A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of the Efficacy and Safety of Brensocatib in Participants with Chronic Rhinosinusitis Without Nasal Polyps – The BiRCh Study

The primary objective of this study is to evaluate the **efficacy** of brensocatib at doses of 10 mg and 40 mg once daily compared with placebo in improving nasal symptoms in participants with **Chronic Rhinosinusitis without Nasal Polyps (CRSsNP)**. This is clinically relevant as it aims to address the persistent nasal symptoms associated with CRSsNP, which can significantly impact patients' quality of life.

Secondary objectives include:

• Evaluating the efficacy of brensocatib compared with placebo in improving computed tomography (CT) sinus opacification.
• Assessing the efficacy of brensocatib in reducing clinical worsening or acute rhinosinusitis.
• Evaluating the improvement in nasal congestion and nasal inspiratory flow with brensocatib compared to placebo.
• Assessing the impact of brensocatib on quality of life.
• Evaluating the pharmacokinetics (PK) of brensocatib in the CRSsNP population.
• Assessing the safety and tolerability of brensocatib compared with placebo over a 24-week treatment period.

The clinical trial involves a total of **134 participants** diagnosed with **Chronic Rhinosinusitis without Nasal Polyps (CRSsNP)**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on specific criteria, including a history of CRSsNP for at least 12 weeks and ongoing symptoms of nasal congestion. The trial population also required a blood eosinophil count of ≤750 cells/μL at screening and a history of previous sinonasal surgery or treatment with systemic corticosteroids or antibiotics for CRS within a year prior to the screening visit. Additionally, participants must have been on a stable daily dose regimen of mometasone furoate nasal spray for at least four weeks before randomization. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the efficacy of brensocatib in improving nasal symptoms compared to a placebo.

The clinical trial is a **Phase 2b**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **brensocatib** in participants with **Chronic Rhinosinusitis without Nasal Polyps (CRSsNP)**. The trial aims to assess the improvement in nasal symptoms with brensocatib at doses of 10 mg and 40 mg once daily compared to placebo. The study is expected to last approximately 24 weeks, with participant involvement beginning from the screening visit and concluding at the end-of-study visit.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, history of CRSsNP, and blood eosinophil count. Following successful screening, participants will be randomized to receive either brensocatib or placebo. The trial includes regular follow-up visits to monitor efficacy and safety endpoints, including changes in the Sinus Total Symptom Score and other secondary measures such as sinus opacification and nasal congestion scores. The end-of-study visit will assess the overall outcomes and any adverse events experienced during the trial.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events or the need for rescue medication due to worsening symptoms. The trial is conducted under strict adherence to regulatory guidelines, ensuring the integrity and reliability of the data collected. Participants will be monitored closely throughout the study to ensure their safety and the validity of the trial results.

The clinical trial involves the administration of several treatments, including **mometasone**, **brensocatib**, and a placebo. **Mometasone** is utilized as an auxiliary treatment in the form of a nasal spray. It is a chemical substance with the active ingredient **mometasone**. The maximum daily dose is 400 µg microgram(s), with a total maximum dose of 92,400 µg microgram(s) over a treatment period of 33 days. The administration route is intranasal, and participant compliance is monitored to ensure adherence to the dosing schedule.

**Brensocatib** is the primary investigational product in this study, administered in the form of a film-coated tablet. It is a chemical compound with the active ingredient **brensocatib**. The trial evaluates two dosing regimens: 10 mg and 40 mg, both administered once daily (QD) orally. The maximum total dose for each regimen is 6,270 mg over a 24-day treatment period. The study aims to assess the efficacy of **brensocatib** in improving nasal symptoms in participants with chronic rhinosinusitis without nasal polyps. Participant compliance is monitored through regular assessments and pill counts.

The placebo used in the study is designed to match the investigational product in size and appearance, utilizing the same excipients as the active drug but without the active substance. It is also administered as a film-coated tablet, ensuring blinding in the double-blind, placebo-controlled study design. The placebo serves as a comparator to evaluate the efficacy of **brensocatib** in the trial.

The efficacy of **brensocatib** in the treatment of Chronic Rhinosinusitis Without Nasal Polyps will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to the 28-day average of daily Sinus Total Symptom Score (sTSS) at Week 24. Secondary endpoints include changes from baseline in the percentage of sinus opacification as measured by volumetry, modified Lund-MacKay (LMK) CT score, and the 28-day average of daily Nasal Congestion Scores (NCS) at Week 24. Additional secondary endpoints involve changes in Peak Nasal Inspiratory Flow (PNIF), Sino-Nasal Outcome Test (SNOT-22) scores, and the requirement for rescue interventions such as antibiotics, systemic corticosteroids (SCS), or nasal surgery due to symptom worsening.

Brensocatib plasma concentration and adverse events (AEs) will also be monitored over the 24-week treatment period, alongside clinical laboratory test results, vital signs, and electrocardiograms (ECGs). These assessments will be conducted at specified intervals to ensure comprehensive data collection and analysis. The trial is designed to provide a robust evaluation of brensocatib's efficacy in improving nasal symptoms compared to placebo, with a focus on both objective measures and patient-reported outcomes.