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Paul H. Gordon, MD; Philippe Corcia, MD, PhD; Lucette Lacomblez, MD; Ksenia Pochigaeva, MD; Jean-Louis Abitbol, MD; Merit Cudkowicz, MD; P. Nigel Leigh, FMedSci; Vincent Meininger, MD, PhD

Arch Neurol. 2009;66(6):758-761.

Objectives  To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis.

Design and Setting  We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with ² and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points.

Patients  In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline.

Main Outcome Measures  Death or combined death, tracheostomy, or permanent assisted ventilation.

Results  Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P = .001) of patients for tracheostomy and 11.1% to 23.1% (P = .05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P = .02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone.

Conclusions  Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.

Author Affiliations: Department of Neurology, Columbia University, New York, New York (Dr Gordon); Fédération des Maladies du Système Nerveux (Drs Gordon, Corcia, Lacomblez, Pochigaeva, and Meininger) and Department of Pharmacology (Dr Lacomblez), Assistance Publique–Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France; Center SLA, Department of Neurology, CHRU, Tours, France (Dr Corcia); Trophos S. A., Marseille, France (Dr Abitbol); Department of Neurology, Harvard Medical School, Boston, Massachusetts (Dr Cudkowicz); and Department of Clinical Neuroscience, King's College London, and Medical Research Centre for Neurodegeneration Research, Institute of Psychiatry, London, England (Dr Leigh).

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