A Phase 2b, Multicenter, Randomized, Double-blind, Parallel group, Placebo-controlled, Dose Range Finding Study to Evaluate the Efficacy, Safety, and Tolerability of Nebulized CSL787 in Adults (18 to 85 years) with Non-cystic Fibrosis Bronchiectasis

The primary objective of this study is to evaluate the effect of nebulized CSL787 (human normal immunoglobulin for nebulization) on the time to first exacerbation in adults with non-cystic fibrosis bronchiectasis. This objective addresses a clinically relevant endpoint in the management of bronchiectasis, as exacerbations are associated with accelerated lung function decline, reduced quality of life, and increased healthcare utilization. The study aims to determine whether inhaled immunoglobulin therapy can prolong the time interval before patients experience their first exacerbation, potentially offering a novel therapeutic approach for this chronic respiratory condition characterized by irreversible airway dilatation and recurrent respiratory infections.

The clinical trial enrolled a total of **233 participants** diagnosed with **non-cystic fibrosis bronchiectasis**. The study population consisted of **adults** aged **18 to 85 years**, including both **male and female subjects**. Participants were selected based on a confirmed primary diagnosis of non-cystic fibrosis bronchiectasis documented by **chest computed tomography (CT) scan** within 12 months prior to enrollment. Key inclusion criteria required participants to have a documented **exacerbation history** within the previous year, defined as either at least two exacerbations requiring **oral and/or intravenous antibiotic therapy** for pulmonary infection, or one such exacerbation combined with a **St. George's Respiratory Questionnaire (SGRQ)** total score greater than 40 at screening. Participants were also required to demonstrate a **postbronchodilator forced expiratory volume in 1 second (FEV1)** greater than 35% of predicted normal and an absolute FEV1 of at least 1 liter, measured according to American Thoracic Society and European Respiratory Society standards. The trial permitted the use of maintenance treatments such as **oral macrolides** or **dipeptidyl peptidase-1 (DPP-1) inhibitors**, provided these medications had been taken at a stable dose for at least 3 months prior to a documented historical exacerbation. No vulnerable populations were included in this study.

This is a Phase 2b, multicenter, randomized, double-blind, parallel group, placebo-controlled, dose range finding study designed to evaluate the efficacy, safety, and tolerability of nebulized CSL787 (human normal immunoglobulin for nebulization) in adults with non-cystic fibrosis bronchiectasis. The primary objective is to evaluate the effect of nebulized CSL787 on the time to first exacerbation. The study will compare two active treatment regimens of CSL787 administered via inhalation using a CE-marked nebulizer device against placebo (inhalation solution) over a treatment period of 6 to 12 months. The estimated recruitment start date is August 2025, with an estimated study completion date in October 2027.

Eligible participants include adults between 18 to 85 years of age with a primary diagnosis of non-cystic fibrosis bronchiectasis confirmed by chest computed tomography scan documented by a radiologist. Participants must have a documented exacerbation history within the previous year, defined as either two or more documented exacerbations requiring oral and/or intravenous antibiotic therapy to treat a pulmonary infection, or one documented exacerbation requiring antibiotic therapy combined with a St. George's Respiratory Questionnaire total score greater than 40 at screening. Additionally, participants must demonstrate postbronchodilator percentage of predicted normal forced expiratory volume in 1 second greater than 35% and FEV1 of at least 1 liter obtained in accordance with American Thoracic Society/European Respiratory Society standards for spirometry during screening and at baseline. Participants on maintenance treatment with oral macrolides or dipeptidyl peptidase-1 inhibitors are allowed provided at least one historical exacerbation occurred while on the medication for at least 3 months at a stable dose.

The primary endpoint is the time to first exacerbation. Secondary endpoints include the annualized exacerbation rate (exacerbation event rate per participant-year of follow-up), the number and percentage of participants achieving a clinically important difference in the Quality of Life–Bronchiectasis Respiratory Symptoms Scale, change from baseline in the QoL-B Respiratory Symptoms Scale, change from baseline in total colony-forming units for pathogenic bacteria isolated from sputum, and the number and percentage of participants with treatment-emergent adverse events and serious adverse events.

The maximum treatment period for the investigational medicinal product CSL787 is 12 months. Participants will undergo a screening visit during which eligibility criteria will be assessed, including chest CT scan confirmation of bronchiectasis if no scan results are available within the previous 12 months, spirometry testing, and assessment of exacerbation history and respiratory symptoms. Following successful screening, eligible participants will be randomized to receive either nebulized CSL787 at one of two dose regimens or placebo. Follow-up visits will be conducted throughout the treatment period to monitor efficacy outcomes, safety parameters, quality of life assessments, and sputum bacterial colonization. An end-of-study visit will be conducted to complete final assessments. The total duration of participant involvement will extend from the screening period through the treatment period and final study visit, spanning approximately 6 to 12 months of active treatment plus the screening period. Conditions that may lead to early termination from the study include withdrawal of consent, safety concerns, protocol deviations, loss to follow-up, or investigator decision based on the participant's best interest.

The experimental treatment consists of **CSL787**, a **human normal immunoglobulin** formulated as an **inhalation solution**. The active substance is derived from blood and represents a structurally diverse substance of human origin. CSL787 is manufactured by CSL Behring LLC and is administered via the **inhalation route** using a **nebulizer**. The nebulizer employed in this study is a CE-marked medical device provided by TÜV SÜD Product Service GmbH. The maximum treatment period is defined as 12 months. The product is designated as the test treatment in this **randomized**, **double-blind**, **parallel group**, **placebo-controlled** study.

The comparator treatment consists of a **placebo** formulated as an inhalation solution. The placebo is administered via the same inhalation route to maintain blinding and ensure comparability between treatment groups. The placebo serves as the control intervention in this dose range finding study evaluating the **efficacy**, **safety**, and **tolerability** of the experimental treatment in adults with **non-cystic fibrosis bronchiectasis**.

Efficacy will be assessed using the primary endpoint of **time to first exacerbation**. Secondary endpoints include the annualized exacerbation rate, which represents the exacerbation event rate per participant-year of follow-up. Quality of life will be evaluated through the **Quality of Life–Bronchiectasis (QoL-B) Respiratory Symptoms Scale**, measuring the number and percentage of participants achieving a clinically important difference, as well as the change from baseline in this scale. Microbiological efficacy will be assessed by measuring the change from baseline in total **colony-forming units** for pathogenic bacteria isolated from sputum. Safety parameters include the number and percentage of participants experiencing **treatment-emergent adverse events** and **serious adverse events**. The treatment period extends up to 12 months, with efficacy and safety assessments conducted throughout the study duration to evaluate the effect of nebulized **human normal immunoglobulin** compared to placebo in prolonging the time to first exacerbation in adults with **non-cystic fibrosis bronchiectasis**.