A Study of Ocrelizumab in Participants With Moderate to Severe Rheumatoid Arthritis (RA)

A Randomized Placebo-Controlled, Multi-Center, Phase I/II Study of the Safety of Escalating Single Intravenous Doses of Ocrelizumab (rhuMAb 2H7, RO4964913, PRO70769) in Patients With Moderate to Severe Rheumatoid Arthritis Receiving Stable Doses of Concomitant Methotrexate But With Unsatisfactory Clinical Response

This study is in two parts and will evaluate the safety, tolerability and efficacy of escalating single intravenous (IV) doses of ocrelizumab compared with placebo in combination with methotrexate in participants with moderate to severe RA. Part 1 is the dose-escalation study, at one of the following dose levels of ocrelizumab [400, 1000, 1500, and 2000 milligrams (mg)]. In Part 2, participants will be randomized to explore tolerability and efficacy of doses which have been shown to be tolerated in Part 1.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Ocrelizumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
  • South Australia
    • Adelaide, South Australia, Australia, 5041
  • Victoria
    • Melbourne, Victoria, Australia, 3004
  • Western Australia
    • Perth, Western Australia, Australia, 6979
• Belgium
  • Gent, Belgium, 9000
  • Leuven, Belgium, 3000
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
    • Edmonton, Alberta, Canada, T6G 2S2
  • Ontario
    • London, Ontario, Canada, N6A 4V2
    • Toronto, Ontario, Canada, M5T 2S8
    • Toronto, Ontario, Canada, M4N 3M5
    • Toronto, Ontario, Canada, M5G 1X5
  • Quebec
    • Quebec City, Quebec, Canada, G1V 3M7
    • Sherbrooke, Quebec, Canada, J1H 5N4
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
• New Zealand
  • Auckland, New Zealand, 2025
  • Auckland City, New Zealand, 0620
• Russian Federation
  • Moscow, Russian Federation, 115522
  • Moscow, Russian Federation, 119049
  • Moscow, Russian Federation, 129110
  • Moscow, Russian Federation, 129327
  • Saint-Petersburg, Russian Federation, 195067
  • St Petersburg, Russian Federation, 194291
  • St. Petersburg, Russian Federation, 190068
• Spain
  • Barcelona, Spain, 08035
  • Barcelona, Spain, 08025
  • Granada, Spain, 18003
  • Madrid, Spain, 28041
  • Madrid, Spain, 28222
  • Madrid, Spain, 28935
  • Sevilla, Spain, 41014
  • Valencia, Spain, 46017
  • Cadiz
    • Cádiz, Cadiz, Spain, 11009
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain, 15706
  • Madrid
    • Alcorcon, Madrid, Spain, 28922
  • Tenerife
    • La Laguna, Tenerife, Spain, 38320
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZD
  • Cambridge, United Kingdom, CB2 2QQ
  • Derby, United Kingdom, DE22 3NE
  • Leeds, United Kingdom, LS1 3EX
  • Liverpool, United Kingdom, L9 7AL
  • London, United Kingdom, E11 1NR
  • London, United Kingdom, SE1 9RT
  • Maidstone, United Kingdom, ME16 9QQ
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
  • Norwich, United Kingdom, NR4 7UY
  • Salford, United Kingdom, M6 8HD
  • Torquay, United Kingdom, TQ2 7AA
  • West Midlands, United Kingdom, M41 5SL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Moderate to severe RA for at least 6 months
• Positive serum rheumatoid factor (>/= 20 international units per milliliter)
• Current treatment with RA on an outpatient basis
• Treatment failure with one disease modifying anti-rheumatic drug (DMARD) or biologic, but have not failed more than six of these agents including methotrexate
• Current treatment with methotrexate for at least 12 weeks, at a stable dose
• Use of highly effective contraception.

