Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial
- William Stohl1,
- Juan Gomez-Reino2,
- Ewa Olech3,
- Jean Dudler4,
- Roy M Fleischmann5,
- Cristiano A F Zerbini6,
- Ali Ashrafzadeh7,
- Susanna Grzeschik7,
- Rebecca Bieraugel8,
- Jennifer Green8,
- Steven Francom7,
- Wolfgang Dummer7
- 1Division of Rheumatology, Los Angeles County & University of Southern California Medical Center and University of Southern California Keck School of Medicine, Los Angeles, California, USA
- 2Rheumatology Unit, Hospital Clinico Universitario, Santiago, Spain
- 3Oklahoma University Health Sciences Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- 4Clinique de rhumatologie et Service de médecine physique et rééducation, HFR Fribourg—Hôpital Cantonal, Fribourg, Switzerland
- 5Department of Rheumatology, University of Texas Southwestern Medical Center, Metroplex Clinical Research Center, Dallas, Texas, USA
- 6Centro Paulista de Investigação Clinica, São Paulo, Brazil
- 7Genentech Inc, South San Francisco, California, USA
- 8Roche Products Ltd, Welwyn Garden City, UK
- Correspondence to Dr William Stohl, Division of Rheumatology, Los Angeles County & University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA;
Contributors WS contributed to the implementation of the trial and is the trial guarantor. JG-R contributed to the implementation of the trial and analysed the data. EO, JD and RMF contributed to the implementation of the trial. CZ contributed to the implementation of the trial and monitored the data collection. AA contributed to the implementation of the trial and to the statistical analysis plan, monitored the data collection, and revised and analysed the data. SG contributed to implementation of the trial and to the statistical analysis plan. RB monitored data collection and revised and analysed the data. JG analysed the data. SF wrote the statistical analysis plan and analysed the data. WD designed the study, designed data collection tools, contributed to implementation of the trial, monitored the data collection, analysed the data and contributed to the statistical analysis plan. All authors contributed to the development of the manuscript and read and approved the final version.
- Received 1 September 2011
- Accepted 11 December 2011
- Published Online First 2 February 2012
Objective To determine the efficacy and safety of ocrelizumab (OCR) with methotrexate (MTX) in MTX-naive rheumatoid arthritis (RA) patients.
Methods In a randomised, double-blind, controlled trial, patients received placebo+MTX (MTX; n=210), OCR 200 mg×2+MTX (OCR 200; n=200) or OCR 500 mg×2+MTX (OCR 500; n=203). OCR/placebo (two intravenous infusions) was given on days 1 and 15, with fixed re-treatment scheduled at weeks 24/26, 52/54 and 76/78. Due to early termination of OCR dosing, there was no formal primary end point analysis (change from baseline in modified total Sharp score (ΔmTSS) at week 104). Analyses are reported for week 52 outcomes.
Results At week 52, treatment with OCR+MTX compared with MTX alone reduced progression of joint damage (mean (SD) change in ΔmTSS: OCR 200, 0.66 (4.51); OCR 500, 0.27 (2.91); MTX alone, 1.59 (4.82); p=0.001 and p=0.003, respectively vs MTX alone) and improved clinical signs and symptoms (American College of Rheumatology 20 response: OCR 200, 73.0%; OCR 500, 71.0%; MTX alone, 57.5%; p<0.005 for each OCR vs MTX alone). Serious infection rates per 100 patient-years were similar with OCR 200 and MTX alone (2.6 (95% CI 0.9 to 6.1) and 3.0 (1.1 to 6.5), respectively), but higher with OCR 500 (7.1 (3.9 to 11.9)).
Conclusions OCR 200 mg and 500 mg with MTX in MTX-naive patients with RA were effective in inhibiting joint damage progression and improving RA signs and symptoms. OCR 500 mg with MTX was associated with an increased rate of serious infections.
Funding F Hoffmann-La Roche and NIH grant M01-RR-00043 to the General Clinical Research Center at the University of Southern California Keck School of Medicine.
Competing interests WS has received research grants from Xencor and is a site investigator for clinical trials in RA and systemic lupus erythematosus sponsored by Genentech/Roche, Pfizer and Human Genome Sciences. JG-R has served on advisory boards for Roche, and has received consultancy fees, grants and payment for lectures from Roche. EO has received grants, consultancy fees and payments for lectures from Genentech, and consultancy fees and grants from Roche. JD has served on advisory boards for Roche Switzerland, Merck Sharp Dohme Switzerland, Pfizer Switzerland, Amgen Switzerland, UCB Switzerland, Abbott Switzerland and Novartis Switzerland, has received consultancy fees from Roche Switzerland, Merck Sharp Dohme Switzerland and UCB Switzerland, has received payment for lectures from Roche, Pfizer, Merck Sharp Dohme, Abbott and UCB, has received payment for manuscript preparation from Roche Switzerland and Merck Sharp Dohme Switzerland, and has received travel/accommodation/meeting expenses from Roche Switzerland, Merck Sharp Dohme Switzerland, Bristol Myers Squibb Switzerland and Pfizer Switzerland. RMF has received research grants from Genentech and Roche. CZ has received consultancy fees and grants from Sanofi, Servier and Pfizer, and research grants from Lilly, Amgen, Roche and Merck. AA was an employee of Genentech and held Genentech stock options during the conduct of the study and manuscript preparation. SG is an employee of Genentech, owns Roche stock and holds Roche stock options. RB and JG are employees of Roche. SF is an employee of Genentech. WD is an employee of Genentech, owns Roche stock and holds Roche stock options.
Patient consent Obtained.
Ethics approval Ethical approval was obtained from the local institutional review board at each study centre.
Provenance and peer review Not commissioned; externally peer reviewed.
This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl