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


METHODS
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 chi(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.


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


METHODS
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.
Gordon
Paul H
PH
Department of Neurology, Columbia University, New York, New York, USA. paul.gordon@psl.aphp.fr
Corcia
Philippe
P
Lacomblez
Lucette
L
Pochigaeva
Ksenia
K
Abitbol
Jean-Louis
JL
Cudkowicz
Merit
M
Leigh
P Nigel
PN
Meininger
Vincent
V
D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000188:drug therapy / Q000401:mortality*; D002986:Clinical Trials as Topic / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects; D017063:Outcome Assessment, Health Care / Q000379:methods*; D010431:Pentoxifylline / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D012121:Respiration, Artificial / Q000401:mortality / Q000706:statistics & numerical data; D012133:Respiratory Paralysis / Q000188:drug therapy / Q000209:etiology / Q000401:mortality*; D014139:Tracheostomy / Q000401:mortality / Q000706:statistics & numerical data; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects
D009281:Naphthalenes; D011725:Pyridines; D014665:Vasodilator Agents; D010431:Pentoxifylline; C462299:xaliproden