Efficacy and Safety Evaluation of BI 1839100 in Reducing Cough Frequency in Idiopathic and Progressive Pulmonary Fibrosis: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to assess the efficacy of **BI 1839100** in reducing 24-hour cough frequency in patients with **idiopathic pulmonary fibrosis** or **progressive pulmonary fibrosis**. In Phase IIa, the focus is on demonstrating a significant reduction in cough frequency from baseline in the highest dose group compared to placebo after 4 weeks of treatment. In Phase IIb, the aim is to establish a non-flat dose-response curve regarding changes in 24-hour cough frequency after 12 weeks, and to characterize the dose-response relationship within the therapeutic range of BI 1839100 concerning both efficacy and safety. This is clinically relevant as it addresses the management of chronic cough, a debilitating symptom in these fibrotic lung diseases, potentially improving patient quality of life.

Secondary objectives include:

• Phase IIa: Evaluating the efficacy by comparing changes from baseline in Cough Severity numerical rating scale (NRS) and visual analogue scale (VAS) scores after 4 weeks between the highest dose group and placebo.
• Phase IIb: Assessing the efficacy of BI 1839100 by determining cough responder status, defined as a ≥30% reduction in 24-hour cough frequency from baseline after 12 weeks.
• Phase IIb: Comparing the absolute change from baseline in forced vital capacity (FVC) after 12 weeks of treatment between BI 1839100 dose groups and the placebo group.

The clinical trial involves a total of **132 participants** diagnosed with either **progressive pulmonary fibrosis (PPF)** or **idiopathic pulmonary fibrosis (IPF)**. The study population includes both male and female subjects, with an age range starting from 18 years for the PPF cohort and 40 years for the IPF cohort. Participants are required to have a chronic cough attributed to their respective conditions, refractory to treatment for known causes. The trial population was selected based on specific inclusion criteria, such as a cough severity visual analog scale (VAS) score of 30 mm or higher and a forced vital capacity (FVC) of at least 45% of the predicted normal value. Additionally, participants may be on stable therapy with nintedanib or pirfenidone, or not on such therapy, provided they meet the stability requirements prior to the trial. The study does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of the investigational drug **BI 1839100** in patients with **idiopathic pulmonary fibrosis (IPF)** or **progressive pulmonary fibrosis (PPF)**. The trial is structured into two phases: Phase IIa and Phase IIb. Phase IIa aims to demonstrate a meaningful reduction in 24-hour cough frequency in the highest dose group of BI 1839100 compared to placebo after 4 weeks of treatment. Phase IIb seeks to establish a non-flat dose-response curve over a 12-week treatment period, characterizing the dose-response relationship regarding efficacy and safety.

The trial will span an estimated duration from August 2024 to November 2025, with participant involvement lasting approximately 12 weeks. Participants will be randomly assigned to receive either BI 1839100 or a placebo, both administered orally in the form of film-coated tablets. The study will include several key visits: an initial **screening visit** to assess eligibility based on inclusion criteria such as chronic cough and lung function parameters, followed by regular **follow-up visits** to monitor treatment response and safety. The trial will conclude with an **end-of-study visit** to evaluate the primary and secondary endpoints, including changes in cough frequency and severity.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial's primary endpoints focus on changes in 24-hour cough frequency, while secondary endpoints include changes in cough severity scores and lung function measurements. The study is not classified as a low-intervention trial, as it aims to investigate the safety and efficacy of a new therapeutic approach in a patient population with rare diseases.

The clinical trial involves the administration of **BI 1839100**, an experimental medication, in the form of a **film-coated tablet**. The active substance, BI 1839100, is of chemical origin and is provided by Boehringer Ingelheim International. The medication is administered orally, with the dosing schedule designed to explore its efficacy and safety over a 12-week treatment period. The trial aims to determine the optimal dose by evaluating the reduction in 24-hour cough frequency in patients with idiopathic pulmonary fibrosis or progressive pulmonary fibrosis. The study will assess the dose-response relationship within the therapeutic range of BI 1839100.

In addition to the experimental medication, a **placebo** is used as a comparator treatment. The placebo is designed to match the size, weight, color, and shape of the BI 1839100 tablets, ensuring blinding in the study. The placebo is also administered orally, following the same dosing schedule as the experimental medication. This placebo-controlled design allows for a rigorous assessment of the efficacy of BI 1839100 by comparing it against a non-active treatment.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol. The trial is conducted in a double-blind manner, meaning neither the participants nor the investigators are aware of the treatment assignments, which helps to minimize bias and ensure the integrity of the study results.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints focus on the change from baseline in 24-hour cough frequency (CC/h) at Week 4 and Week 12 for patients with **idiopathic pulmonary fibrosis** (IPF) in Phase IIa. Secondary endpoints include the absolute change from baseline in Cough Severity Numerical Rating Scale (NRS) score and Cough Severity Visual Analog Scale (VAS) score at Week 4, as well as the cough responder status, defined as a ≥30% reduction in 24-hour cough frequency from baseline at Week 12 in Phase IIb. Additionally, the absolute change from baseline in forced vital capacity (FVC) in milliliters at Week 12 will be evaluated.

The efficacy parameters will be measured and collected at specified timepoints, including Week 4 and Week 12, using validated scales and patient-reported outcomes. The analysis will focus on demonstrating a meaningful reduction in cough frequency and characterizing the dose-response relationship within the therapeutic range of BI 1839100. The trial aims to establish a non-flat dose-response curve regarding efficacy and safety over the 12-week treatment period.