinical Remission (DAS28-CRP <2.6) or Low Disease Activity (DAS28-CRP ≤3.2)
Description	Percentage of participants with clinical remission and low disease activity as measured by DAS28-CRP for Arm A and Arm B at Week 24 of the Initial Treatment, at 24 weeks after first re-treatment, and at 24 weeks after second retreatment. DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity and <2.6 = remission.
Time Frame	Week 24 of the Initial Treatment, 24 weeks after first retreatment, and 24 weeks after second retreatment

Outcome Measure Data

Analysis Population Description

ITT Population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Remission: Initial Treatment, Week 24 (n=70,73)	14.3 20.4%	8.2 11.2%
Remission: 1st Re-treatment, Week 24 (n=66,67)	18.2 26%	9.0 12.3%
Remission: 2nd Retreatment, Week 24 (n=43,40)	16.3 23.3%	7.5 10.3%
Low activity: Initial Treatment, Week 24 (n=70,73)	37.1 53%	27.4 37.5%
Low activity: 1st Retreatment, Week 24 (n=66,67)	34.8 49.7%	35.8 49%
Low activity: 2nd Retreatment, Week 24 (n=43,40)	27.9 39.9%	30.0 41.1%

5. Secondary Outcome

Title	DAS28-CRP AUC Weighted Time
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and <2.6=remission.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Mean (Standard Deviation) [units on a scale*week]	3.82 (0.71)	3.88 (0.71)

6. Secondary Outcome

Title	Time to Achieve DAS28-CRP Remission After the First Course
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Group
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants were randomized to receive a single rituximab 1000 mg IV infusion (Retreatment Arm A) or 2 x rituximab 1000 mg IV infusions 15 days apart (Retreatment Arm B). All participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.
Measure Participants	143
Median (95% Confidence Interval) [weeks]	56.0

7. Secondary Outcome

Title	Time to Achieve DAS28-CRP Remission After Retreatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	66	68
1st retreatment (n=66,68)	NA	78.1
2nd retreatment (n=49,48)	NA	NA

8. Secondary Outcome

Title	Time to Achieve DAS28-CRP ≤3.2 After the First Course of Treatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Group
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants were randomized to receive a single rituximab 1000 mg IV infusion (Retreatment Arm A) or 2 x rituximab 1000 mg IV infusions 15 days apart (Retreatment Arm B). All participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.
Measure Participants	143
Median (95% Confidence Interval) [weeks]	28.0

9. Secondary Outcome

Title	Time to Achieve DAS28-CRP ≤3.2 After Retreatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	66	68
1st retreatment (n=66,68)	31.0	22.1
2nd retreatment (n=49,48)	16.9	29.0

10. Secondary Outcome

Title	Duration of DAS28-CRP Remission After the First Course of Treatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population; only participants with a response (DAS28-CRP <2.6) during initial treatment (at any point) were included in the analysis.

Arm/Group Title	Randomized Group
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants were randomized to receive a single rituximab 1000 mg IV infusion (Retreatment Arm A) or 2 x rituximab 1000 mg IV infusions 15 days apart (Retreatment Arm B). All participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.
Measure Participants	34
Median (95% Confidence Interval) [weeks]	11.7

11. Secondary Outcome

Title	Duration of DAS28-CRP Remission After Retreatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP <2.6=remission.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population; only participants with a response (DAS28-CRP <2.6) during retreatment (at any point) were included in the analysis. n=number of participants assessed at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	21	22
1st retreatment (n=21,22)	16.0	8.0
2nd retreatment (n=17,11)	9.0	8.0

12. Secondary Outcome

Title	Duration of DAS28-CRP ≤3.2 After the First Course of Treatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population; only participants with a response (DAS28-CRP ≤3.2) during first course of treatment (at any point) were included in the analysis.

Arm/Group Title	Randomized Group
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants were randomized to receive a single rituximab 1000 mg IV infusion (Retreatment Arm A) or 2 x rituximab 1000 mg IV infusions 15 days apart (Retreatment Arm B). All participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.
Measure Participants	65
Median (95% Confidence Interval) [weeks]	14.3

13. Secondary Outcome

Title	Duration of DAS28-CRP ≤3.2 After Retreatment
Description	DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.
Time Frame	Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Outcome Measure Data

Analysis Population Description

ITT population; only participants with a response (DAS28-CRP ≤3.2) during retreatment (at any point) were included in the analysis. n=number of participants assessed at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	35	40
1st retreatment (n=35,40)	27.0	17.0
2nd retreatment (n=29,23)	10.1	16.0

14. Secondary Outcome

Title	Percentage of Participants Achieving American College of Rheumatology 20%, 50%, and 70% Improvement (ACR20/ACR50/ACR70)
Description	ACR20/50/70 response defined as ≥20%, 50%, or 70% improvement, respectively, in TJC and SJC, and ≥20%, 50%, or 70% improvement, respectively, in at least 3 of 5 remaining ACR core measures: Patient Global Assessment of Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity (on a visual analog scale [VAS]); Health Assessment Questionnaire-Disability Index (HAQ-DI); and CRP.
Time Frame	Week 24 of the initial treatment, 24 weeks after first retreatment, and 24 weeks after second retreatment

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
ACR20: Initial Treatment, Week 24	78.6 112.3%	75.3 103.2%
ACR20: 1st Retreatment, Week 24	63.6 90.9%	61.2 83.8%
ACR20: 2nd Retreatment, Week 24	65.1 93%	60.0 82.2%
ACR50: Initial Treatment, Week 24	35.7 51%	32.9 45.1%
ACR50: 1st Retreatment, Week 24	33.3 47.6%	32.8 44.9%
ACR50: 2nd Retreatment, Week 24	32.6 46.6%	42.5 58.2%
ACR70: Initial Treatment, Week 24	12.9 18.4%	11.0 15.1%
ACR70: 1st Retreatment, Week 24	16.7 23.9%	19.4 26.6%
ACR70: 2nd Retreatment, Week 24	18.6 26.6%	20.0 27.4%

