Evaluation of Budesonide, Glycopyrronium Bromide, and Formoterol Fumarate on Cardiopulmonary Outcomes in Chronic Obstructive Pulmonary Disease Patients

The primary objective of this study is to evaluate the effect of combination **triple therapy** (BGF MDI 320/14.4/9.6 µg) compared with dual bronchodilator therapy (GFF MDI 14.4/9.6 µg) on severe cardiopulmonary outcomes in patients with **Chronic Obstructive Pulmonary Disease (COPD)**. This is clinically relevant as it aims to determine the efficacy of a more comprehensive treatment approach in reducing severe outcomes associated with COPD, which can significantly impact patient morbidity and mortality.

Secondary objectives include evaluating the effect of the combination triple therapy compared with dual bronchodilator therapy on:

• Severe COPD exacerbations
• Severe cardiac events
• Cardiopulmonary deaths
• Moderate/severe COPD exacerbations
• Myocardial Infarction hospitalization (or cardiac death)
• Heart Failure acute healthcare visit/hospitalization (or cardiac death)

The clinical trial involves a total of **3635 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**. The study population comprises both male and female subjects, aged between **40 to 80 years**. Participants were selected based on specific criteria, including a confirmed diagnosis of COPD, a history of smoking with at least 10 pack-years, and a baseline peripheral blood eosinophil count of ≥ 100 cells/mm³. The trial does not include a vulnerable population. Participants are required to demonstrate an acceptable metered-dose inhaler (MDI) administration technique and must be willing to adjust their current COPD therapy as per the protocol. Lifestyle considerations include a history of smoking, and participants must fulfill at least one cardiovascular disease or risk factor criterion. The trial aims to evaluate the effect of combination triple therapy compared with dual bronchodilator therapy on severe cardiopulmonary outcomes.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of a combination triple therapy using Budesonide, Glycopyrronium, and Formoterol Fumarate Metered-Dose Inhaler (MDI) compared to dual bronchodilator therapy with Glycopyrronium and Formoterol Fumarate MDI in patients with **Chronic Obstructive Pulmonary Disease (COPD)**. The primary objective is to assess the effect on severe cardiopulmonary outcomes. The trial is expected to commence recruitment on July 23, 2024, and conclude by March 7, 2028, with a maximum treatment period of 36 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, smoking history, and COPD diagnosis. This visit will also include assessments like a post-bronchodilator FEV1/FVC ratio and peripheral blood eosinophil count. Following successful screening, participants will be randomized and begin treatment. Regular follow-up visits will be scheduled to monitor health status, adherence to the inhalation technique, and any adverse events. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints, including time to first severe cardiac or COPD event.

Participant involvement is expected to last up to 36 months, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or any adverse events that, in the investigator's opinion, warrant discontinuation. The study will employ a double-blind methodology to ensure unbiased results, with blinding achieved through modifications such as changing the color of the dust cap on the inhaler actuator. The trial will be conducted across multiple centers, ensuring a diverse participant pool and robust data collection.

The clinical trial involves the administration of **SALBUTAMOL**, a selective beta-2-adrenoreceptor agonist, as an auxiliary treatment. The pharmaceutical form of SALBUTAMOL is a pressurised inhalation suspension. The route of administration is via **inhalation**. The maximum daily dose is 1200 micrograms, with a total dose not exceeding 400 micrograms per administration. The treatment period is set for a maximum of 36 weeks. Compliance with the dosing schedule will be monitored throughout the trial.

The experimental treatment in this study is the **Trixeo Aerosphere**, which contains a combination of **budesonide**, **glycopyrronium bromide**, and **formoterol fumarate dihydrate**. This product is also a pressurised inhalation suspension and is administered via inhalation. The maximum daily dose is set at 4 dosage forms, with a total dose of 4 dosage forms per administration. The treatment period is also 36 weeks. For blinding purposes, the Trixeo Aerosphere will be assembled using the same dose indicator and actuator as the Bevespi Aerosphere, both previously approved for use with Trixeo Aerosphere.

The comparator treatment is the **Bevespi Aerosphere**, which contains **glycopyrronium bromide** and **formoterol fumarate dihydrate**. This product is administered as a pressurised inhalation suspension via inhalation. The maximum daily dose is 4 dosage forms, with a total dose of 4 dosage forms per administration. The treatment period is 36 weeks. For blinding purposes, the colour of the dust cap on the actuator will be changed to white. Compliance with the dosing schedule will be monitored to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed by evaluating the effect of combination triple therapy with Budesonide, Glycopyrronium, and Formoterol Fumarate Metered-Dose Inhaler (BGF MDI) compared to dual bronchodilator therapy with Glycopyrronium and Formoterol Fumarate MDI (GFF MDI) on severe cardiopulmonary outcomes in patients with Chronic Obstructive Pulmonary Disease (COPD). The primary endpoint for efficacy assessment is the time to the first severe cardiac or **COPD** event. Secondary endpoints include time to the first severe COPD exacerbation, time to the first severe cardiac event, time to cardiopulmonary death, moderate/severe COPD exacerbation rate, time to myocardial infarction (MI) hospitalization or cardiac death, and time to heart failure (HF) acute healthcare visit or hospitalization or cardiac death.

These endpoints will be measured and collected throughout the trial duration, with specific timepoints for assessment not explicitly detailed. The trial is designed as a randomized, double-blind, parallel-group, multi-center, Phase III study. The efficacy parameters will be analyzed to determine the relative effectiveness of the BGF MDI therapy compared to the GFF MDI therapy in reducing severe cardiopulmonary outcomes in the target population. The trial is expected to conclude by March 2028, with recruitment starting in July 2024.