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Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

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Summary

Background

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis.

Methods

The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178.

Findings

Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI −8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [−31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population.

Interpretation

The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis.

Funding

Boehringer Ingelheim.

Introduction

Interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) might be associated with a progressive fibrosing phenotype, characterised by increasing fibrosis on high resolution CT (HRCT), decline in lung function, worsening symptoms and quality of life, and early mortality.1, 2, 3 ILDs associated with a progressive fibrosing phenotype include, among others, chronic hypersensitivity pneumonitis (HP),4 idiopathic non-specific interstitial pneumonia (iNSIP),5 unclassifiable idiopathic interstitial pneumonia (IIP),6 sarcoidosis,7 and autoimmune ILDs such as those associated with rheumatoid arthritis (RA-ILD)8 and systemic sclerosis (SSc-ILD).9 Similar to observations in patients with IPF, short-term decline in forced vital capacity (FVC) has been associated with early mortality in patients with progressive fibrosing ILDs.10, 11, 12 Based on their clinical and pathophysiological similarities, it has been postulated that progressive fibrosing ILDs be lumped together for the purpose of investigating potential therapies.1 A similar basket approach has been used in trials of other diseases with unmet medical needs.13, 14

Research in context

Evidence before this study

Interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) might be associated with a progressive fibrosing phenotype. In the INBUILD trial, nintedanib slowed the rate of decline in forced vital capacity (FVC) versus placebo in patients with fibrosing ILDs other than IPF who met criteria for progression of ILD in the 24 months before screening. We searched PubMed for all English-language papers published between Jan 1, 1990, and Nov 1, 2019, using the search terms “hypersensitivity pneumonitis”, “idiopathic non-specific interstitial pneumonia”, “unclassifiable idiopathic interstitial pneumonia”, “sarcoidosis” or “exposure-related interstitial lung disease”, “autoimmune disease”, “rheumatoid arthritis”, “systemic sclerosis” or “mixed connective tissue disease” with “nintedanib”. We found no studies other than the INBUILD trial that have investigated the effects of nintedanib in patients with ILD diagnoses other than IPF.

Added value of this study

Although the INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific ILD subgroups, these new analyses suggest that the effect of nintedanib on reducing the rate of decline in FVC was consistent across prespecified subgroups based on ILD diagnosis, both in patients with a usual interstitial pneumonia-like fibrotic pattern on high-resolution computed tomography (HRCT) and in patients with other fibrotic patterns on HRCT. The safety profile of nintedanib in the subgroups was consistent with observations in the overall population.

Implications of all the available evidence

An accurate initial ILD diagnosis is crucial to inform prognosis and ensure that patients receive optimal management, but once progressive fibrosis occurs despite management, diagnostic precision is less important in establishing who will benefit from treatment with nintedanib.

Nintedanib is a tyrosine-kinase inhibitor that has been shown in non-clinical studies to inhibit processes fundamental to the progression of lung fibrosis.15, 16 Clinical trials have shown that nintedanib reduces the rate of progression of ILD in patients with IPF17 and SSc-ILD.18 The INBUILD trial was a prospective, randomised, placebo-controlled trial of nintedanib in which patients with fibrosing ILDs other than IPF were grouped together on the basis of the progressive behaviour of their ILD.19 The results showed that nintedanib slowed ILD progression as measured by the rate of decline in FVC (mL/year) compared with placebo,20 with adverse events that were similar to those observed in patients with IPF and SSc-ILD.17, 18, 20 Although the INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific ILD subgroups, exploratory subgroup analyses based on grouped ILD diagnoses were prespecified. In this study we aimed to establish the effect of nintedanib on FVC decline and its safety profile in subgroups based on ILD diagnosis.

Section snippets

Study design and participants

The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries.20 The trial was carried out in compliance with the protocol,20 the principles of the Declaration of Helsinki and the Harmonised Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonisation, and was approved by local authorities. All participants provided written informed consent.

Eligibility criteria for the INBUILD trial have been

Results

Participants were recruited between Feb 23, 2017, and April 27, 2018. A total of 663 of 1010 participants assessed for eligibility received at least one dose of nintedanib (n=332) or placebo (n=331), of whom 412 (62·1%) had a UIP-like fibrotic pattern on HRCT.

The distribution of participants across the nine ILD subgroups in the overall population is shown in the appendix p 4. The largest subgroups were HP (173 participants [26%]), iNSIP (125 participants [19%]), unclassifiable IIP (114

Discussion

Participants were selected for participation in the INBUILD trial based on the progressive longitudinal behaviour of their fibrosing ILD, irrespective of their underlying diagnosis (with the exclusion of IPF) or fibrotic pattern on HRCT. We have previously reported that the effect of nintedanib versus placebo on the annual rate of decline in FVC (mL/year) in this trial was consistent between patients with a UIP-like fibrotic pattern on HRCT (relative reduction 61%) and patients with other

Data sharing

Information on data sharing is provided in the appendix.

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    Full list of investigators included in appendix p 2

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