A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis

by Luc Dupuis, Reinhard Dengler, Michael T. Heneka, Thomas Meyer, Stephan Zierz, Jan Kassubek, Wilhelm Fischer, Franziska Steiner, Eva Lindauer, Markus Otto, Jens Dreyhaupt, Torsten Grehl, Andreas Hermann, Andrea S. Winkler, Ulrich Bogdahn, Reiner Benecke, Bertold Schrank, Carsten Wessig, Julian Grosskreutz, Albert C. Ludolph, the GERP ALS Study Group

Background

Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).

Methods/Principal Findings

We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71–2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated.

Conclusion/Significance

Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.

Trial Registration

Clinicaltrials.gov NCT00690118.

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