A Study to Evaluate the Efficacy and Safety of Mabthera Alone and in Combination With Either Cyclophosphamide or Methotrexate in Patients With Rheumatoid Arthritis

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Completed

CT.gov ID

NCT02693210

Collaborator

(none)

161

Enrollment

Locations

Arms

Duration (Months)

4.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

WA16291 is a Phase IIa "proof-of-concept" study. The primary objective of this study is to determine the safety and efficacy of rituximab (a B cell depleting chimeric monoclonal antibody) used either as monotherapy or in combination with methotrexate or cyclophosphamide in participants with rheumatoid arthritis who have failed prior Disease Modifying Anti-Rheumatic Drug (DMARD) therapy and currently have an inadequate clinical response to methotrexate.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Cyclophosphamide Drug: Methotrexate Other: Placebo Cyclophosphamide Other: Placebo Methotrexate Other: Placebo Rituximab Drug: Rituximab	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

161 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomised, Double Dummy Controlled, Parallel Group Study of the Efficacy and Safety of MabThera (Rituximab) Alone or in Combination With Either Cyclophosphamide or Methotrexate, in Patients With Rheumatoid Arthritis

Study Start Date :

Feb 1, 2001

Actual Primary Completion Date :

Aug 1, 2002

Actual Study Completion Date :

Aug 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group A: Methotrexate Participants will receive methotrexate at dosage >=10 milligrams per week (mg/week) orally as determined by the investigator. They also receive placebo infusion on days 1 and 15 in place of rituximab and on Days 3 and 17 in place of cyclophosphamide.	Drug: Methotrexate Participants will receive >= 10 mg/week methotrexate orally up to 24 weeks Other: Placebo Cyclophosphamide Participants will receive placebo in place of cyclophosphamide on Days 3 and 17 Other: Placebo Rituximab Participants will receive placebo in place of rituximab on days 1 and 15
Experimental: Group B: Rituximab Monotherapy Participants will receive 1 g intravenous infusions of rituximab on Days 1 and 15. They also receive Weekly placebo orally instead of methotrexate and placebo infusion in place of cyclophosphamide on Days 3 and 17.	Other: Placebo Cyclophosphamide Participants will receive placebo in place of cyclophosphamide on Days 3 and 17 Other: Placebo Methotrexate Participants will receive weekly oral placebo in place of Methotrexate Drug: Rituximab Participants will receive 1g infusions of rituximab on Days 1 and 15
Experimental: Group C: Rituximab and Cyclophosphamide Participants will receive 1g IV infusion of rituximab on Days 1 and 15 and 750 mg infusion of Cyclophosphamide on Days 3 and 17. They also receive weekly oral placebo in place of methotrexate.	Drug: Cyclophosphamide Participants will receive 750 mg infusions of cyclophosphamide on Days 3 and 17 Other: Placebo Methotrexate Participants will receive weekly oral placebo in place of Methotrexate Drug: Rituximab Participants will receive 1g infusions of rituximab on Days 1 and 15
Experimental: Group D: Methotrexate and Rituximab Participants will receive >=10 mg/week methotrexate orally along with 2 times 1 gram (g) rituximab IV infusions on Days 1 and 15. Participants will also receive placebo infusions on Days 3 and 17 in place of cyclophosphamide.	Drug: Methotrexate Participants will receive >= 10 mg/week methotrexate orally up to 24 weeks Other: Placebo Cyclophosphamide Participants will receive placebo in place of cyclophosphamide on Days 3 and 17 Drug: Rituximab Participants will receive 1g infusions of rituximab on Days 1 and 15

Outcome Measures

Primary Outcome Measures

Percentage of participants achieving American College of Rheumatology (ACR) 50 response at Week 24 [Week 24]

