A randomised, double-blind, placebo-controlled, parallel group trial evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of BI 1291583 one tablet once daily over 12 weeks versus placebo in adult patients with cystic fibrosis bronchiectasis (ClairaflyTM)

The primary objective of this study is to estimate the number and percentage of patients with **cystic fibrosis bronchiectasis** who experience at least one treatment-emergent adverse event (TEAE) during the trial. This is clinically relevant as it provides critical safety data on the tolerability of BI 1291583, a novel therapeutic agent, compared to placebo over a 12-week period.

Secondary objectives include:

• Estimating the pharmacodynamic (PD) effect at week 8 following the initial administration of the drug, which is important for understanding the drug's biological activity and potential therapeutic impact.
• Estimating the pharmacokinetic (PK) effect after the first dose and at steady state following multiple doses of BI 1291583, which is essential for determining the drug's absorption, distribution, metabolism, and excretion characteristics.

The clinical trial involves a total of **8 participants** diagnosed with **cystic fibrosis bronchiectasis**. The study population includes both male and female subjects, aged 18 years and older, who have a historical clinical diagnosis of cystic fibrosis, confirmed by symptoms and sweat chloride levels, or CF-causing CFTR mutations. Participants must also have an investigator-confirmed diagnosis of bronchiectasis by CT scan and a clinical history consistent with the condition, such as chronic cough and recurrent respiratory infections. The trial population was selected based on their ability to provide spontaneous or induced sputum samples and a history of pulmonary exacerbations requiring antibiotic treatment. Lifestyle considerations include the requirement for women of childbearing potential to use highly effective birth control methods, and men to use male contraception if their partner is of childbearing potential. The trial includes a vulnerable population, ensuring that all participants have provided signed and dated informed consent in accordance with ICH-GCP and local legislation.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel group** study to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of the investigational drug **BI 1291583** in adult patients with **cystic fibrosis bronchiectasis**. The trial will involve the administration of one tablet of BI 1291583 once daily over a period of 12 weeks, with a placebo group for comparison. The primary objective is to estimate the number and percentage of patients experiencing at least one treatment-emergent adverse event (TEAE) during the trial. Secondary endpoints include the relative change from baseline in neutrophil elastase activity in sputum at week 8, as well as pharmacokinetic parameters such as AUC and Cmax for the first dose and at steady state.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age, historical clinical diagnosis of cystic fibrosis, and investigator-confirmed diagnosis of bronchiectasis by CT scan. Participants must have a history of pulmonary exacerbations requiring antibiotic treatment and be able to provide sputum samples. The trial will include follow-up visits to monitor safety and efficacy, with the end-of-study visit marking the conclusion of the participant's involvement. The overall trial duration is estimated to end by December 16, 2024, with recruitment starting on February 28, 2024.

Participants are expected to be involved in the study for approximately 16 weeks, including the screening period. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or withdrawal of consent. The trial is conducted in accordance with ICH-GCP guidelines and local legislation, ensuring the ethical treatment of participants throughout the study.

The clinical trial involves the administration of **BI 1291583**, a chemical compound formulated as a tablet. Each tablet contains 5 mg of the active substance **BI 1291583**. The medication is administered orally once daily over a period of 12 weeks, with a maximum total dose of 425 mg. The trial aims to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of this experimental medication in adult patients with cystic fibrosis bronchiectasis. Participant compliance is monitored through regular assessments and adherence checks.

In addition to the experimental medication, a **placebo tablet** matching BI 1291583 is used as a comparator treatment in this double-blind, placebo-controlled trial. The placebo is designed to mimic the appearance of the BI 1291583 tablet but does not contain any active pharmaceutical ingredients. It is administered orally once daily, following the same schedule as the experimental medication, to maintain blinding and ensure the integrity of the study results.

**Salbutamol sulfate** is included as an auxiliary treatment in the trial. It is provided in the form of a pressurised inhalation suspension, with a maximum daily dose of 400 µg. The route of administration is via inhalation, and it is used as needed to manage respiratory symptoms associated with cystic fibrosis bronchiectasis. The use of salbutamol sulfate is monitored to ensure it does not interfere with the primary objectives of the trial.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the occurrence of treatment-emergent adverse events (TEAEs) up to 16 weeks from the first drug administration. This will provide a measure of the safety profile of the investigational product, **BI 1291583**, in comparison to placebo. Secondary endpoints include the relative change from baseline in neutrophil elastase (NE) activity in sputum at week 8, which is chosen to align with potential cycling antibiotic use. Additionally, pharmacokinetic parameters such as the area under the curve over a dosing interval (AUCτ) for the first dose, maximum concentration (Cmax) for the first dose, AUCτ at steady state (AUCτ,ss), and Cmax at steady state (Cmax,ss) will be evaluated.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints, with the NE activity being measured at week 8. The pharmacokinetic parameters will be assessed following the first dose and at steady state to provide comprehensive data on the drug's behavior in the body. These assessments will be performed using validated laboratory tests and analytical methods to ensure accuracy and reliability of the data collected. The trial is designed to provide a robust evaluation of the efficacy and safety of BI 1291583 in adult patients with cystic fibrosis bronchiectasis over a 12-week treatment period.