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From Fédération des maladies du système nerveux (V.M., L.L.) and Department of Pharmacology (L.L.), AP-HP, Hôpital de la Salpétrière, Paris, France; Department of Biostatistics, Institut Curie, Paris, France (B.A., L.L.); ExonHit Therapeutics, Paris, France (P.G., L.L.); Department of Clinical Neuroscience, Institute of Psychiatry, King’s College, London, United Kingdom (P.N.L., L.L.); Department of Neurology, University of Ulm, Germany (A.L., L.L.); and Department of Neurology, University of Leuven, Belgium (W.R.).
Address correspondence and reprint requests to Dr. Vincent Meininger, Fédération des maladies du système nerveux, Pavillon Paul Castaigne, Hôpital de la Salpétrière, 47, boulevard de l’Hôpital, 75013 Paris, France; e-mail: vincent.meininger{at}psl.aphp.fr
Objective: To assess the efficacy and safety of pentoxifylline, a US Food and Drug Administration–approved drug, in patients with ALS treated with riluzole.
Methods: The authors conducted a double-blind, randomized, placebo-controlled, multicenter trial. Four hundred patients with probable or definite ALS and vital capacity less than 100% were randomly assigned to treatment with placebo or 1.2 g pentoxifylline daily. The primary outcome was death. Secondary outcomes were rates of deterioration of ALS Functional Rating Scale–Respiratory and muscle strength. The primary intention-to-treat analysis was the survival comparison of drug vs placebo, assessed before (log-rank test) and after adjustment (Cox model) for predefined prognostic factors.
Results: At the end of the study, after 547 days of follow-up, 103 patients (51.7%) in the pentoxifylline group and 120 (59.7%) in the placebo group were alive (unadjusted risk 1.28, p = 0.107; adjusted risk 1.43, p = 0.02). In contrast, analysis of secondary outcome functional variables did not show the same negative effect of the drug. The most common adverse reactions were nausea, dysphagia, and flushing, all reversible after stopping the drug.
Conclusions: Pentoxifylline is not beneficial in ALS and should be avoided in patients treated with riluzole. The discrepancy between survival and measures of functional changes urges caution in equating these end points in phase III trials, and suggests that both survival and function should be used in phase III trials.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the January 10 issue to find the title link for this article.
*See the Appendix for a list of Group members.
Disclosure: ExonHit Pharma funded the study and participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. P.G. is an employee of ExonHit Pharma.
Received May 16, 2005. Accepted in final form October 4, 2005.
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