Chest
Original Research Diffuse Lung DiseaseStudy Design Implications of Death and Hospitalization as End Points in Idiopathic Pulmonary Fibrosis
Section snippets
Cohort Description and Enrichment Strategies
The study cohort comprised patients enrolled in the following IPFnet clinical trials: STEP-IPF (Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis), ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis), and PANTHER-IPF (Prednisone, Azathioprine, and N-acetylcysteine: a Study That Evaluates Response in Idiopathic Pulmonary Fibrosis).15, 16, 17Patients randomized to warfarin in ACE-IPF or the three-drug regimen (prednisone, azathioprine, acetylcysteine) in
Cohort Description
The study cohort comprised 517 patients enrolled in the IPFnet clinical trials (Table 1). These patients were older, primarily men, and primarily former smokers. Patients with GAP stage 1 comprised 26.3% of the cohort; GAP stage 2, 43.9%; and GAP stage 3, 29.8%. Twenty-seven deaths and 77 hospitalizations were observed in the study cohort over a total follow-up time of 22,135 weeks.
Estimated Rates of Death and Death Plus Hospitalization
Estimated rates of death and death plus hospitalization from IPFnet data by individual and combined GAP stages at
Discussion
The results demonstrate that study design decisions, particularly those regarding cohort enrichment strategies, have a substantial impact on the sample size requirements for IPF clinical trials using clinical end points. A clinical trial with death plus hospitalization as the primary end point in patients at low risk of death (ie, GAP stage 1) would require approximately five times the number of subjects as the same trial in patients with IPF and a high risk of death (ie, GAP stage 3).
For most
Acknowledgments
Author contributions:H. R. C. and K. J. A. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. H. R. C. and K. J. A. contributed to the study concept and design, and H. R. C., K. K. B., F. J. M., G. R., R. S. R., and K. J. A. contributed to the data acquisition, analysis, and interpretation, revision of the manuscript, and approval of the final version.
Financial/nonfinancial disclosures:The authors have
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Cited by (29)
Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial
2018, The Lancet Respiratory MedicineCitation Excerpt :Future studies of treatment for abnormal GER in IPF should directly address the effect of anti-acid medications on the progression of disease, and the distinct contributions of acid and non-acid GER. The number of clinical events and death in the no surgery group are consistent with what is predicted on the basis of baseline demographics and physiology.27–29 All deaths were preceded by definite or suspected acute exacerbations.
Patients with fibrotic interstitial lung disease hospitalized for acute respiratory worsening: A large cohort analysis
2016, ChestCitation Excerpt :These findings suggest that acute respiratory decline sufficient to require hospitalization contributes to significant morbidity and mortality independent of severity of baseline lung disease or comorbidities. This has significant implication for use of respiratory hospitalization or short-term all-cause mortality as end points in clinical trial design.15,16 Brown and colleagues15 also recognized that hospitalizations occurred frequently in IPF with significant discharge morbidity.
Pharmacological treatment of idiopathic pulmonary fibrosis: An update
2015, Drug Discovery TodayCitation Excerpt :In addition, owing to the availability of two drugs with definite treatment effects (e.g., pirfenidone and nintedanib), it would be unethical to perform a mortality study in patients with mild to moderate disease. Mortality studies might be best suited for patients with end-stage disease, patients who are having an acute exacerbation [27,28], or other subsets of patients who are deemed to be at high risk of disease progression [29]. Change in forced vital capacity (FVC) is considered a marker of disease progression in IPF and is a widely used primary endpoint, given its efficiency, reliability, and regulatory precedent [30].
Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: Analysis of a pooled cohort from three clinical trials
2015, The Lancet Respiratory MedicineCitation Excerpt :This progress has led to discussion about the choice of endpoints used in clinical trials in idiopathic pulmonary fibrosis.4–8 The feasibility of all-cause mortality as a primary endpoint is limited by low event rates in patients with idiopathic pulmonary fibrosis and mild-to-moderate physiological impairment, meaning that large sample sizes or long trial durations would be necessary to measure differences in this outcome.6,9 Therefore, surrogate endpoints with higher event rates need to be identified.
Dr Martinez is currently at Weill Cornell Medical Center (New York, NY).
FUNDING/SUPPORT:This study was supported by National Heart, Lung, and Blood Institute [Grants U10HL080513 (data coordinating center), U10HL80413, U10HL80274, U10HL80370, U10HL80371, U10HL80383, U10HL80411, U10HL80509, U10HL80510, U10HL80543, U10HL80571, and U10HL80685 (clinical centers)].
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originally published Online First August 21, 2014.