Evaluation of Inhaled Colistimethate Sodium in Adult Bronchiectasis Patients with Asymptomatic Pseudomonas aeruginosa Infection: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of **ColiFin®** therapy compared to standard of care (SOC) on achieving sputum/airway culture negativity for **Pseudomonas aeruginosa** (PA) 28 weeks after randomization in patients with bronchiectasis. This is clinically relevant as achieving culture negativity may indicate successful eradication of the infection, potentially leading to improved patient outcomes and reduced disease progression.

Secondary objectives include evaluating the effect of ColiFin® therapy compared to SOC on various clinical parameters over a 28-week period:

• Change in PA bacterial density in sputum.
• Frequency of mild to moderate pulmonary exacerbations requiring antibiotic treatment.
• Frequency of severe exacerbations leading to hospitalizations.
• Time to first pulmonary exacerbation requiring antibiotic treatment.
• Quality of life (QoL) measured by the St. George’s Respiratory Questionnaire (SGRQ).
• Respiratory Symptom Score (RSS) measured by the Quality of Life Questionnaire Bronchiectasis (QoL-B).
• Overall QoL measured by the QoL-B.
• Change in percent predicted forced expiratory volume in one second (ppFEV1).
• Change in antibiotic susceptibility in isolated sputum PA.
• Safety of ColiFin® therapy during the study.

The clinical trial involves participants diagnosed with **bronchiectasis**, a condition confirmed by chest CT scan. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a new positive sputum culture for Pseudomonas aeruginosa (PA) that is not older than 12 weeks at the time of screening. The trial excludes individuals with recent onset or worsening of respiratory symptoms within the last two months prior to the new positive PA sputum culture. The health status of participants is generally stable, as those with significant recent respiratory changes are not included. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial. The trial does not involve a vulnerable population, and both genders are represented. Key inclusion criteria include the requirement for women of childbearing potential to use effective contraception and for male participants to use condoms during the study period. The sponsor has not disclosed additional details about the selection process for the trial population.

The clinical trial is designed to evaluate the effect of **ColiFin®** therapy compared to standard of care (SOC) in achieving sputum/airway culture negativity for **Pseudomonas aeruginosa** (PA) 28 weeks after randomization in adult patients with **bronchiectasis**. This is a randomized, controlled, open-label, proof-of-concept trial. The trial is expected to run from February 2023 to March 2026, with an estimated participant involvement duration of 28 weeks. The study will include an initial screening visit, followed by treatment and follow-up visits, and conclude with an end-of-study visit.

Participants will be screened to confirm eligibility, which includes criteria such as age ≥ 18 years, verified bronchiectasis by chest CT scan, and a new positive sputum culture for PA. The screening visit will also involve obtaining written informed consent and conducting a negative serum/urine pregnancy test for women of childbearing potential. Following successful screening, participants will be randomized to receive either the investigational product, **ColiFin®**, or SOC. The investigational product is administered via inhalation as a nebulizer solution, with a maximum daily dose of 4 million IU and a total treatment period of 28 days.

Study visits will be scheduled to monitor the primary endpoint, which is the proportion of participants achieving three consecutively negative sputum/airway cultures for PA 28 weeks post-randomization. Secondary endpoints include changes in PA levels in sputum, rates of pulmonary exacerbations, and changes in quality of life and respiratory symptoms. Participants will be required to attend regular follow-up visits to assess these outcomes and ensure adherence to the treatment protocol.

The trial will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the use of **ColiFin®**, an experimental medication formulated as a **nebuliser solution**. The active substance in ColiFin® is **colistimethate sodium**, classified under the pharmacotherapeutic group of other antibacterial agents, specifically polymyxins, with the ATC code J01XB01. The medication is provided as a powder for the preparation of a solution intended for inhalation use. The maximum daily dose is 4 million international units (IU), with a total maximum dose of 112 million IU over the treatment period. The treatment is administered via inhalation, and the maximum treatment period is 28 days. The product is manufactured by PARI PHARMA GMBH and is not a paediatric formulation.

In addition to the experimental treatment, the study includes a standard-of-care (SOC) therapy as a comparator. The primary objective of the trial is to evaluate the effect of ColiFin® therapy compared to SOC in achieving sputum or airway culture negativity for **Pseudomonas aeruginosa** 28 weeks after randomization. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the proportion of sputum/airway culture negativity, defined as three consecutively negative sputum/airway cultures for **Pseudomonas aeruginosa** (PA), measured 28 weeks after randomization. This endpoint will determine the effectiveness of ColiFin® therapy compared to standard of care (SOC) in achieving culture negativity.

Secondary endpoints include several measures to further evaluate the treatment's impact. These are: the change in PA (semi-quantitative) in sputum from baseline to Day 29 of treatment, the rate of pulmonary exacerbations and severe exacerbations (hospitalizations) within 28 weeks post-randomization, and the time to first pulmonary exacerbation after treatment initiation. Additionally, changes from baseline in the respiratory symptom domain of the St. George's Respiratory Questionnaire (SGRQ) and quality of life as measured by both SGRQ and Quality of Life-Bronchiectasis (QOL-B) will be assessed until 28 weeks after randomization. Other secondary endpoints include changes in percent predicted forced expiratory volume in one second (ppFEV1) and antibiotic susceptibility in isolated sputum PA until 28 weeks post-randomization.