The natural history of progressive fibrosing interstitial lung diseasesThe natural history of progressive fibrosing interstitial lung diseases

Kevin K. Brown, Fernando J. Martinez, Simon L.F. Walsh, Victor J. Thannickal, Antje Prasse, Rozsa Schlenker-Herceg,Rainer-Georg Goeldner, Emmanuelle Clerisme-Beaty, Kay Tetzlaff, Vincent Cottin, Athol U. Wells

European Respiratory Journal 2020 55: 2000085; DOI: 10.1183/13993003.00085-2020

Abstract
We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs).

Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year−1) and mortality over 52 weeks in the INBUILD trial with pooled data from the INPULSIS trials.

The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (−192.9 mL·year−1 and −221.0 mL·year−1, respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52 weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95).

These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality.

Introduction
Idiopathic pulmonary fibrosis (IPF) is, by definition, a progressive fibrosing interstitial lung disease (ILD). In addition to IPF, there are a number of other ILDs that may develop a progressive fibrosing phenotype characterised by declining lung function, an increasing extent of fibrosis on high-resolution computed tomography (HRCT), worsening symptoms and quality of life, and early mortality. Along with these clinical similarities, progressive fibrosing ILDs appear to share pathobiological mechanisms that may represent a common fibrotic response to tissue injury.

The ILDs that can be complicated by progressive fibrosis include idiopathic non-specific interstitial pneumonia (iNSIP), unclassifiable idiopathic interstitial pneumonia (IIP), hypersensitivity pneumonitis (HP), autoimmune ILDs such as rheumatoid arthritis-associated ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), sarcoidosis and occupation-associated lung disease. Similar to IPF, a decline in forced vital capacity (FVC) is predictive of mortality in patients with these other fibrosing ILDs. Given their clinical and pathophysiological similarities, and the rarity of the individual diseases, it has been proposed that fibrosing ILDs with a progressive phenotype be “lumped” together for the purposes of investigating certain potential therapies.

Nintedanib is an intracellular inhibitor of tyrosine kinases. In the two INPULSIS trials in patients with IPF, nintedanib reduced the rate of decline in FVC (mL·year−1) over 52 weeks by about 50% compared to placebo. Recently, the efficacy and safety of nintedanib in subjects with a variety of ILD diagnoses other than IPF, grouped based on the progressive clinical behaviour of their fibrosing ILD despite management deemed appropriate in clinical practice, were investigated in the INBUILD trial. The results showed that, as in the INPULSIS trials, nintedanib reduced the rate of decline in FVC (mL·year−1) over 52 weeks by about 50% compared to placebo. We used data from subjects who received placebo in the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing ILDs. Specifically, we wanted to compare the clinical course of IPF and other progressive fibrosing ILDs, explore whether specific ILD diagnoses were associated with different rates of progression and investigate whether a relative decline in FVC was associated with mortality in patients with IPF and other progressive fibrosing ILDs.

Materials and methods
Trial design
The two INPULSIS trials and the INBUILD trial were randomised, double-blind, placebo-controlled trials with a 52-week treatment period. The trial designs have been described and the trial protocols are publicly available. The trials were carried out in compliance with the principles of the Declaration of Helsinki and the Harmonised Tripartite Guideline for Good Clinical Practice of the International Conference on Harmonisation, and were approved by the local authorities. Subjects provided written informed consent before trial entry. In all these trials, the primary endpoint was the annual rate of decline in FVC (mL·year−1), assessed over 52 weeks.

INPULSIS trials
Briefly, subjects in the INPULSIS trials were aged ≥40 years and had a clinical diagnosis of IPF. To be eligible for inclusion based on an HRCT scan (taken within the previous ≤12 months), patients had to have a usual interstitial pneumonia (UIP)-like fibrotic pattern defined as meeting criteria A, B and C, A and C, or B and C defined as follows: A: definite honeycomb lung destruction with basal and peripheral predominance; B: presence of reticular abnormality and traction bronchiectasis consistent with fibrosis with basal and peripheral predominance; C: atypical features are absent, specifically nodules and consolidation. Ground glass opacity, if present, was to be less extensive than reticular opacity pattern. Subjects had an FVC ≥50% predicted and a diffusing capacity of the lung for carbon monoxide (DLCO) ≥30% predicted and <80% predicted. There were no inclusion criteria regarding longitudinal disease behaviour. Subjects were randomised 3:2 to receive nintedanib or placebo.

INBUILD trial
Subjects in the INBUILD trial were aged ≥18 years and had a fibrosing ILD other than IPF diagnosed by the investigator according to their usual clinical practice. Patients with IPF were actively excluded. For every subject, the investigator documented an ILD diagnosis on the case report form based on the following nine options: iNSIP, unclassifiable IIP, HP, RA-ILD, mixed connective tissue disease-associated ILD (MCTD-ILD), SSc-ILD, exposure-related ILD, sarcoidosis and other fibrosing ILD. Subjects had features of fibrosing lung disease (reticular abnormality with traction bronchiectasis with or without honeycombing) with an extent of >10% on an HRCT scan (taken within the previous ≤12 months), confirmed by central review, FVC ≥45% predicted and DLCO ≥30% predicted and <80% predicted.

Subjects had to meet one of the following criteria for disease progression in the 24 months before screening, as determined by the investigator, despite management as deemed appropriate in clinical practice for the individual ILD: 1) a relative decline in FVC ≥10% predicted; 2) a relative decline in FVC ≥5% predicted but <10% predicted and worsened respiratory symptoms; 3) a relative decline in FVC ≥5% predicted but <10% predicted and increased extent of fibrosis on HRCT; 4) worsened respiratory symptoms and increased extent of fibrosis on HRCT.

Subjects were randomised 1:1 to receive nintedanib or placebo. Randomisation was stratified according to the fibrotic pattern on HRCT (UIP-like fibrotic pattern or other fibrotic patterns). The criteria used to identify a UIP-like fibrotic pattern on HRCT in the INBUILD trial were the same as the criteria used in the INPULSIS trials. For each subject, the trial consisted of two parts: Part A, which comprised 52 weeks of treatment; and Part B, a variable treatment period beyond Week 52 during which subjects continued to receive blinded treatment until all subjects had completed Part A. Subjects who discontinued treatment were asked to attend all visits as originally planned, including an end-of-treatment visit and a follow-up visit 4 weeks later. The second database lock took place after all patients had completed the follow-up visit or had entered the open-label extension study. The protocol did not allow for use of azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, rituximab, cyclophosphamide, or oral corticosteroids >20 mg·day−1 at randomisation, but initiation of these medications was allowed after 6 months of study treatment in cases of clinically significant deterioration of ILD or connective tissue disease, at the discretion of the investigator.

Analyses

 

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