Efficacy and Safety Evaluation of Tanimilast (CHF6001) as an Add-On to Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease and Chronic Bronchitis

The primary objective of this study is to evaluate the **efficacy** of two doses of CHF6001 as an add-on to maintenance triple therapy, which includes inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), in reducing the rate of moderate and severe exacerbations in patients with **Chronic Obstructive Pulmonary Disease (COPD)** and Chronic Bronchitis after 52 weeks of treatment. This is clinically relevant as reducing exacerbations can significantly improve patient outcomes and quality of life, as well as reduce healthcare utilization.

Secondary objectives include:

• Evaluating the efficacy of the two doses of CHF6001 add-on to maintenance triple therapy on health-related quality of life after 52 weeks of treatment, as measured by the change in the St. George's Respiratory Questionnaire (SGRQ) total score.
• Assessing the efficacy of the two doses of CHF6001 on lung function, health-related quality of life, and severe exacerbations in a pooled analysis of specific study cohorts, as well as other clinical outcome measures, in comparison with maintenance triple therapy alone.
• Evaluating the safety and tolerability of the two doses of CHF6001.

The clinical trial involves a total of **2263 participants** diagnosed with **chronic obstructive pulmonary disease (COPD)** and chronic bronchitis. The study population includes both male and female subjects aged 40 years and older. Participants were selected based on their established diagnosis of COPD with chronic bronchitis, and they must have a history of smoking, either as current smokers or ex-smokers who quit at least six months prior to the screening, with a smoking history of at least 10 pack years. The trial includes individuals who are currently prescribed maintenance triple therapy (ICS, LABA, LAMA) and have been receiving this treatment for at least 12 months prior to screening. Participants are required to have a post-bronchodilator FEV1 of less than 60% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio of less than 0.7. Additionally, they must have experienced at least one moderate or severe COPD exacerbation in the previous year and have a COPD Assessment Test (CAT) score of 10 or higher. The trial population is composed of individuals who are willing and able to use electronic devices for COPD questionnaires and perform required outcome measurements, such as spirometry maneuvers. The study includes both genders and considers vulnerable populations, ensuring that females of childbearing potential have a negative pregnancy test at screening and agree to use acceptable contraceptive measures.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group study to evaluate the efficacy and safety of two doses of CHF6001 DPI as an add-on to maintenance triple therapy in subjects with **Chronic Obstructive Pulmonary Disease (COPD)** and chronic bronchitis. The trial aims to assess the reduction in the rate of moderate and severe exacerbations over a 52-week treatment period. Participants will be randomly assigned to receive either CHF6001 DPI or a placebo, both administered as an **inhalation powder**. The trial is expected to conclude by June 2025, with recruitment having commenced in June 2021.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit, or screening, will confirm eligibility based on criteria such as age, smoking history, and COPD diagnosis. Participants must demonstrate the ability to use electronic devices for COPD questionnaires and perform required outcome measurements. Follow-up visits will occur at regular intervals to monitor health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including changes in the annual rate of exacerbations and quality of life measures.

Participant involvement is expected to last for the full 52 weeks of the trial. However, conditions such as adverse events, lack of efficacy, or withdrawal of consent may lead to early termination from the study. The primary endpoint is the annual rate of moderate and severe exacerbations, while secondary endpoints include changes in the St. George's Respiratory Questionnaire (SGRQ) scores, time to first exacerbation, and medication discontinuation rates. The trial is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **CHF6001 DPI**, an experimental medication formulated as an **inhalation powder**. The active substance in CHF6001 DPI is **tanimilast**, a chemical compound also known by its synonyms such as CHF-6001 and TRANIMILAST. The medication is produced by CHIESI FARMACEUTICI S.P.A. and is administered via **inhalation use**. Two dosing regimens are evaluated: a maximum daily dose of 3200 µg and a lower dose of 1600 µg, with a total maximum dose of 1164800 µg and 582400 µg respectively, over a treatment period of 52 weeks. The trial aims to assess the efficacy of CHF6001 DPI as an add-on to maintenance triple therapy in subjects with Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis.

The study also includes a **placebo** designed to match CHF6001 DPI, ensuring the double-blind nature of the trial. The placebo is administered in the same pharmaceutical form and route as the experimental medication, which is **inhalation powder** for **inhalation use**. The placebo serves as a comparator to evaluate the efficacy of CHF6001 DPI when added to the standard maintenance triple therapy, which includes inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). The placebo is utilized to maintain the integrity of the study design and to provide a baseline for assessing the therapeutic benefits of the experimental treatment.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints over a 52-week period. The primary endpoint is the annual rate of moderate and severe exacerbations in subjects with Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis. This will be measured to determine the efficacy of two doses of CHF6001 DPI as an add-on to maintenance triple therapy compared to a placebo.

Secondary endpoints include several parameters: change from baseline in the St. George's Respiratory Questionnaire (SGRQ) Total score at week 52, time to first moderate/severe exacerbation, annual rate of severe exacerbations, and time to first severe exacerbation. Additional secondary endpoints involve changes from baseline in morning pre-dose **FEV1** at week 52, changes in SGRQ Domain scores, and SGRQ response defined as a change from baseline in SGRQ score ≤ -4 at week 52. The trial will also assess changes from baseline to the last inter-visit period (week 40-52) in the average E-RS total and sub-scale scores, E-RS response (change from baseline in E-RS total score ≤ -2) at week 52, and changes in the percentage of days without intake of rescue medication and in the average daily use of rescue medication (number of puffs/day).

Furthermore, the time to study medication discontinuation due to any reason, and the time to first moderate or severe exacerbation or study medication discontinuation due to any adverse events, lack of efficacy, or death (composite endpoint) will be evaluated. These efficacy parameters will be collected and analyzed using validated scales and patient-reported outcomes at specified timepoints, including baseline, week 52, and during the last inter-visit period. The trial will utilize electronic devices for COPD questionnaires and spirometry maneuvers to ensure accurate and reliable data collection.