Exclusion Criteria:

• Rheumatic autoimmune disease or inflammatory joint disease, other than RA
• Concurrent treatment with any disease-modifying anti-rheumatic drug (DMARD) (other than methotrexate) or any anti-tumor necrosis factor (TNF) -alfa or other biologic therapy
• Treatment with any other investigational drug within 4 weeks of screening
• Previous treatment with cell-depleting therapies, IV gamma-globulin, intra-articular or parenteral corticosteroids, and receipt of live/attenuated vaccine prior to screening
• Previous treatment with rituximab or any other anti-cluster of differentiation 20 (CD20) agent
• History of severe allergic or anaphylactic reactions to humanized monoclonal antibodies
• Known active bacterial, viral or fungal infections
• History of active tuberculosis and primary or secondary immunodeficiency
• History of concomitant diseases such as cardiovascular disease, nervous system, pulmonary disease, renal, hepatic, endocrine or gastrointestinal disorders
• Pregnancy or lactation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Ocrelizumab 1000 mg; Participants will receive single IV infusion of ocrelizumab 1000 mg.	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769
Experimental: Part 1: Ocrelizumab 1500 mg; Participants will receive single IV infusion of ocrelizumab 1500 mg.	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769
Experimental: Part 1: Ocrelizumab 2000 mg; Participants will receive single IV infusion of ocrelizumab 2000 mg.	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769
Experimental: Part 1: Ocrelizumab 400 mg; Participants will receive single IV infusion of ocrelizumab 400 milligrams (mg)	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769
Placebo Comparator: Part 1: Placebo; Participants will receive single IV infusion of placebo matched to ocrelizumab.	Drug: Placebo; Participants will receive single IV infusion of placebo.
Experimental: Part 2: Ocrelizumab 1000 mg; Participants will receive single IV infusion of ocrelizumab 1000 mg.	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769
Experimental: Part 2: Ocrelizumab 1500 mg; Participants will receive single IV infusion of ocrelizumab 1500 mg.	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769
Experimental: Part 2: Ocrelizumab 400 mg; Participants will receive single IV infusion of ocrelizumab 400 mg.	Drug: Ocrelizumab; Participants will receive single IV infusion of ocrelizumab at 400, 1000, 1500, and 2000 mg.; Other Names: RO4964913, rhuMAb 2H7, PRO70769

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants with Adverse Events (AEs) or Serious AEs (SAEs)	Baseline up to approximately 7.25 years
Percentage of Participants with Anti-Ocrelizumab Antibodies	Baseline up to approximately 7.25 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants with American College of Rheumatology (ACR) 20%, 50%, and 70% (ACR20/50/70) Response at Week 24	Week 24
Disease Activity Score at Week 24	Week 24
Percentage of Participants achieving European League Against Rheumatism (EULAR) Response at Week 24	Week 24
Maximum Plasma Concentration (Cmax) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Time to Blood B-Cell Depletion	Baseline up to approximately 7.25 years
Terminal Elimination Half-Life (t1/2) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity AUC(0-inf) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Area Under the Plasma Concentration-Time Curve From Time 0 to Last Quantifiable Concentration AUC(0-last) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Time to Maximum Observed Plasma Concentration (Tmax) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Terminal Rate Constant of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Systemic Clearance (CL) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Mean Residence Time (MRT) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Steady State Volume of Distribution (Vss) of Ocrelizumab	Pre-infusion (0 hours); 30 minutes post infusion on Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 (up to Week 24), and Weeks 36, 48 (Post Week 24)
Duration of Blood B-Cell Depletion	Baseline up to approximately 7.25 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: March 22, 2016
• First Submitted That Met QC Criteria: March 24, 2016
• First Posted (Estimate): March 25, 2016

Study Record Updates

• Last Update Posted (Estimate): March 28, 2016
• Last Update Submitted That Met QC Criteria: March 25, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Immunologic Factors; Ocrelizumab
• Other Study ID Numbers: WA18230; 2004-002132-26 (EudraCT Number)