15. Secondary Outcome

Title	Percentage of Participants Achieving a Response During Initial Treatment by European League Against Rheumatism (EULAR) Category
Description	DAS28-based EULAR response criteria were used to measure individual response as no response, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders = change from baseline >1.2 with a DAS28 score of ≤3.2; moderate responders = change from baseline >1.2 with a DAS28 score of >3.2 to ≤ 5.1 or change from baseline >0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders = change from baseline ≤0.6 or change from baseline >0.6 and ≤ 1.2 with a DAS28 score of >5.1.
Time Frame	Day 15, Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

Overall population

Arm/Group Title	Randomized Group	Nonrandomized Group
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants were randomized to receive a single rituximab 1000 mg IV infusion (Retreatment Arm A) or 2 x rituximab 1000 mg IV infusions 15 days apart (Retreatment Arm B). All participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15, methylprednisolone 100 mg IV at 30 minutes before each rituximab infusion, and MTX ≥10 mg/week by mouth or parenterally throughout treatment course.
Measure Participants	143	81
Good response: Day 15	4 5.7%	3 4.1%
Good response: Week 6	5 7.1%	4 5.5%
Good response: Week 12	15 21.4%	4 5.5%
Good response: Week 24	32 45.7%	3 4.1%
Moderate response: Day 15	22 31.4%	20 27.4%
Moderate response: Week 6	59 84.3%	29 39.7%
Moderate response: Week 12	73 104.3%	35 47.9%
Moderate response: Week 24	66 94.3%	15 20.5%
No response: Day 15	74 105.7%	78 106.8%
No response: Week 6	36 51.4%	67 91.8%
No response: Week 12	11 15.7%	61 83.6%
No response: Week 24	3 4.3%	82 112.3%

16. Secondary Outcome

Title	Percentage of Participants Achieving a Response During Retreatment by EULAR Category
Description	DAS28-based EULAR response criteria were used to measure individual response as no response, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders = change from baseline >1.2 with a DAS28 score of ≤3.2; moderate responders = change from baseline >1.2 with a DAS28 score of >3.2 to ≤ 5.1 or change from baseline >0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders = change from baseline ≤0.6 or change from baseline >0.6 and ≤ 1.2 with a DAS28 score of >5.1.
Time Frame	Week 24, 24 weeks after 1st retreatment, 24 weeks after 2nd retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Good response: Week 24 (n=70,73)	37 52.9%	26 35.6%
Good response: 1st retreatment (n=66,67)	35 50%	36 49.3%
Good response: 2nd retreatment (n=43,40)	28 40%	30 41.1%
Moderate response: Week 24 (n=70,73)	60 85.7%	71 97.3%
Moderate response: 1st retreatment (n=66,67)	53 75.7%	52 71.2%
Moderate response: 2nd retreatment (n=43,40)	54 77.1%	50 68.5%
No response: Week 24 (n=70,73)	3 4.3%	3 4.1%
No response: 1st retreatment (n=66,67)	12 17.1%	12 16.4%
No response: 2nd retreatment (n=43,40)	19 27.1%	20 27.4%

17. Secondary Outcome

Title	Percentage of Participants With Rheumatoid Factor (RF) at 24 Weeks After Treatment
Description	RF is the auto antibody directed against immunoglobulin G (IgG) and its concentration is observed in human serum or plasma. RF value higher than 20 international units per milliliter (IU/mL) is considered positive.
Time Frame	Week 24 of the initial treatment, 24 weeks after first re-treatment, and 24 weeks after second retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	69	71
Negative: Initial treatment, Week 24 (n=69,71)	33.3 (273.09) 47.6%	38.0 (408.24) 52.1%
Positive: Initial treatment, Week 24 (n=69,71)	66.7 (114.63) 95.3%	62.0 (386.02) 84.9%
Negative: 1st Retreatment, Week 24 (n=44,43)	36.4 (79.14) 52%	48.8 (65.29) 66.8%
Positive: 1st Retreatment, Week 24 (n=44,43)	63.6 (75.68) 90.9%	51.2 (41.01) 70.1%
Negative: 2nd retreatment, Week 24 (n=15,12)	46.7 66.7%	83.3 114.1%
Positive: 2nd retreatment, Week 24 (n=15,12)	53.3 76.1%	16.7 22.9%

18. Secondary Outcome

Title	Percentage of Participants With Anti-cyclic Citrullinated Protein (Anti-CCP) Antibodies at 24 Weeks After Treatment
Description	Anti-CCP antibodies are auto antibodies (antibodies directed against 1 or more of an individual's own proteins) that are frequently detected in the blood of rheumatoid arthritis participants. Anti-CCP antibodies value higher than 10 U/mL is considered positive.
Time Frame	Week 24 of the initial treatment, 24 weeks after first re-treatment, and 24 weeks after second retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	69	71
Negative: Initial treatment, Week 24 (n=69,71)	17.4 24.9%	22.5 30.8%
Positive: Initial treatment, Week 24 (n=69,71)	82.6 118%	77.5 106.2%
Negative: 1st Retreatment, Week 24 (n=44,43)	22.7 32.4%	20.9 28.6%
Positive: 1st Retreatment, Week 24 (n=44,43)	77.3 110.4%	79.1 108.4%
Negative: 2nd retreatment, Week 24 (n=15,12)	13.3 19%	41.7 57.1%
Positive: 2nd retreatment, Week 24 (n=15,12)	86.7 123.9%	58.3 79.9%

