Decline in forced vital capacity as a surrogate for mortality in patients with pulmonary fibrosis

Author:

Maher Toby M.12ORCID,Stowasser Susanne3,Voss Florian4,Bendstrup Elisabeth5ORCID,Kreuter Michael6,Martinez Fernando J.7,Sime Patricia J.8,Stock Christian4

Affiliation:

1. Keck School of Medicine University of Southern California Los Angeles California USA

2. Imperial College London London UK

3. Boehringer Ingelheim International GmbH Ingelheim am Rhein Germany

4. Boehringer Ingelheim Pharma GmbH & Co. KG Ingelheim am Rhein Germany

5. Centre for Rare Lung Diseases, Department of Respiratory Diseases and Allergy and Department of Clinical Medicine Aarhus University Hospital Aarhus Denmark

6. Center for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Care Medicine, Thoraxklinik University of Heidelberg, Member of the German Center for Lung Research Heidelberg Germany

7. Weill Cornell Medicine New York New York USA

8. Department of Internal Medicine Virginia Commonwealth University Richmond Virginia USA

Abstract

AbstractBackground and ObjectiveSurrogate endpoints enable determination of meaningful treatment effects more efficiently than applying the endpoint of ultimate interest. We used data from trials of nintedanib in subjects with pulmonary fibrosis to assess decline in forced vital capacity (FVC) as a surrogate for mortality.MethodsData from the nintedanib and placebo groups of trials in subjects with idiopathic pulmonary fibrosis, other forms of progressive pulmonary fibrosis, and pulmonary fibrosis due to systemic sclerosis (NCT00514683, NCT01335464, NCT01335477, NCT01979952, NCT02999178, NCT02597933) were pooled. Using joint models for longitudinal and time‐to‐event data, we assessed the association between decline in FVC % predicted and time to death over 52 weeks. The rate of change in FVC % predicted and the current value of FVC % predicted were modelled longitudinally and estimates applied as predictors in time‐to‐event models.ResultsAmong 2583 subjects with pulmonary fibrosis, both a greater rate of decline in FVC % predicted and a lower current value of FVC % predicted were associated with an increased risk of death over 52 weeks (HR 1.79 [95% CI: 1.57, 2.03] and HR 1.24 [1.17, 1.32] per 5‐percentage point decrease, respectively). Associations between the rate of change in FVC % predicted and the risk of death were consistent between patients with IPF and other ILDs.ConclusionData from clinical trials in subjects with pulmonary fibrosis of diverse aetiology demonstrate a strong association between decline in FVC % predicted and mortality over 52 weeks, supporting FVC decline as a surrogate for mortality in these patients.

Funder

Boehringer Ingelheim

Publisher

Wiley

Subject

Pulmonary and Respiratory Medicine

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