Secondary Outcome Measures

Percentage of participants achieving ACR 20 and ACR 70 responses at Week 24 [Week 24]
Area Under the Curve (AUC) of American College of Rheumatology Response (ACRn) [Baseline up to Week 24]
AUC of the mean Disease Activity Scores (DAS) [Baseline up to Week 24]
Change from Baseline in the Swollen Joint Count [Baseline, Weeks 12, 16, 20 and 24]
Change from Baseline in the Tender Joint Count [Baseline, Weeks 12, 16, 20 and 24]
Change from Baseline in participant's global assessment of disease activity using a Visual Analog Scale (VAS) [Baseline, Weeks 8, 12, 16, 20 and 24]
Change from Baseline in physician's global assessment of disease activity using VAS [Baseline, Weeks 8, 12, 16, 20 and 24]
Change from Baseline in the Health Assessment Questionnaire - Disease Index (HAQ-DI) scores [Baseline, Weeks 12, 16, 20 and 24]
Change from Baseline in participant's pain measured by VAS [Baseline, Weeks 12, 16, 20 and 24]
Change from Baseline in C-Reactive Protein (CRP) Levels [Baseline, Weeks 12, 16, 20 and 24]
Change from Baseline in Erythrocyte Sedimentation Rate (ESR) [Baseline, Weeks 12, 16, 20 and 24]
Mean change in Rheumatoid factor levels at 24 weeks [Baseline and Week 24]
Percentage of participants who withdrew due to insufficient therapeutic response [Up to 24 Weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants with moderate to severe rheumatoid arthritis (RA) who have previously failed 1-5 DMARDS who currently have partial clinical response to treatment with methotrexate
Using methotrexate as a single DMARD for at least 16 weeks, of which the last 4 weeks prior to baseline on a stable oral dose greater than or equal to (>=) 10 milligrams per week (mg/week)
=21 years of age
Swollen Joint Count (SJC) and Tender Joint Count (TJC) >= 8 (out of 66 and 68 joints respectively)
At least 2 of the following parameters at Baseline: C- Reactive Protein >= 15 mg/dL; Erythrocyte Sedimentation Rate >= 30 millimeters per hour (mm/hr); Morning stiffness

45 minutes

Rheumatoid factor titer >=20 International units per milliliter (IU/mL)
Corticosteroid (less than or equal to [=<] 12.5 milligrams per deciliter [mg/d] prednisone or equivalent) or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are permitted if stable for at least 4 weeks prior to baseline

Exclusion Criteria:

American Rheumatism Association (ARA) Class IV RA disease
Concurrent treatment with any DMARD (apart from randomized treatment) or anti-TNF-alpha therapy
Active infection or history of recurrent significant infection
Prior history of cancer including solid tumors and hematologic malignancies (except basal carcinoma of the skin that have been excised and cured)
Evidence of serious uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders
Bone/joint surgery within 6 weeks prior to screening
Rheumatic Autoimmune disease other than RA
Active rheumatoid vasculitis
Prior history of gout
Chronic fatigue syndrome

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Darlinghurst		Australia	2010
2	Kogarah		Australia	2217
3	Woodville		Australia	5011
4	Diepenbeek		Belgium	3590
5	Gent		Belgium	9000
6	Liege		Belgium	4000
7	Winnipeg	Manitoba	Canada	R3A 1M4
8	Toronto	Ontario	Canada	M5G 1X5
9	Montreal	Quebec	Canada	H2L 1S6
10	Praha		Czech Republic	128 50
11	Leipzig		Germany	04107
12	Ratingen		Germany	40882
13	Wiesbaden		Germany	65191
14	Haifa		Israel	31048
15	Haifa		Israel	34354
16	Brescia		Italy	25123
17	Genova		Italy	16132
18	Modena		Italy	41100
19	Siena		Italy	53100
20	Leiden		Netherlands	2333 ZA
21	Lublin		Poland	20-022
22	Poznan		Poland	61-545
23	Warszawa		Poland	02-637
24	Wroclaw		Poland	50-556
25	Guadalajara		Spain	19002
26	La Laguna		Spain	38320
27	Madrid		Spain	28007
28	Madrid		Spain	28046
29	Sevilla		Spain	41014
30	Cannock		United Kingdom	WS11 5XY
31	Leeds		United Kingdom	LS1 3EX
32	London		United Kingdom	W1P 9PG
33	Stoke-on-trent		United Kingdom	ST6 7AG