19. Secondary Outcome

Title	Physician's Global Assessment of Disease Activity
Description	The Physician's Global Assessment of disease activity is assessed on a 0 to 100 millimeter (mm) horizontal VAS by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Physicians were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high disease activity).
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Initial treatment, Day 1 (n=70,73)	65.0 (15.0)	64.1 (15.0)
Initial treatment, Week 24 (n=69,71)	27.9 (18.6)	27.2 (16.2)
Before 1st retreatment (n=64,63)	33.7 (17.4)	26.9 (17.1)
1st retreatment, Day 1 (n=60,61)	44.4 (20.8)	43.3 (18.5)
1st retreatment, Week 12 (n=56,62)	30.4 (18.8)	28.4 (18.0)
1st retreatment, Week 24 (n=60,59)	31.9 (19.1)	24.8 (16.3)

20. Secondary Outcome

Title	Patient Global Assessment of Disease Activity
Description	The Patient's Global Assessment of Disease Activity is assessed on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Re-treatment Arm A: Single 1000 mg IV Rituximab	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Initial treatment, Day 1 (n=70,73)	63.0 (20.4)	64.2 (18.0)
Initial treatment, Week 24 (n=70,73)	29.9 (22.3)	32.6 (22.7)
Before 1st retreatment (n=65,67)	33.2 (19.6)	34.7 (22.3)
1st retreatment, Day 1 (n=65,66)	43.7 (21.2)	46.6 (21.3)
1st retreatment, Week 12 (n=63,65)	34.8 (21.2)	34.5 (25.3)
1st retreatment, Week 24 (n=64,60)	35.1 (24.6)	34.1 (23.1)

21. Secondary Outcome

Title	Patient's Global Assessment of Pain
Description	The participants assessed their pain over the past 24 hours on a 0 to 100 mm horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high pain levels).
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Initial Treatment, Day 1 (n=70,73)	61.9 (22.3)	60.1 (19.9)
Initial Treatment, Week 24 (n=70,73)	28.5 (22.0)	30.0 (21.7)
Before 1st retreatment (n=65,67)	34.4 (21.3)	32.9 (23.0)
1st re-treatment, Day 1 (n=65,67)	41.1 (21.5)	45.2 (22.4)
1st retreatment, Week 12 (n=64,60)	34.3 (21.4)	33.9 (25.6)
1st retreatment, Week 24 (n=64,60)	34.4 (24.6)	34.3 (23.7)

22. Secondary Outcome

Title	Participant Assessment of Fatigue
Description	Participants were asked to rate their level of fatigue over the last 7 days on a 100-mm VAS. The left-hand extreme of the line equals 0 mm, and is described as "no fatigue" and the right-hand extreme equals 100 mm as "extreme fatigue". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high levels of fatigue).
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Initial Treatment, Day 1 (n=70,73)	62.1 (21.4)	62.0 (22.5)
Initial Treatment, Week 24 (n=70,73)	37.1 (24.2)	39.8 (25.8)
Before 1st retreatment (n=64,66)	44.5 (20.8)	41.2 (26.1)
1st retreatment, Day 1 (n=65,64)	50.6 (22.6)	51.7 (21.6)
1st retreatment, Week 12 (n=63,65)	45.2 (23.0)	45.3 (25.5)
1st retreatment, Week 24 (n=64,60)	43.0 (25.3)	38.9 (23.6)

23. Secondary Outcome

Title	Cortisone Intake AUC (Time- and Weight-Weighted)
Description	All cortisone intakes (in mg) were taken into account (oral, IV [including the cortisone administration before the rituximab infusion], intramuscular, and intra-articular).
Time Frame	Day 1 (each infusion), Week 24, Week 104

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	69	73
Day 1 to Week 104 (n=69,73)	0.08 (0.06)	0.09 (0.06)
1st retreatment to Week 104 (n=65,68)	0.08 (0.06)	0.09 (0.06)
Week 24 to Week 104 (n=69,73)	0.08 (0.06)	0.09 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Day 1 to Week 104
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.389
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	1st retreatment to Week 104
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.374
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Weel 24 to Week 104
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.277
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

24. Secondary Outcome

Title	Total Mean Dose of Cortisone Between Week 24 and Week 104
Description	All cortisone intakes were taken into account, including oral, IV (including the cortisone administration before the rituximab infusion), intramuscular and intra-articular.
Time Frame	Week 24 to Week 104

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Total cortisone: Week 24 to Week 104	2542.9 (2085.6)	2842.5 (2124.9)
Oral cortisone: Week 24 to Week 104	2384.0 (2092.6)	2425.1 (2046.6)
IV cortisone: Week 24 to Week 104	199.1 (92.3)	384.9 (193.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Total cortisone: Week 24 to Week 104
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.278
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	Oral cortisone: Week 24 to Week 104
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.887
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Randomized Group, Nonrandomized Group
	Comments	IV cortisone: Week 24 to Week 104
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

25. Secondary Outcome

Title	HAQ-DI Scores
Description	HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0=least difficulty and 3 extreme difficulty.
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	72
Initial treatment, Day 1 (n=70,69)	1.74 (0.61)	1.75 (0.69)
Initial treatment, Week 24 (n=68,72)	1.25 (0.67)	1.31 (0.74)
Before 1st retreatment (n=64,67)	1.26 (0.67)	1.35 (0.73)
1st retreatment, Day 1 (n=58,58)	1.32 (0.68)	1.42 (0.73)
1st retreatment, Week 12 (n=62,61)	1.31 (0.66)	1.33 (0.72)
1st retreatment, Week 24 (n=63,59)	1.26 (0.72)	1.32 (0.72)

