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

Abstract

BackgroundPioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).Methods/Principal FindingsWe 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/SignificancePioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.Trial RegistrationClinicaltrials.gov NCT00690118.

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

“…Although PPAR gamma expression is high in AD, PPAR gamma agonists have been used in AD humans and various AD animal models and have been shown to induce beneficial effects, partly due to their anti-inflammatory effects [61][62][63][64][65][66][67]. Even if the PPAR gamma agonist pioglitazone, in combination with riluzole, does not increase survival in ALS patients [54], PPAR gamma represents a useful therapeutic target in several animal models. Inhibition of the Wnt/betacatenin pathway might also represent a therapeutic approach in ALS animal model.…”

“…There is also preservation of the median fiber diameter of the quadriceps muscle, indicating a morphological and functional protection of motor neurons induced by pioglitazone. However, in a phase II double-blind controlled clinical trial, the PPAR gamma agonist pioglitazone in combination with riluzole does not increase survival in ALS patients [54].…”

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

“…The anti-diabetic drug pioglitazone improved motor performance, delayed weight loss, attenuated motor neuron loss, and extended survival in a SOD 1 mouse model [158]; however, pioglitazone failed to show efficacy in a phase II clinical trial of ALS patients [159]. Furthermore, it has been suggested that anti-diabetic drugs are detrimental in ALS in light of emerging evidence that some features of the metabolic syndrome may be protective in ALS [160].…”

The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis

“…Among the drugs mentioned that have been evaluated in pre-clinical models, celecoxib and pioglitazone were both assessed in a randomized, double-blind, placebo-controlled trial, but gave disappointing results as there were no effects on motor function and survival rate [240,241]. When minocycline was tested in a randomized placebo-controlled phase III trial, it not only did not show any benefits, it in fact displayed serious harmful effect in patients [242].…”