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From California Pacific Medical Center (R.M.), San Francisco; University of Miami School of Medicine (W.B.), Miami, FL; Novartis Pharmaceuticals (J.H., D.S., E.V.), East Hanover, NJ; Hôpital Pitié-Salpêtrière-Fédération de Neurologie (V.M.), Paris, France; Columbia University (H.M.), New York, NY; California Pacific Medical Center Research Institute (D.M.), San Francisco; Novartis Pharmaceuticals (H.P.), Switzerland; University of Milan Medical School (V.S.), Milan, Italy; London Health Sciences Centre (M. Strong), London, Ontario, Canada; and The Royal London Hospital (M. Swash), London, UK.
Address correspondence and reprint requests to Dr. Robert G. Miller, California Pacific Medical Center, 2324 Sacramento Street, #111, San Francisco, CA 94115 millerrx{at}sutterhealth.org
Background: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS.
Methods: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT).
Results: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT).
Conclusion: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.
Editorial, see page 719
*The TCH346 Study Group members are listed in the appendix.
Disclosure: Ellen Vernotica, Jean Hubble, Harald Pohlmann, and Dirk Sauer are current employees of the sponsor, but only Dirk Sauer and Harald Pohlmann have equity and stock interests; Robert Miller and Merit Cudkowicz received honorarium less than $10,000 from the study sponsor. No other authors have any type of financial interest.
Received July 4, 2006. Accepted in final form March 22, 2007.
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  N. Y. Harel, E. J. Sorenson, R .G. Miller, W .G. Bradley, M . Cudkowicz, V . Meininger, H . Mitsumoto, D .H. Moore, V . Silani, M . Strong, et al. WHAT IS NEXT IN ALS CLINICAL TRIALS? Neurology, April 15, 2008; 70(16): 1365 - 1366. [Full Text] [PDF]
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A. Hoke, E. J. Sorenson, R .G. Miller, W .G. Bradley, M . Cudkowicz, V . Meininger, H . Mitsumoto, D .H. Moore, V . Silani, M . Strong, et al. WHAT IS NEXT IN ALS CLINICAL TRIALS? Neurology, April 15, 2008; 70(16): 1366 - 1367. [Full Text] [PDF]
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E. J. Sorenson What is next in ALS clinical trials? Neurology, August 21, 2007; 69(8): 719 - 720. [Full Text] [PDF]
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