26. Secondary Outcome

Title	Short Form 12 (SF-12) Physical Health Composite Score
Description	Physical and Mental Health Composite Scores of SF-12 were computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	63	68
Initial treatment, Day 1 (n=62,65)	31.11 (7.55)	31.07 (7.41)
Initial Tteatment, Week 24 (n=63,68)	38.81 (8.39)	40.05 (8.64)
Before 1st retreatment (n=21,22)	39.44 (8.45)	39.52 (9.99)
1st retreatment, Day 1 (n=47,44)	36.57 (6.75)	35.81 (8.97)
1st retreatment, Week 12 (n=13,10)	38.36 (9.30)	38.05 (10.77)
1st retreatment, Week 24 (n=40,36)	36.53 (7.75)	36.86 (8.13)

27. Secondary Outcome

Title	SF-12 Mental Health Composite Score
Description	Mental Health Composite Scores of SF-12 were computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	63	68
Initial treatment, Day 1 (n=62,65)	36.03 (10.03)	37.13 (9.40)
Initial treatment, Week 24 (n=63,68)	43.08 (9.74)	40.99 (9.01)
Before 1st retreatment (n=21,22)	44.94 (9.94)	41.57 (8.66)
1st retreatment, Day 1 (n=47,44)	40.87 (10.53)	38.52 (7.87)
1st retreatment, Week 12 (n=13,10)	41.84 (11.36)	34.69 (11.06)
1st retreatment, Week 24 (n=40,36)	40.90 (10.61)	41.60 (8.87)

28. Secondary Outcome

Title	Medical Outcomes Study Sleep Scale (MOS-Sleep) Composite Sleep Problems 6 (SLP6) Index
Description	The MOS Sleep Scale measures most constructs of sleep. The scale has a battery of questions to measure specific aspects of sleep in participants with co-morbidities. The SLP6 index is comprised of 6 items: provides a summary of sleep problems and contains questions from the sleep disturbance, sleep adequacy, respiratory impairment, and somnolence domains. The SLP6 index score ranges between 0 and 100, with higher values corresponding to more sleep problems.
Time Frame	Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population;n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	68	70
Initial treatment, Day 1 (n=68,66)	52.15 (15.32)	49.89 (15.81)
Initial treatment, Week 24 (n=65,70)	43.73 (14.90)	40.50 (17.17)
Before 1st retreatment (n=62,65)	45.44 (13.97)	41.27 (17.01)
1st retreatment, Day 1 (n=57,56)	46.25 (16.53)	44.94 (16.02)
1st retreatment, Week 12 (n=61,59)	43.64 (14.41)	43.74 (18.60)
1st retreatment, Week 24 (n=63,59)	44.74 (15.35)	40.08 (16.76)

29. Secondary Outcome

Title	Percentage of Participants Reporting Acceptable Disease Activity Symptom State Assessed Using Patient Acceptable and Unacceptable Symptom State (PASS)
Description	Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of disease activity they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Week 24	73.4 104.9%	75.4 103.3%
1st retreatment, Week 12	73.3 104.7%	62.5 85.6%
1st retreatment, Week 24	70.5 100.7%	64.3 88.1%

30. Secondary Outcome

Title	Patient Global Assessment of Disease Activity in Participants Reporting Acceptable Symptoms Using PASS
Description	The Patient's Global Assessment of Disease Activity assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours) on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants with 'acceptable' symptom state assessed using PASS were included in the analysis. n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	47	52
Week 24 (n=47,52)	23.4 (18.5)	28.4 (19.1)
1st retreatment, Week 12 (n=44,35)	27.4 (16.6)	27.3 (21.8)
1st retreatment, Week 24 (n=43,36)	26.3 (19.5)	25.7 (16.4)

31. Secondary Outcome

Title	Percentage of Participants With Minimum Clinically Important Improvement (MCII) in Disease Activity
Description	Participants were asked how their disease activity had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse-more disease activity.
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Week 24	75.4 107.7%	81.2 111.2%
1st retreatment, Week 12	65.6 93.7%	63.0 86.3%
1st retreatment, Week 24	66.7 95.3%	66.1 90.5%

32. Secondary Outcome

Title	Change From Baseline in Patient Global Assessment of Disease Activity in Participants With MCII
Description	The Patient's Global Assessment of Disease Activity was assessed in participants reporting MCII on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).
Time Frame	Baseline, Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants with MCII were included in the analysis. n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	49	56
Week 24 (n=49,56)	-12.4 (20.7)	-4.6 (22.9)
1st retreatment, Week 12 (n=38,30)	-4.2 (16.0)	-9.2 (17.7)
1st retreatment, Week 24 (n=40,37)	-2.5 (17.8)	-2.9 (20.6)

33. Secondary Outcome

Title	Percentage of Participants Reporting Acceptable Symptom State in Functioning Assessed Using PASS
Description	Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of function they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of function they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Week 24	74.2 106%	72.7 99.6%
1st retreatment, Week 12	75.9 108.4%	60.0 82.2%
1st retreatment, Week 24	70.2 100.3%	62.1 85.1%

34. Secondary Outcome

Title	HAQ-DI Scores in Participants Reporting Acceptable Function Using PASS
Description	HAQ-DI was assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours). HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0=least difficulty and 3 extreme difficulty.
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants with 'acceptable' symptom state assessed using PASS were included in the analysis. n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	46	48
Week 24 (n=46,48)	1.16 (0.69)	1.16 (0.74)
1st retreatment, Week 12 (n=44,33)	1.20 (0.70)	1.08 (0.71)
1st retreatment, Week 24 (n=40,36)	1.14 (0.75)	1.08 (0.72)

