A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.
BACKGROUND
Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).


RESULTS
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.


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


BACKGROUND
Clinicaltrials.gov NCT00690118.
Department of Neurology, University of Ulm, Ulm, Germany.
Luc
L
Dupuis
Reinhard
R
Dengler
Michael T
MT
Heneka
Thomas
T
Meyer
Stephan
S
Zierz
Jan
J
Kassubek
Wilhelm
W
Fischer
Franziska
F
Steiner
Eva
E
Lindauer
Markus
M
Otto
Jens
J
Dreyhaupt
Torsten
T
Grehl
Andreas
A
Hermann
Andrea S
AS
Winkler
Ulrich
U
Bogdahn
Reiner
R
Benecke
Bertold
B
Schrank
Carsten
C
Wessig
Julian
J
Grosskreutz
Albert C
AC
Ludolph
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000401:mortality; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008875:Middle Aged; D000077205:Pioglitazone; D019782:Riluzole / Q000008:administration & dosage*; D015996:Survival Rate; D045162:Thiazolidinediones / Q000008:administration & dosage*
D000927:Anticonvulsants; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D019782:Riluzole; D000077205:Pioglitazone