Efficacy and Safety of Tanimilast DPI as Add-On to Triple Therapy in Chronic Obstructive Pulmonary Disease with 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 a combination of 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 over a 52-week period. This is clinically relevant as reducing exacerbations can significantly improve patient outcomes and quality of life, as well as decrease healthcare utilization.

Secondary objectives include:

• Evaluating the efficacy of the two doses of CHF6001 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, compared to maintenance triple therapy alone.
• Evaluating the safety and tolerability of the two doses of CHF6001.
• Comparing the efficacy, safety, and tolerability of the two doses of CHF6001 with Roflumilast.

The clinical trial involves a total of **2959 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**, specifically those with chronic bronchitis. The study population includes both **males and females aged 40 years and older**. Participants are required to have a documented history of at least one moderate or severe COPD exacerbation in the previous year and must be symptomatic at screening, defined by a COPD Assessment Test (CAT) score of 10 or higher. The trial includes current smokers or ex-smokers who quit smoking at least six months prior to the screening visit, with a smoking history of at least 10 pack years. Participants must be prescribed maintenance triple therapy, consisting of inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), according to GOLD 2020 recommendations, for at least 12 months prior to screening. The trial population was selected based on their ability to use electronic devices for COPD questionnaires and perform required outcome measurements, such as spirometry maneuvers. Females of childbearing potential must have a negative pregnancy test at screening and agree to use acceptable contraceptive measures. The study does not provide specific information on the general health status or lifestyle considerations beyond smoking history and medication adherence.

The clinical trial is designed as a **randomized**, **double-blind**, double-dummy, placebo- and active-controlled 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 will span a duration of 52 weeks, with the primary objective being to assess the reduction in the rate of moderate and severe exacerbations compared to a placebo arm. Participants will be randomly assigned to receive either CHF6001 DPI, Roflumilast (Daliresp®) 500µg, or a matching placebo, with the study medications administered via **inhalation** or **oral use** as appropriate.

The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, smoking history, and COPD diagnosis. Following successful screening, participants will undergo randomization and commence treatment. Regular follow-up visits will be scheduled throughout the trial to monitor safety, adherence, and efficacy outcomes, including spirometry maneuvers and completion of COPD questionnaires. The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last for the entire 52-week duration of the trial. However, conditions that may lead to early termination from the study include adverse events, lack of efficacy, or withdrawal of consent. The primary endpoint is the annual rate of moderate and severe exacerbations over the 52 weeks, while secondary endpoints include changes in SGRQ Total score, time to first exacerbation, and changes in FEV1, among others. The trial aims to provide comprehensive data on the efficacy and safety of CHF6001 DPI as an adjunctive treatment in COPD management.

The clinical trial involves the administration of **Roflumilast (Daliresp®)** in two different dosages as part of the experimental treatment. **Roflumilast** is provided in tablet form and is administered orally. The trial includes two dosages: 500 µg and 250 µg. The 500 µg dosage is administered once daily, with a maximum daily dose of 500 µg and a total maximum dose of 168,000 µg over a treatment period of 48 weeks. The 250 µg dosage is also administered once daily, with a maximum daily dose of 250 µg and a total maximum dose of 7,000 µg over a treatment period of 4 weeks. The active substance in both formulations is **Roflumilast**, a chemical compound developed by Chiesi Farmaceutici S.P.A.

The trial also evaluates the efficacy of **CHF6001 DPI**, an inhalation powder containing the active substance **Tanimilast**. This medication is administered via inhalation and is available in two dosages: 3200 µg and 1600 µg. The 3200 µg dosage is administered daily, with a maximum total dose of 1,164,800 µg over a 52-week period. The 1600 µg dosage is also administered daily, with a maximum total dose of 582,400 µg over the same period. **Tanimilast** is a chemical compound, and the product is also developed by Chiesi Farmaceutici S.P.A.

In addition to the experimental medications, the study includes placebo treatments to match both **Roflumilast (Daliresp®)** and **CHF6001 DPI**. These placebos are used to maintain the double-blind nature of the trial and are administered in the same form and frequency as their respective active treatments. The placebo for **Roflumilast** is provided in tablet form, while the placebo for **CHF6001 DPI** is provided as an inhalation powder. The use of placebos ensures that any observed effects can be attributed to the active medications rather than psychological or other non-specific effects.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. This monitoring is crucial for maintaining the integrity of the trial results and for accurately assessing the efficacy and safety of the experimental treatments. The trial is designed to evaluate the efficacy of the experimental treatments in reducing the rate of moderate and severe exacerbations in subjects with Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis over a 52-week period.

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 effectiveness of two doses of CHF6001 DPI as an add-on to maintenance triple therapy compared to a placebo.

Secondary endpoints include several measures: 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 Forced Expiratory Volume in 1 second (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 Evaluating Respiratory Symptoms (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.

Data collection will occur at specified intervals, with efficacy parameters being measured using validated scales and patient-reported outcomes. The analysis will focus on the time to study medication discontinuation due to any reason, time to first moderate or severe exacerbation, or study medication discontinuation due to class-related adverse events, lack of efficacy, or death, as well as the time to its individual components. These assessments will provide comprehensive insights into the efficacy of the treatment regimen under investigation.