The CombiRx Trial: A Multi-Center, Double-Blind, Randomized Study Comparing the Combined Use of Interferon Beta-1a and Glatiramer Acetate to Either Agent Alone in Participants with Relapsing-Remitting Multiple Sclerosis - Clinical Outcomes (PL02.003)

Abstract

Objective: To determine if combined use of interferon beta-1a (IFN) 30ug weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either alone in relapsing remitting multiple sclerosis (RRMS). Background This double-blind, multi-center, randomized RRMS clinical trial compared IFN plus GA versus single agent arms with matching placebo. Entry criteria included: EDSS ≤ 5.5, RRMS, age 18-60, ≥2 relapses in prior 3 years and no prior use of either medication. Design/Methods: 1,008 participants were randomized and underwent quarterly clinical assessments until the last subject enrolled completes 3 years in January 2012. Magnetic resonance imaging (MRI) was done at baseline and 6, 12, 24 and 36 months. The primary MRI variable was change in the Z4 composite MRI score (unweighted sum of the individual Z scores for enhanced tissue, T2-hyperintense and T1-hypointense lesion volumes, and normalized CSF - an inverse measure of atrophy) from baseline to 36 months by treatment cohort using general linear models. Assuming differences between groups on the Z4 composite, selected additional measures will be formally addressed as follows: cumulative sum of the number of enhanced and unique active lesions, differences in the cubed root of the T2 and T1 lesion volumes, and differences in brain atrophy analyzed over the 36 months on intent to treat basis. Results: Recruitment occurred from January 2005-April 2009. At baseline 39.7% of participants had enhancements, a median total T2 lesion volume of 7.48 ml (T1-hypointense component 0.84 ml), and mean Z4 composite = 0. On study MRI data will be provided, with clinical outcome data presented separately. Conclusions: CombiRx was a uniquely sponsored collaboration between NIH, academic institutions, practicing neurologists and pharma/biotech; the largest test thus far of the potential for combining immunotherapies in early RRMS. It provides the longest controlled clinical, MRI and biomarker dataset of any MS trial. Supported by: NIH/NINDS (5U01NS045719). Disclosure: Dr. Wolinsky has received personal compensation for activities with Astellas, Bayer Pharmaceuticals Corporation, Bayer Multiple Sclerosis Council, Celgene Corporation, Eli Lilly & Company, Roche Diagnostics Corporation, Novartis, Sanofi-Aventis Pharmaceuticals and Teva Neuroscience as consultant and participant on monitoring and advisory boards. Dr. Wolinsky has received (royalty or license fee or contractual rights) payments from University of Texas Health Science Center at Houston. Dr. Wolinsky has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Narayana has received personal compensation for activities with Teva Neuroscience. Dr. Nelson has received personal compensation for activities with Bayer HealthCare, Biogen Idec, EMD Serono, National MS Society, MS Association of America, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, and the University of Massachusetts Medical School. Dr. Nelson has received research support from Novartis and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Datta has nothing to disclose. Dr. Cofield has received personal compensation for activities with GlaxoSmithKline, Inc., Teva Neuroscience, Orthotech Biotech, the Department of Defense, and the American Academy for Orthopedic Surgery. Dr. Cutter has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Cleveland Clinic, Daiichi Pharmaceutical Corporation, GlaxoSmithKline, Inc., Genmab Biopharmaceuticals, Eli Lilly & Company, Medivation, Modigenetech, Ono Pharmaceutical, PTC Therapeutics, Teva Neuroscience, Vivus, University of Pennsylvania, NHLBI, NINDS, NMSS, Alexion, Bayhill Therapeutics, Bayer Pharmaceuticals Corporation, Celgene, Novartis, Consortium of MS Centers, Genzyme Corporation, Klein-Buendel Incorporated, Nuron Biotech, Peptimmune, Somnus Pharmaceuticals, Sandoz, University of Texas Southwestern and Visioneering Technologies, Inc. Dr. Cutter has received compensation for serving on the board of Pythagoras, INC. Dr. Cutter has received research support from various pharmaceutical corporations. Dr. Conwit has nothing to disclose. Dr. Gustafson has nothing to disclose. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases.