Phase III Double-Blind RCT of BI 1015550 in Progressive Pulmonary Fibrosis Patients (FIBRONEER-ILD)

At December 17, 2024

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with progressive pulmonary fibrosis (FIBRONEER-ILD)

PMID: 37709661

Abstract:

Introduction: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD).

Methods and analysis: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, stratified by background nintedanib use. Patients must be diagnosed with pulmonary fibrosis other than IPF that is progressive, based on predefined criteria. Patients must have forced vital capacity (FVC) ≥45% predicted and haemoglobin-corrected diffusing capacity of the lung for carbon monoxide ≥25% predicted. Patients must be receiving nintedanib for at least 12 weeks, or not receiving nintedanib for at least 8 weeks, prior to screening. Patients on stable treatment with permitted immunosuppressives (eg, methotrexate, azathioprine) may continue their treatment throughout the trial. Patients with clinically significant airway obstruction or other pulmonary abnormalities, and those using immunosuppressives that may confound FVC results (cyclophosphamide, tocilizumab, mycophenolate, rituximab) or high-dose steroids will be excluded. The primary endpoint is absolute change from baseline in FVC (mL) at week 52. The key secondary endpoint is time to the first occurrence of any acute ILD exacerbation, hospitalisation for respiratory cause or death, over the duration of the trial.

Ethics and dissemination: The trial is being carried out in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The study results will be disseminated at scientific congresses and in peer-reviewed publications.

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Abstract: Background: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. Methods: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. Results: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, –39.1 to 50.5) in the BI 1015550 group and –81.7 ml (95% credible interval, –133.5 to –44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, –32.8 to 38.2) in the BI 1015550 group and –59.2 ml (95% credible interval, –111.8 to –17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. Conclusions: In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.) Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease with high mortality.1,2 Currently, there are two approved antifibrotic drugs — nintedanib and pirfenidone — that slow, but do not stop, the progression of fibrosis.3-5 Therefore, there is a need for additional treatments that can be used alone or with existing antifibrotic therapies.6 Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic properties.7,8 Preferential inhibition of the PDE4B subtype may be beneficial in the treatment of IPF because it may harness these properties9,10 and is also associated with a more acceptable safety profile than nonselective PDE4 inhibitors.7,10 IPF is a rare disease, which makes the recruitment of large numbers of patients in early-phase clinical trials a challenge. In this trial, we used Bayesian analysis11,12 to incorporate informative historical data from phase 2–4 clinical trials of nintedanib for the control groups. Consistent decreases in the forced vital capacity (FVC) that have been observed in the placebo groups of these trials3,4,13–16 make such an approach suitable for proof-of-concept studies of new drug candidates for the treatment of IPF. In this multicenter, randomized, double-blind, phase 2 trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of PDE4B,17 in patients with IPF according to background nonuse or use of an antifibrotic agent.

Phase III Double-Blind RCT of BI 1015550 in Idiopathic Pulmonary Fibrosis Patients (FIBRONEER-IPF)

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF) PMID: 37597969 Abstract: IntroductionThere is an unmet need for new treatments for idiopathic pulmonary fibrosis (IPF). The oral preferential phosphodiesterase 4B inhibitor, BI 1015550, prevented a decline in forced vital capacity (FVC) in a phase II study in patients with IPF. This study design describes the subsequent pivotal phase III study of BI 1015550 in patients with IPF (FIBRONEER-IPF). Methods and analysis: In this placebo-controlled, double-blind, phase III trial, patients are being randomised in a 1:1:1 ratio to receive 9 mg or 18 mg of BI 1015550 or placebo two times per day over at least 52 weeks, stratified by use of background antifibrotics (nintedanib/pirfenidone vs neither). The primary endpoint is the absolute change in FVC at week 52. The key secondary endpoint is a composite of time to first acute IPF exacerbation, hospitalisation due to respiratory cause or death over the duration of the trial. Ethics and dissemination: The trial is being carried out in compliance with the ethical principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The results of the study will be disseminated at scientific congresses and in peer-reviewed publications. Trial registration number: NCT05321069.

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