All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials.
BACKGROUND
FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials.


OBJECTIVE
To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF.


METHODS
The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design.


RESULTS
A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients.


CONCLUSIONS
The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.
1 University of California, San Francisco, California.
Talmadge E
TE
King
Carlo
C
Albera
Williamson Z
WZ
Bradford
Ulrich
U
Costabel
Roland M
RM
du Bois
Jonathan A
JA
Leff
Steven D
SD
Nathan
Steven A
SA
Sahn
Dominique
D
Valeyre
Paul W
PW
Noble
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002423:Cause of Death; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000401:mortality*; D007371:Interferon-gamma / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011728:Pyridones / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012107:Research Design; D018401:Sample Size; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; D011994:Recombinant Proteins; C554125:interferon gamma-1b; D007371:Interferon-gamma; C093844:pirfenidone