Chest
Volume 148, Issue 1, July 2015, Pages 196-201
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Original Research
Diffuse Lung Disease
Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis

https://doi.org/10.1378/chest.14-2817Get rights and content

BACKGROUND

FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF.

METHODS

Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC.

RESULTS

The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis.

CONCLUSIONS

Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF.

TRIAL REGISTRY

ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov

Section snippets

Patients

All study participants who were randomized to treatment with pirfenidone 2,403 mg/d (n = 278) or placebo (n = 277) in the ASCEND study were included in the analyses. Eligibility criteria for the ASCEND study have been previously described.1 Briefly, eligible patients were between the ages of 40 and 80 years with a centrally confirmed diagnosis of IPF at least 6 months prior to randomization. Physiologic eligibility criteria included a baseline percent predicted FVC ≥ 50% and ≤ 90%, percent

Results

A total of 555 patients were included in the analysis. The proportion of patients with missing FVC data at the week 52 study visit is summarized in Table 1. A total of 482 patients (86.6%) completed an FVC assessment at the week 52 study visit (243 [87.4%] in the pirfenidone group and 239 [86.3%] in the placebo group). Fewer patients in the pirfenidone group compared with placebo had a missing value due to death (11 [4.0%] vs 20 [7.2%]), and slightly more patients in the pirfenidone group

Discussion

We found a consistent and statistically persuasive treatment effect of pirfenidone on the change in FVC in patients with IPF in multiple sensitivity analyses using a variety of statistical tests and data imputation methods. In each analysis, the distribution of FVC change from baseline to week 52 in the ASCEND trial was systematically different between the treatment groups and favored treatment with pirfenidone. The strength of the statistical finding was consistent across all analyses and was

Conclusions

In conclusion, our results confirm the robustness of the statistical finding on the primary end point of change from baseline to week 52 in percent predicted FVC in the ASCEND study and corroborate the estimated magnitude of the pirfenidone treatment effect on FVC change in patients with IPF. Additionally, our findings demonstrate the effect of various analytic methods and data imputation strategies on the magnitude of change in FVC, thereby providing benchmarks to facilitate comparisons with

Acknowledgments

Author contributions: D. J. L. is the guarantor of the manuscript and takes responsibility for the integrity of the data and the accuracy of the data analysis. D. J. L., W. Z. B., E. A. F., I. G., M. K. G., D. K., T. E. K., L. H. L., S. D. N., C. A. P., S. A. S., J. J. S., and P. W. N. contributed to the conception and design of the ASCEND study, as well as the acquisition and interpretation of original data, approved the final draft, and vouch for the accuracy of the overall content of the

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    FUNDING/SUPPORT: This study was sponsored by InterMune (Brisbane, CA).

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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