RAPID COMMUNICATION Phase III Dose-Comparison Study of Glatiramer Acetate for Multiple Sclerosis Giancarlo Comi, MD, 1 Jeffrey A. Cohen, MD, 2 Douglas L. Arnold, MD, 3 Daniel Wynn, MD, 4 and Massimo Filippi, MD 5 for the FORTE Study Group Objective: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40mg compared to a 20mg dose. Methods: Patients with multiple sclerosis (MS) with 1 documented relapse in 12 months prior to screening, or 2 documented relapses in 24 months prior to screening, and Expanded Disability Status Scale (EDSS) score 0 to 5.5 were enrolled. Patients were evaluated at screening, baseline, and at months 1, 2, 3, 6, 9, and 12. Primary endpoint was rate of confirmed relapses observed during 12-month study. Analysis was by intent-to-treat. Results: A total of 1,155 patients randomized to GA 20mg (n ¼ 586) or 40mg (n ¼ 569). The groups were well- matched at baseline on demographic, clinical, and magnetic resonance imaging (MRI) characteristics. The primary endpoint was similar in both groups (relative risk [RR] ¼ 1.07; 95% confidence interval [CI], 0.88–1.31; p ¼ 0.486) with mean annualized relapse rates (ARRs) of 0.33 for the 20mg group, 0.35 for the 40mg group, and 0.27 for patients from both groups who completed the entire 1-year treatment. A total of 77% of patients remained relapse- free in both groups. Both groups showed a reduction in mean number of gadolinium-enhancing and new T2 lesions over time with trend for faster reduction in the first trimester with the 40mg dose compared with 20mg dose. Both doses were well-tolerated with a safety profile similar to that observed in previous studies of 20mg GA. Interpretation: In relapsing-remitting MS patients, both the currently-approved GA 20mg and 40mg doses were safe and well-tolerated, with no gain in efficacy for the higher dose. ANN NEUROL 2011;69:75–82 G latiramer acetate (GA) is 1 of 7 disease modifying agents currently-approved to treat relapsing-remit- ting multiple sclerosis (RRMS). In 3 double-blind pla- cebo-controlled trials, subcutaneous (sc) GA at a once- daily 20mg dose significantly reduced relapse frequency, magnetic resonance imaging (MRI) disease activity, and burden. 1–3 Additionally, it has been shown that GA 20mg is able to significantly reduce the rate of developing clini- cally definite multiple sclerosis (MS) and MRI activity in patients with a first demyelinating event suggestive of the disease. 4 The efficacy of GA in MS is thought to result from induction of immune tolerance; ie, reduced T cell proliferation and a shift to a T helper 2 (Th2) cytokine profile. 5 Reaching immune tolerance could depend on the dose and the frequency of administration of the mixture of polypeptides of GA, suggesting that higher doses of GA may be more efficacious in influencing disease course. Studies of GA administered by sc injection in RRMS used a 20mg daily dose, the currently-approved regimen. Small early studies provided little data regarding doses other than 20mg daily. 6 A phase II dose-comparative study suggested 40mg given sc once daily was well tolerated and showed a trend for an increased effect on clinical and MRI activity in RRMS compared to the marketed dose. 7 Based on these initial results, a double-blind, placebo-controlled trial was undertaken to determine whether a dose of 40mg is more effective than the currently available dose of 20mg in reducing relapse rate, MRI activity, and the accumula- tion of white matter lesion burden in patients with RRMS. Patients and Methods Patients Enrollment started in September 2006 and was completed in May 2007. Key inclusion criteria included: (1) age 18–55 years View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22316 Received Jul 20, 2010, and in revised form Oct 19, 2010. Accepted for publication Oct 22, 2010. Address correspondence to Dr Comi, Institute of Experimental Neurology, Department of Neurology, University Vita-Salute, Scientific Institute SanRaffaele, Via Olgettina 48, 20132 Milan, Italy. E-mail: g.comi@hsr.it From the 1 Institute of Experimental Neurology, Department of Neurology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy; 2 Mellen Center U-10, Cleveland Clinic Foundation, Cleveland, OH; 3 McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Canada; 4 Consultants in Neurology Multiple Sclerosis Center, Consultants in Neurology, Ltd, Northbrook, IL; 5 Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, Milan, Italy. V C 2011 American Neurological Association 75