Efficacy and Safety of BI 1015550 in Individuals with Interstitial Lung Abnormalities and a Family History of Pulmonary Fibrosis: A Randomized, Placebo-Controlled Trial

The primary objective is to investigate the efficacy of nerandomilast in reducing the overall risk of worsening pulmonary fibrosis or lung abnormalities in individuals with a family history of the disease. Secondary objectives include evaluating the reduction of fibrosis progression through the following metrics:

• Quantitative HRCT scoring.
• Changes in lung function assessed via forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO).

This clinical trial involves 49 participants, including both males and females, who are aged between 30 and 59 years. The study population consists of individuals with a family history of pulmonary fibrosis, encompassing conditions such as interstitial lung diseases and familial pulmonary fibrosis. Inclusion requires at least one first-degree relative with a confirmed diagnosis of pulmonary fibrosis, which may include idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, or fibrosis due to known genetic causes. Eligible participants must demonstrate evidence of interstitial lung abnormalities via high-resolution computed tomography involving at least 5% of a single lung zone. Additional physiological requirements include a forced vital capacity of at least 80% of the predicted normal and a diffusing capacity of the lungs for carbon monoxide corrected for hemoglobin of at least 70% of the predicted normal.

This double-blind, randomized, placebo-controlled exploratory trial is designed to investigate the efficacy and safety of nerandomilast in individuals presenting with interstitial lung abnormalities or interstitial lung disease and a family history of pulmonary fibrosis. The study methodology involves the administration of either nerandomilast or a matching placebo via oral use for a duration of 24 months. The research process begins with a screening visit to assess eligibility based on criteria such as age, family history, high-resolution computed tomography findings, forced vital capacity, and diffusing capacity of the lungs for carbon monoxide. Following successful screening, participants will undergo scheduled follow-up assessments to monitor physiologic and radiologic changes. The trial aims to measure the time to clinical worsening, defined by specific declines in respiratory function or increases in lung abnormalities. Participant involvement is expected to span the 24-month treatment period, though conditions leading to early termination may occur as determined by the study protocol.

The experimental medication nerandomilast (BI 1015550), also identified as 1-[[(5R)-2-[4-(5-chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]-cyclobutanemethanol, is administered as a film-coated tablet via oral use. The study utilizes two specific dosages: 36 mg and 18 mg.

A placebo matching BI 1015550 is employed as a comparator treatment in this double blind, randomized study.

The primary efficacy endpoint is the time to physiologic or radiologic worsening of interstitial lung abnormalities or interstitial lung disease. Worsening is defined as a relative decline in forced vital capacity (FVC) of more than 10% from baseline, an absolute decline in diffusing capacity of the lungs for carbon monoxide (DLCO) of more than 10% from baseline, or an absolute increase in the weighted reticulovascular score (wRVS) by more than 2% combined with a total disease extent (TDE) increase of more than 2.5% on high-resolution computed tomography (HRCT) as measured by e-Lung Quantitative HRCT scoring. This assessment is conducted over the entire trial duration.

Secondary efficacy parameters include the following:

• Absolute change from baseline in wRVS and TDE via e-Lung Quantitative HRCT scoring at weeks 26, 52, and 104.
• Absolute change from baseline in FVC (% predicted) and DLCO (% predicted) at weeks 26, 52, and 104.
• Time to relative decline in FVC (% predicted) of more than 10% over 52 weeks and over the whole trial.
• Time to absolute decline in FVC (% predicted) of more than 5% over 52 weeks and over the whole trial.
• Time to absolute decline in DLCO (% predicted) of more than 10% over 52 weeks and over the whole trial.
• Time to absolute increase in wRVS by more than 2% and TDE by more than 2.5% on chest HRCT using e-Lung Quantitative HRCT scoring over 52 weeks and over the whole trial.
• Time to physiologic or radiologic worsening of interstitial lung abnormalities or interstitial lung disease over 52 weeks.