Efficacy and Safety Evaluation of BI 1015550 in Progressive Fibrosing Interstitial Lung Diseases: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this clinical trial is to evaluate the **efficacy** and safety of BI 1015550 in patients with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs). The trial aims to demonstrate a reduction in lung function decline, as measured by the change from baseline in Forced Vital Capacity (FVC), when compared to placebo. This is clinically relevant as it addresses the progressive nature of PF-ILDs, which is characterized by a decline in lung function, leading to significant morbidity and mortality.

Secondary objectives include:

• Demonstrating BI 1015550's ability to reduce the occurrence of clinically meaningful events such as acute ILD exacerbations, hospitalization for respiratory causes, or death over the duration of the trial when compared to placebo.
• Showing an effect of BI 1015550 on symptoms and lung function.

The clinical trial involves a total of **875 participants** diagnosed with **Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs)**. The study population includes both male and female subjects aged 18 years and older, with no specific vulnerable populations selected. Participants were chosen based on their diagnosis of progressive fibrosing ILD, excluding idiopathic pulmonary fibrosis (IPF), and their ability to provide informed consent. The trial does not restrict participants based on their current treatment with nintedanib, as long as they meet the criteria for stable therapy or have not been on the treatment for a specified period. Participants are required to have a Forced Vital Capacity (FVC) of at least 45% of the predicted normal and a DLCO corrected for Hemoglobin of at least 25% predicted normal. Women of childbearing potential must adhere to strict birth control measures. The trial does not impose specific lifestyle considerations such as diet or physical activity, focusing instead on the medical condition and treatment stability of the participants.

The clinical trial is designed to evaluate the **efficacy** and safety of BI 1015550 in patients with **Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs)**. This is a randomized, double-blind, placebo-controlled trial, which will span a duration of at least 52 weeks. Participants will be randomly assigned to receive either the active treatment, BI 1015550, or a matching placebo. The primary objective is to demonstrate a reduction in lung function decline, specifically measuring the change from baseline in Forced Vital Capacity (FVC) at Week 52. Secondary endpoints include time to first acute ILD exacerbation, hospitalization for respiratory causes, or death, among others.

The trial will commence with an inclusion (screening) visit, where eligibility criteria will be assessed. Key inclusion criteria include patients aged 18 years or older with a confirmed diagnosis of progressive fibrosing ILD, excluding idiopathic pulmonary fibrosis (IPF). Participants must have a Forced Vital Capacity (FVC) of at least 45% of the predicted normal value and a Diffusing Capacity for Carbon Monoxide (DLCO) of at least 25% of the predicted normal value. Women of childbearing potential must use highly effective birth control methods. The screening period will ensure that patients are either on a stable therapy with nintedanib or not on treatment with nintedanib for a specified duration prior to the first visit.

Following the screening, participants will undergo randomization and begin the treatment phase, which will last for a maximum of 116 weeks. Study visits will be scheduled at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the primary and secondary endpoints. Participant involvement is expected to last until the end of the trial, unless early termination is warranted due to adverse events, withdrawal of consent, or non-compliance with the study protocol.

The clinical trial involves the administration of **BI 1015550**, an investigational medication, in the form of a **film-coated tablet**. The active substance in BI 1015550 is chemically derived and 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**. The medication is administered orally, with a maximum daily dose of 18 mg and a total maximum dose of 14,646 mg over a treatment period of up to 116 days. The primary objective of the trial is to evaluate the efficacy and safety of BI 1015550 in reducing lung function decline in patients with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs).

In addition to the experimental treatment, a **placebo** matching BI 1015550 is used as a comparator in this double-blind, randomized, placebo-controlled trial. The placebo is designed to mimic the appearance of the BI 1015550 film-coated tablet but does not contain the active substance. The placebo is also administered orally, following the same dosing schedule as the active treatment, to ensure blinding and maintain the integrity of the study design.

The efficacy of BI 1015550 in patients with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs) will be assessed through a double-blind, randomized, placebo-controlled trial over a period of at least 52 weeks. The primary endpoint for evaluating efficacy is the **absolute change from baseline in Forced Vital Capacity (FVC) [mL] at Week 52**. This measurement will be used to demonstrate a reduction in lung function decline when comparing BI 1015550 to placebo.

Secondary endpoints include several time-to-event analyses: time to the first occurrence of any component of a composite endpoint (first acute ILD exacerbation, first hospitalization for respiratory cause, or death), time to first acute ILD exacerbation or death, time to hospitalization for respiratory cause or death, time to absolute decline in FVC % predicted of >10% from baseline or death, and time to absolute decline in Diffusing Capacity of Lung for Carbon Monoxide (DLCO) % predicted of >15% from baseline or death. Additionally, the trial will assess absolute changes from baseline in the Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea, Cough, and Fatigue domain scores at Week 52, as well as changes in FVC % predicted and DLCO % predicted at the same timepoint.