A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis

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, GERP ALS Study Group, Nadja Borisow, Theresa Holm, Andre Maier, Thomas Meyer, Paula Budde, Torsten Grehl, Anne-Katrin Guettsches, Malte Bewersdorff, Michael Heneka, Andreas Hermann, Alexander Storch, Tobias Frank, Bettina Göricke, Jochen Weishaupt, Katharina Eger, Frank Hanisch, Stephan Zierz, Anna-Lena Cordes, Reinhard Dengler, Sonja Koerner, Katja Kollewe, Susanne Petri, Julian Grosskreutz, Albrecht Kunze, Tino Prell, Thomas Ringer, Jan Zinke, Johanna Anneser, Gian Domenico Borasio, Christine Chahli, Andrea S Winkler, Matthias Boentert, Bianca Stubbe-Draeger, Peter Young, Ulrich Bogdahn, Steffen Franz, Verena Haringer, Norbert Weidner, Reiner Benecke, Stefanie Meister, Johannes Prudlo, Matthias Wittstock, Johannes Dorst, Corinna Hendrich, Albert C Ludolph, Anne-Dorte Sperfeld, Ulrike Weiland, Sabine Neidhardt, Berthold Schrank, Marcus Beck, Peter Kraft, Klaus Toyka, Jochen Ulzheimer, Carsten Wessig, 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, GERP ALS Study Group, Nadja Borisow, Theresa Holm, Andre Maier, Thomas Meyer, Paula Budde, Torsten Grehl, Anne-Katrin Guettsches, Malte Bewersdorff, Michael Heneka, Andreas Hermann, Alexander Storch, Tobias Frank, Bettina Göricke, Jochen Weishaupt, Katharina Eger, Frank Hanisch, Stephan Zierz, Anna-Lena Cordes, Reinhard Dengler, Sonja Koerner, Katja Kollewe, Susanne Petri, Julian Grosskreutz, Albrecht Kunze, Tino Prell, Thomas Ringer, Jan Zinke, Johanna Anneser, Gian Domenico Borasio, Christine Chahli, Andrea S Winkler, Matthias Boentert, Bianca Stubbe-Draeger, Peter Young, Ulrich Bogdahn, Steffen Franz, Verena Haringer, Norbert Weidner, Reiner Benecke, Stefanie Meister, Johannes Prudlo, Matthias Wittstock, Johannes Dorst, Corinna Hendrich, Albert C Ludolph, Anne-Dorte Sperfeld, Ulrike Weiland, Sabine Neidhardt, Berthold Schrank, Marcus Beck, Peter Kraft, Klaus Toyka, Jochen Ulzheimer, Carsten Wessig

Abstract

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.

Conflict of interest statement

Competing Interests: Takeda Pharma GmbH partly funded this study. The trial used Pioglitazone which is a Takeda product. There are no other patents, products in development or marketed products to disclose. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Study flow chart.
Figure 1. Study flow chart.
The figure presents the numbers of participants who were randomly assigned, received pioglitazone or placebo, and were analysed for the primary outcome.
Figure 2. Survival upon pioglitazone.
Figure 2. Survival upon pioglitazone.
Kaplan-Meier plot for survival, the primary endpoint of the trial. Placebo-treated patients are in blue and pioglitazone treated patients are in red. Ticks represent censored patients. The shaded box indicates the first month of treatment during which a stepwise increase in pioglitazone dosage was performed. Numbers below the X axis indicate the number of patients still alive (“at risk”, i.e. living and not censored) at entry, 6, 12 and 18 months after randomization.
Figure 3. ALS-FRS upon pioglitazone.
Figure 3. ALS-FRS upon pioglitazone.
Total changes in ALS-FRS-R score after initiation of the treatment. Placebo-treated patients are in blue and pioglitazone treated patients are in red. The table below indicates the number of patients (n) per time point. Error bars are standard errors.

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