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

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.

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.

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.

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.