35. Secondary Outcome

Title	Percentage of Participants With MCII in Functioning
Description	Participants were asked how their functioning had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse.
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Week 24	73.4 104.9%	76.5 104.8%
1st retreatment, Week 12	65.0 92.9%	63.0 86.3%
1st retreatment, Week 24	65.5 93.6%	57.9 79.3%

36. Secondary Outcome

Title	Change From Baseline in HAQ-DI in Participants With MCII
Description	HAQ-DI was assessed in participants with MCII. HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0=least difficulty and 3 extreme difficulty.
Time Frame	Baseline, Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants with MCII were included in the analysis. n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	47	52
Week 24 (n=47,52)	-0.11 (0.46)	-0.06 (0.56)
1st retreatment, Week 12 (n=38,30)	-0.03 (0.30)	-0.11 (0.39)
1st retreatment, Week 24 (n=38,30)	-0.07 (0.24)	-0.09 (0.29)

37. Secondary Outcome

Title	Percentage of Participants With Acceptable Symptom State in Pain Assessed Using PASS
Description	Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of pain they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	70	73
Week 24	74.2 106%	75.0 102.7%
1st retreatment Week 12	70.2 100.3%	61.8 84.7%
1st retreatment, Week 24	72.9 104.1%	61.4 84.1%

38. Secondary Outcome

Title	Patient Global Assessment of Pain in Participants Reporting Acceptable Symptoms Using PASS
Description	Patient Global Assessment of Pain assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours) on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Higher values correspond to worst state of participant (high pain levels).
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants with 'acceptable' symptom state assessed using PASS were included in the analysis. n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	46	51
Week 24 (n=46,51)	21.5 (16.2)	26.4 (18.5)
1st retreatment, Week 12 (n=40,34)	26.8 (17.3)	27.6 (22.4)
1st retreatment, Week 24 (n=43,35)	26.3 (20.1)	25.1 (17.3)

39. Secondary Outcome

Title	Percentage of Participants With MCII in Pain
Description	Participants were asked how their pain had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse pain.
Time Frame	Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	63	70
Week 24 (n=63,70)	76.2 108.9%	80.0 109.6%
1st retreatment, Week 12 (n=59,55)	71.2 101.7%	69.1 94.7%
1st retreatment, Week 24 (n=61,57)	68.9 98.4%	61.4 84.1%

40. Secondary Outcome

Title	Change From Baseline in Patient Global Assessment of Pain in Participants With MCII
Description	The participants assessed their pain over the past 24 hours on a 0 to 100 mm horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high pain levels).
Time Frame	Baseline, Week 24, 12 and 24 weeks after 1st retreatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants with MCII were included in the analysis. n=number of participants assessed for the specified parameter at a given visit.

Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg	Randomized Retreatment Arm B: Rituximab 1000 mg x 2
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.
Measure Participants	48	56
Week 24 (n=48,56)	-13.5 (21.0)	-4.3 (23.9)
1st retreatment, Week 12 (n=39,35)	-2.7 (13.6)	-8.9 (16.4)
1st retreatment, Week 24 (n=42,35)	-3.5 (24.3)	-3.2 (18.4)

