Chest
Volume 146, Issue 5, November 2014, Pages 1256-1262
Journal home page for Chest

Original Research Diffuse Lung Disease
Study Design Implications of Death and Hospitalization as End Points in Idiopathic Pulmonary Fibrosis

https://doi.org/10.1378/chest.14-0492Get rights and content

BACKGROUND

The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point.

METHODS

Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts.

RESULTS

Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio.

CONCLUSIONS

Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization.

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

References (18)

  • TE King et al.

    INSPIRE Study Group. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial

    Lancet

    (2009)
  • PW Noble et al.

    CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials

    Lancet

    (2011)
  • G Raghu et al.

    ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management

    Am J Respir Crit Care Med

    (2011)
  • G Raghu et al.

    Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials

    Am J Respir Crit Care Med

    (2012)
  • RM du Bois et al.

    Idiopathic pulmonary fibrosis: lung function is a clinically meaningful endpoint for phase III trials

    Am J Respir Crit Care Med

    (2012)
  • AU Wells et al.

    European IPF Consensus Group. Hot of the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good

    Thorax

    (2012)
  • TE King et al.

    All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials

    Amer J Respir Crit Care Med

    (2014)
  • JA Bjoraker et al.

    Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (1998)
  • AG Nicholson et al.

    The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis

    Am J Respir Crit Care Med

    (2000)
There are more references available in the full text version of this article.

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 Medicine
    Citation 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, Chest
    Citation 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 Today
    Citation 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 Medicine
    Citation 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.

View all citing articles on Scopus

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)].

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

originally published Online First August 21, 2014.

View full text