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A clinical trial of creatine in ALS

From the Department of Neurology (Dr. Shefner, T. Conrad, J. Taft, and M. Chilton), Upstate Medical University, Syracuse, NY; Department of Neurology (Dr. Cudkowicz, L. Urbinelli, and M. Qureshi) and Biostatistics Center (Dr. Schoenfeld and H. Zhang), Massachusetts General Hospital, Boston; Department of Neurology (Dr. Pestronk), Washington University, St. Louis, MO; Department of Neurology (Drs. Caress and Donofrio), Wake Forest University, Winston-Salem, NC; Department of Neurology (Dr. Sorenson), Mayo Clinic, Rochester, MN; Department of Neurology (Dr. Bradley), University of Miami, FL; Department of Neurology (Dr. Lomen-Hoerth), University of California at San Francisco; Department of Neurology (Dr. Pioro), Cleveland Clinic, OH; Department of Neurology (Dr. Rezania), University of Chicago, IL; Department of Neurology (Dr. Ross), University of Kentucky, Lexington; Department of Neurology (Dr. Pascuzzi), University of Indiana, Bloomington; Department of Neurology (Dr. Heiman-Patterson), MCP-Hahnemann, Philadelphia, PA; Department of Neurology (Dr. Tandan), University of Vermont, Burlington; Department of Neurology (Dr. Mitsumoto), Columbia University, New York, NY; Department of Neurology (Dr. Rothstein), Johns Hopkins University, Baltimore, MD; and Department of Chemistry (Drs. Smith-Palmer and Burke, and D. MacDonald), St. Francis Xavier University, Antigonish, Nova Scotia.

Address correspondence and reprint requests to Dr. Jeremy M. Shefner, Department of Neurology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13104; e-mail: shefnerj{at}upstate.edu

Background: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons.

Methods: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale–Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly.

Results: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials.

Conclusion: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Received February 9, 2004. Accepted in final form June 23, 2004.

*Members of the NEALS Consortium are listed in the Appendix on page 1660.

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