Adverse Events

Time Frame	Baseline to 104 weeks; related serious adverse events (SAEs) were collected and reported regardless of time elapsed from last dose of study drug; unrelated SAEs were collected during the study and for up to 24 weeks after last dose of study drug.
Arm/Group Title	Randomized Retreatment Arm A: Rituximab 1000 mg		Randomized Retreatment Arm B: Rituximab 1000 mg x 2		Nonrandomized: Rituximab 1000 mg
Arm/Group Description	Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received one additional infusion of rituximab 1000 mg IV. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and MTX ≥10 mg/week by mouth or parenteral throughout course of treatment.		Participants received rituximab 1000 mg IV on Days 1 and 15. After Week 24, if DAS28 was >3.2, participants received two additional infusions of rituximab 1000 mg IV, 15 days apart. Participants received methylprednisolone 100 mg IV 30 minutes before each rituximab infusion and ≥10 mg/week MTX by mouth or parenteral throughout course of treatment.		Participants received rituximab 1000 mg IV on Days 1 and 15, methylprednisolone 100 mg IV at 30 minutes before each rituximab infusion, and MTX ≥10 mg/week by mouth or parenterally throughout treatment course.
All Cause Mortality
	Randomized Retreatment Arm A: Rituximab 1000 mg		Randomized Retreatment Arm B: Rituximab 1000 mg x 2		Nonrandomized: Rituximab 1000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Randomized Retreatment Arm A: Rituximab 1000 mg		Randomized Retreatment Arm B: Rituximab 1000 mg x 2		Nonrandomized: Rituximab 1000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/66 (28.8%)		25/68 (36.8%)		16/81 (19.8%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Cardiac disorders
Tachycardia	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Ear and labyrinth disorders
Vertigo	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Endocrine disorders
Goitre	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Eye disorders
Cataract	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Retinal detachment	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Gastrointestinal disorders
Abdominal strangulated hernia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Gastrooesophageal reflux disease	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Gingival bleeding	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
General disorders
Cyst	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Gait disturbance	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Oedema peripheral	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Pain	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pyrexia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Infections and infestations
Abdominal wall abscess	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Bursitis infective	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Cellulitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Hepatitis B	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Perianal abscess	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pertussis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pharyngitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pneumonia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Prostate infection	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pyelonephritis acute	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Injury, poisoning and procedural complications
Tendon rupture	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Dislocation of joint prosthesis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Femoral neck fracture	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Joint sprain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Rib fracture	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Spinal compression fracture	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/66 (0%)		0/68 (0%)		2/81 (2.5%)
Diabetes mellitus	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Hyperglycaemia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis	0/66 (0%)		4/68 (5.9%)		2/81 (2.5%)
Osteoarthritis	2/66 (3%)		2/68 (2.9%)		1/81 (1.2%)
Arthralgia	1/66 (1.5%)		2/68 (2.9%)		1/81 (1.2%)
Arthropathy	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Arthritis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Back pain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Bone erosion	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Muscle haemorrhage	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Neck pain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Pain in extremity	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Rheumatoid nodule	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Tenosynovitis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Basal cell carcinoma	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Bowen's disease	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Breast cancer	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Lipoma	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Uterine leiomyoma	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Nervous system disorders
Sciatica	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Headache	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Restless legs syndrome	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Psychiatric disorders
Depression	0/66 (0%)		1/68 (1.5%)		1/81 (1.2%)
Mania	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Renal and urinary disorders
Calculus bladder	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Reproductive system and breast disorders
Bartholinitis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Respiratory, thoracic and mediastinal disorders
Lung disorder	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Pulmonary embolism	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Vascular disorders
Hypertensive crisis	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Vasculitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Other (Not Including Serious) Adverse Events
	Randomized Retreatment Arm A: Rituximab 1000 mg		Randomized Retreatment Arm B: Rituximab 1000 mg x 2		Nonrandomized: Rituximab 1000 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/66 (92.4%)		65/68 (95.6%)		72/81 (88.9%)
Blood and lymphatic system disorders
Lymphopenia	1/66 (1.5%)		2/68 (2.9%)		3/81 (3.7%)
Anaemia	1/66 (1.5%)		2/68 (2.9%)		0/81 (0%)
Iron deficiency anaemia	1/66 (1.5%)		2/68 (2.9%)		0/81 (0%)
Neutropenia	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Haemorrhagic anaemia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Lymphadenopathy	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Thrombocythaemia	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Cardiac disorders
Tachycardia	0/66 (0%)		3/68 (4.4%)		1/81 (1.2%)
Ventricular extrasystoles	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Angina pectoris	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Bundle branch block left	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Palpitations	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Ear and labyrinth disorders
Vertigo	5/66 (7.6%)		1/68 (1.5%)		3/81 (3.7%)
Tinnitus	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Ear discomfort	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Vertigo positional	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Endocrine disorders
Goitre	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Hyperthyroidism	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Eye disorders
Conjunctivitis	5/66 (7.6%)		1/68 (1.5%)		0/81 (0%)
Cataract	1/66 (1.5%)		1/68 (1.5%)		1/81 (1.2%)
Dry eye	2/66 (3%)		0/68 (0%)		1/81 (1.2%)
Chalazion	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Visual acuity reduced	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Visual disturbance	0/66 (0%)		0/68 (0%)		2/81 (2.5%)
Eye irritation	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Eye pain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Keratitis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Keratoconjunctivitis sicca	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Ocular discomfort	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Ocular hyperaemia	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Ocular hypertension	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Retinal detachment	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Retinopathy hypertensive	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Uveitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Gastrointestinal disorders
Nausea	7/66 (10.6%)		5/68 (7.4%)		6/81 (7.4%)
Abdominal pain upper	5/66 (7.6%)		1/68 (1.5%)		4/81 (4.9%)
Abdominal pain	3/66 (4.5%)		2/68 (2.9%)		2/81 (2.5%)
Vomiting	4/66 (6.1%)		2/68 (2.9%)		2/81 (2.5%)
Diarrhoea	2/66 (3%)		3/68 (4.4%)		1/81 (1.2%)
Gastrointestinal disorder	1/66 (1.5%)		0/68 (0%)		2/81 (2.5%)
Gastrooesophageal reflux disease	0/66 (0%)		3/68 (4.4%)		1/81 (1.2%)
Aphthous stomatitis	1/66 (1.5%)		2/68 (2.9%)		0/81 (0%)
Constipation	2/66 (3%)		0/68 (0%)		0/81 (0%)
Dysphagia	3/66 (4.5%)		0/68 (0%)		0/81 (0%)
Gingivitis	2/66 (3%)		1/68 (1.5%)		0/81 (0%)
