FVC variability in patients with IPF and role of 6-min walk test to predict further change

Steven D. Nathan, Ming Yang, Elizabeth A. Morgenthien, John L. Stauffer
2020 European Respiratory Journal  
Disease progression in idiopathic pulmonary fibrosis (IPF) is monitored by decline in forced vital capacity (FVC) [1] . An absolute or relative decline in % predicted FVC ⩾10% is associated with mortality [2, 3] . Measures of FVC decline were selected as primary endpoints in the pivotal phase 3 trials of antifibrotic therapies [4] [5] [6] . Despite consistent trends for FVC decline in the IPF population, the rate of disease progression in individuals is unpredictable and highly variable:
more » ... cant variability in FVC is observed over time, and prior declines are a poor predictor of future FVC decline [1, 7, 8] . In new trials in IPF, the margin for reducing FVC decline is smaller (∼70 mL) in patients who are receiving an investigational drug with background antifibrotics than in the placebo arms of past trials (130-210 mL) [9] . Considering additional clinical variables in trial endpoints may provide the ability to identify small changes in FVC that represent disease progression. The objectives of this post hoc analysis of data from patients with IPF enrolled in phase 3 clinical trials were to examine the variability in FVC (mL) across 3-month follow-up visits and, using 6-min walk distance (6MWD), to explore whether combined clinical measures can more accurately predict disease progression than short-term changes in FVC alone. Patients randomised to receive placebo in ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) and all patients randomised to receive interferon-γ-1b or placebo in GIPF-001 (NCT00047645) were included [4, 5, 10] . Eligibility criteria were previously described [4, 5, 10] . Data from all trials were included to evaluate the first objective in a broader IPF population. However, only data from ASCEND and CAPACITY were included to evaluate the second objective because 6MWD was not captured in GIPF-001. Spirometry tests were performed every 3 months for 52-72 weeks [4, 5, 10] . Tests were performed in accordance with the 2005 American Thoracic Society (ATS) manual in ASCEND and CAPACITY and the 1987 ATS standardisation in GIPF-001 [11, 12] . Pre-bronchodilator FVC values used in this analysis were: the best effort (or maximum acceptable effort if best effort was unavailable; from at least three measurements) from ASCEND, the maximum recorded (from at least three measurements) from CAPACITY and the value reported on the case report form from GIPF-001. Changes in pre-bronchodilator FVC (mL) in individuals were calculated as the difference between measurements at the first and second visits of each 3-month interval (e.g. baseline to month 3, month 3 to month 6). The probability of further change in FVC after an initial 3-month relative decline (2% decrements) was calculated for the subsequent 3-month interval. The role of the 6MWD in validating these small relative changes (2% decrements) in FVC was assessed in data from ASCEND and CAPACITY. Concurrent 3-month change in 6MWD was categorised as decreased (⩽−5% of initial value), stable (>−5% to <5%) or improved (⩾5%). The probability of further change in FVC in the subsequent 3 months after an initial 3-month relative decline in FVC was categorised by both the initial relative decline in FVC and concurrent change in 6MWD. The probability of ⩽−10% relative change in FVC over 6 months was estimated by identifying combinations of initial and subsequent 3-month change categories that indicated patients had ⩽−10% total change. Only initial intervals with declines in FVC and consecutive 3-month intervals were considered. FVC decrements of 2% and 5% change in 6MWD were @ERSpublications Variability in 3-month changes in FVC was examined in 954 patients with IPF (n=3966 observations) from phase 3 trials; concurrent 3-month decline in the FVC and 6MWD (n=1321 observations) predicted further decline in FVC over the subsequent 3 months http://bit.ly/2GfBKW3 Cite this article as: Nathan SD, Yang M, Morgenthien EA, et al. FVC variability in patients with idiopathic pulmonary fibrosis and role of 6-min walk test to predict further change. Eur Respir J 2020; 55: 1902151 [https://doi.
doi:10.1183/13993003.02151-2019 pmid:32029447 pmcid:PMC7236864 fatcat:swuunbgmbvelxiqsisfjja43vu