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Neurology 2003;61:456-464
© 2003 American Academy of Neurology

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis

M.E. Cudkowicz, MD MSc, J.M. Shefner, MD PhD, D.A. Schoenfeld, PhD, R.H. Brown Jr., DPhil MD, H. Johnson, BS MPH, M. Qureshi, MD MPH, M. Jacobs, MPH, J.D. Rothstein, MD PhD, S.H. Appel, MD, R.M. Pascuzzi, MD, T.D. Heiman-Patterson, MD, P.D. Donofrio, MD, W.S. David, MD PhD, J.A. Russell, DO, R. Tandan, MD FRCP, E.P. Pioro, MD PhD, K.J. Felice, DO, J. Rosenfeld, MD PhD, R.N. Mandler, MD, G.M. Sachs, MD, W.G. Bradley, DM FRCP, E.M. Raynor, MD, G.D. Baquis, MD, J.M. Belsh, MD, S. Novella, MS, J. Goldstein, MD and J. Hulihan, MD for the Northeast ALS Consortium*

From the Neurology Clinical Trials Unit (Drs. Cudkowicz and Qureshi, H. Johnson), Department of Neurology (Drs. Cudkowicz, Brown, and Qureshi, H. Johnson), Biostatistic Center Department of Medicine (Dr. Schoenfeld, M. Jacobs), Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Neurology (Dr. Shefner), Upstate Medical University, Syracuse, NY; Department of Neurology (Dr. Rothstein), Johns Hopkins University, Baltimore, MD; Department of Neurology (Dr. Appel), Baylor College of Medicine, Houston, TX; Department of Neurology (Dr. Pascuzzi), Indiana University, Indianapolis, IN; Department of Neurology (Dr. Heiman-Patterson), MCP Hahnemann, Philadelphia, PA; Department of Neurology (Dr. Donofrio), Wake Forest University School of Medicine, Winston-Salem, NC; Department of Neurology (Dr. David), Hennepin County Medical Center, Minneapolis, MN; Department of Neurology (Dr. Russell), Lahey Clinic Medical Center, Burlington, MA; Department of Neurology (Dr. Tandan), University of Vermont College of Medicine, Burlington, VT; Department of Neurology (Dr. Pioro), Cleveland Clinic Foundation, Cleveland, OH; Department of Neurology (Dr. Felice), University of Connecticut Health Center, Farmington, CT; Department of Neurology (Dr. Rosenfeld), The Carolinas Medical System, Charlotte, NC; Department of Neurology (Dr. Mandler), George Washington University Hospital, Washington, DC; Department of Neurology (Dr. Sachs), Rhode Island Hospital, Providence, RI; Department of Neurology (Dr. Bradley), University of Miami School of Medicine, Miami, FL; Department of Neurology (Dr. Raynor), Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology (Dr. Baquis), Baystate Medical Center, Springfield, MA; Department of Neurology (Dr. Belsh), Robert Wood Johnson Medical School, New Brunswick, NJ; Department of Neurology (Dr. Goldstein, S. Novella), Yale University School of Medicine, New Haven, CT; and Ortho-McNeil Pharmaceutical, Inc. (Dr. Hulihan), Raritan, NJ.

Address correspondence and reprint requests to Dr. Merit Cudkowicz, Neurology Clinical Trials Unit, Massachusetts General Hospital, 15 Parkman Street, WACC 836, Boston, MA 02114; e-mail: mcudkowicz{at}partners.org

Objective: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.

Methods: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.

Results: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).

Conclusions: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.




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