Dyspepsia	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Haemorrhoids	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Inguinal hernia	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Toothache	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Abdominal strangulated hernia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Anal fissure	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Dry mouth	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Enterocolitis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Frequent bowel movements	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Gastric ulcer	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Gingival bleeding	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Melaena	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Rectal haemorrhage	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
General disorders
Asthenia	11/66 (16.7%)		11/68 (16.2%)		6/81 (7.4%)
Pyrexia	3/66 (4.5%)		4/68 (5.9%)		4/81 (4.9%)
Fatigue	1/66 (1.5%)		1/68 (1.5%)		3/81 (3.7%)
Oedema peripheral	1/66 (1.5%)		2/68 (2.9%)		1/81 (1.2%)
Feeling hot	2/66 (3%)		0/68 (0%)		1/81 (1.2%)
Chest pain	0/66 (0%)		0/68 (0%)		2/81 (2.5%)
Drug intolerance	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Face oedema	0/66 (0%)		1/68 (1.5%)		1/81 (1.2%)
Malaise	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Oedema	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Adverse drug reaction	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Chest discomfort	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Chills	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Cyst	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Gait disturbance	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
General physical health deterioration	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Influenza like illness	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Infusion site phlebitis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Injection site pain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Localised oedema	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Mucosal inflammation	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Pain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Sense of oppression	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Hepatobiliary disorders
Cholestasis	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Cytolytic hepatitis	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Hepatomegaly	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Immune system disorders
Hypersensitivity	0/66 (0%)		0/68 (0%)		2/81 (2.5%)
Allergy to chemicals	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Drug hypersensitivity	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Infections and infestations
Bronchitis	13/66 (19.7%)		16/68 (23.5%)		11/81 (13.6%)
Urinary tract infection	9/66 (13.6%)		12/68 (17.6%)		14/81 (17.3%)
Gastroenteritis	8/66 (12.1%)		10/68 (14.7%)		3/81 (3.7%)
Nasopharyngitis	7/66 (10.6%)		6/68 (8.8%)		2/81 (2.5%)
Rhinitis	3/66 (4.5%)		4/68 (5.9%)		6/81 (7.4%)
Pharyngitis	4/66 (6.1%)		6/68 (8.8%)		2/81 (2.5%)
Tonsillitis	4/66 (6.1%)		3/68 (4.4%)		0/81 (0%)
Sinusitis	4/66 (6.1%)		2/68 (2.9%)		1/81 (1.2%)
Influenza	3/66 (4.5%)		3/68 (4.4%)		0/81 (0%)
Oral herpes	1/66 (1.5%)		2/68 (2.9%)		2/81 (2.5%)
Upper respiratory tract infection	2/66 (3%)		3/68 (4.4%)		0/81 (0%)
Bronchopneumonia	2/66 (3%)		1/68 (1.5%)		0/81 (0%)
Fungal skin infection	2/66 (3%)		0/68 (0%)		1/81 (1.2%)
Localised infection	0/66 (0%)		2/68 (2.9%)		1/81 (1.2%)
Tracheitis	2/66 (3%)		1/68 (1.5%)		0/81 (0%)
Acute sinusitis	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Cystitis	0/66 (0%)		1/68 (1.5%)		1/81 (1.2%)
Escherichia urinary tract infection	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Fungal infection	2/66 (3%)		0/68 (0%)		0/81 (0%)
Onychomycosis	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Oral fungal infection	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Rhinotracheitis	0/66 (0%)		1/68 (1.5%)		1/81 (1.2%)
Sinobronchitis	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Vulvovaginal mycotic infection	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Abdominal wall abscess	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Bronchiectasis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Bursitis infective	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Campylobacter intestinal infection	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Cellulitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Chronic sinusitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Ear infection	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Folliculitis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Gastroenteritis viral	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Hepatitis B	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Hordeolum	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Infected sebaceous cyst	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Laryngitis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Lung infection	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Otitis externa	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Perianal abscess	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pertussis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pneumonia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Prostate infection	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pyelonephritis acute	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Skin infection	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Subcutaneous abscess	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Tinea pedis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Tinea versicolour	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Tooth infection	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Vaginal candidiasis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Vaginal infection	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Viral infection	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Viral upper respiratory tract infection	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Injury, poisoning and procedural complications
Joint injury	1/66 (1.5%)		2/68 (2.9%)		0/81 (0%)
Limb injury	2/66 (3%)		1/68 (1.5%)		0/81 (0%)
Tendon rupture	1/66 (1.5%)		1/68 (1.5%)		1/81 (1.2%)
Ankle fracture	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Rib fracture	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Spinal compression fracture	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Traumatic haematoma	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Accidental overdose	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Animal bite	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Chest injury	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Dislocation of joint prosthesis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Femoral neck fracture	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Femur fracture	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Foot fracture	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Humerus fracture	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Joint dislocation	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Joint sprain	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Procedural pain	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Skin injury	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Stress fracture	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Tibia fracture	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Wrist fracture	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Investigations
Transaminases increased	2/66 (3%)		1/68 (1.5%)		1/81 (1.2%)
Weight increased	2/66 (3%)		1/68 (1.5%)		1/81 (1.2%)
Eosinophil count increased	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Gamma-glutamyltransferase increased	0/66 (0%)		1/68 (1.5%)		1/81 (1.2%)
Hepatic enzyme increased	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Weight decreased	0/66 (0%)		1/68 (1.5%)		1/81 (1.2%)
Alanine aminotransferase increased	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Aspartate aminotransferase increased	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Bacteria urine identified	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Blood lactate dehydrogenase increased	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Blood phosphorus decreased	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Blood thyroid stimulating hormone decreased	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Cardiac murmur	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Deoxyribonucleic acid (DNA) antibody positive	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Electrocardiogram repolarisation abnormality	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Lymphocyte count decreased	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Neutrophil count decreased	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Neutrophil count increased	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
White blood cell count increased	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Metabolism and nutrition disorders
Hypercholesterolaemia	7/66 (10.6%)		2/68 (2.9%)		1/81 (1.2%)
Hyperglycaemia	1/66 (1.5%)		2/68 (2.9%)		1/81 (1.2%)
Diabetes mellitus inadequate control	0/66 (0%)		0/68 (0%)		3/81 (3.7%)
Hypertriglyceridaemia	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Diabetes mellitus	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Dyslipidaemia	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Hypokalaemia	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Anorexia	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Diabetes mellitus non-insulin-dependent	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Iron deficiency	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Obesity	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Vitamin D deficiency	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis	8/66 (12.1%)		12/68 (17.6%)		8/81 (9.9%)
Back pain	10/66 (15.2%)		10/68 (14.7%)		3/81 (3.7%)
Arthralgia	2/66 (3%)		6/68 (8.8%)		3/81 (3.7%)
Myalgia	1/66 (1.5%)		5/68 (7.4%)		0/81 (0%)
Neck pain	2/66 (3%)		3/68 (4.4%)		1/81 (1.2%)
Osteoarthritis	2/66 (3%)		2/68 (2.9%)		1/81 (1.2%)
Bursitis	1/66 (1.5%)		0/68 (0%)		3/81 (3.7%)
Musculoskeletal pain	2/66 (3%)		1/68 (1.5%)		1/81 (1.2%)
Pain in extremity	0/66 (0%)		1/68 (1.5%)		2/81 (2.5%)
Arthritis	2/66 (3%)		0/68 (0%)		0/81 (0%)
Arthropathy	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Intervertebral disc disorder	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Osteonecrosis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Osteoporosis	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Tendonitis	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Bone erosion	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Bone pain	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Dupuytren's contracture	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Haemarthrosis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Joint effusion	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Limb discomfort	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Monarthritis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Muscle haemorrhage	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Muscle spasms	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Osteopenia	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Osteoporotic fracture	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Pain in jaw	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Rheumatoid nodule	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Rotator cuff syndrome	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Sjogren's syndrome	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Synovial cyst	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Synovitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Tendon disorder	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Tenosynovitis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Toe deformity	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma	2/66 (3%)		0/68 (0%)		0/81 (0%)
Adenocarcinoma	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Basal cell carcinoma	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Basosquamous carcinoma	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Bowen's disease	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Breast cancer	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Skin papilloma	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Uterine leiomyoma	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Vaginal papilloma	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Nervous system disorders
Headache	7/66 (10.6%)		11/68 (16.2%)		10/81 (12.3%)
Sciatica	3/66 (4.5%)		6/68 (8.8%)		4/81 (4.9%)
Migraine	0/66 (0%)		3/68 (4.4%)		1/81 (1.2%)
Restless legs syndrome	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Burning sensation	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Carpal tunnel syndrome	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Cervical root pain	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Cervicobrachial syndrome	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Diabetic neuropathy	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Dystonia	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Epilepsy	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Memory impairment	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Paraesthesia	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Parkinsonism	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Sinus headache	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Syncope	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Psychiatric disorders
Depression	2/66 (3%)		5/68 (7.4%)		5/81 (6.2%)
Insomnia	0/66 (0%)		4/68 (5.9%)		2/81 (2.5%)
Anxiety	1/66 (1.5%)		3/68 (4.4%)		0/81 (0%)
Sleep disorder	2/66 (3%)		1/68 (1.5%)		0/81 (0%)
Depressive symptom	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Mania	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Renal and urinary disorders
Haematuria	0/66 (0%)		3/68 (4.4%)		0/81 (0%)
Calculus bladder	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Dysuria	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Hypertonic bladder	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Proteinuria	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Renal colic	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Renal impairment	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Urinary retention	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Reproductive system and breast disorders
Bartholinitis	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Cystocele	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Metrorrhagia	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Vaginal haemorrhage	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	11/66 (16.7%)		4/68 (5.9%)		3/81 (3.7%)
Larynx irritation	2/66 (3%)		2/68 (2.9%)		1/81 (1.2%)
Productive cough	2/66 (3%)		2/68 (2.9%)		1/81 (1.2%)
Rhinitis allergic	3/66 (4.5%)		1/68 (1.5%)		1/81 (1.2%)
Throat irritation	1/66 (1.5%)		2/68 (2.9%)		2/81 (2.5%)
Pharyngolaryngeal pain	1/66 (1.5%)		1/68 (1.5%)		1/81 (1.2%)
Asthma	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Chronic obstructive pulmonary disease	2/66 (3%)		0/68 (0%)		0/81 (0%)
Dysphonia	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Dyspnoea exertional	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Lung disorder	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Sleep apnoea syndrome	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Dyspnoea	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Epistaxis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Haemoptysis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Pharyngeal erythema	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pharyngeal oedema	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Pulmonary embolism	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Rhinorrhoea	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/66 (1.5%)		6/68 (8.8%)		5/81 (6.2%)
Rash	4/66 (6.1%)		2/68 (2.9%)		1/81 (1.2%)
Erythema	2/66 (3%)		2/68 (2.9%)		1/81 (1.2%)
Dermatitis allergic	0/66 (0%)		3/68 (4.4%)		2/81 (2.5%)
Eczema	2/66 (3%)		1/68 (1.5%)		0/81 (0%)
Urticaria	2/66 (3%)		0/68 (0%)		1/81 (1.2%)
Alopecia	1/66 (1.5%)		1/68 (1.5%)		0/81 (0%)
Hyperhidrosis	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Night sweats	2/66 (3%)		0/68 (0%)		0/81 (0%)
Rash pruritic	0/66 (0%)		2/68 (2.9%)		0/81 (0%)
Angioedema	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Blister	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Ecchymosis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Eczema nummular	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Ingrowing nail	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Intertrigo	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Photosensitivity reaction	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Skin exfoliation	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Swelling face	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Surgical and medical procedures
Cataract operation	1/66 (1.5%)		1/68 (1.5%)		1/81 (1.2%)
Apicectomy	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Corneal operation	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Skin neoplasm excision	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Therapy regimen changed	0/66 (0%)		0/68 (0%)		1/81 (1.2%)
Vascular disorders
Hypertension	4/66 (6.1%)		1/68 (1.5%)		3/81 (3.7%)
Hot flush	3/66 (4.5%)		2/68 (2.9%)		3/81 (3.7%)
Hypertensive crisis	1/66 (1.5%)		0/68 (0%)		1/81 (1.2%)
Hypotension	0/66 (0%)		0/68 (0%)		2/81 (2.5%)
Arteriosclerosis	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Orthostatic hypotension	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Phlebitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Thrombophlebitis superficial	0/66 (0%)		1/68 (1.5%)		0/81 (0%)
Vasculitis	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Venous insufficiency	1/66 (1.5%)		0/68 (0%)		0/81 (0%)
Venous thrombosis	0/66 (0%)		0/68 (0%)		1/81 (1.2%)

Limitations/Caveats

Nonserious adverse events (AEs) presented in this record include all AEs reported during the study, not just nonserious events.

More Information

Certain Agreements

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

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.