Efficacy and Safety Assessment of Budesonide, Glycopyrronium, and Formoterol Fumarate MDI in Adults and Adolescents with Severe Asthma

The primary objective of this study is to evaluate the effect of **Budesonide**, **Glycopyrronium**, and **Formoterol Fumarate** Metered Dose Inhaler (BGF MDI) compared to Budesonide and Formoterol Fumarate (BFF) MDI or Symbicort Pressurized MDI on lung function in participants with inadequately controlled asthma. This is clinically relevant as it aims to determine the efficacy of BGF MDI in improving pulmonary function, which is crucial for managing severe asthma and reducing associated morbidity.

Secondary objectives include:

• Assessing the effect of BGF MDI relative to BFF MDI or Symbicort pMDI on lung function, patient-reported outcomes (PROs), and symptoms in participants with inadequately controlled asthma.
• Evaluating the impact of BGF MDI compared to BFF MDI or Symbicort pMDI on asthma exacerbations in participants with inadequately controlled asthma.

The clinical trial involves a total of **879 participants** diagnosed with **severe and inadequately controlled asthma**. The study population includes both male and female subjects, aged between 12 to 80 years, with a body mass index (BMI) of less than 40 kg/m². Participants were selected based on their documented history of physician-diagnosed asthma for at least one year prior to the study, and they must have been regularly using a stable daily inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) regimen with medium-to-high ICS doses for at least four weeks prior to the study. The trial includes individuals who are willing and able to adjust their current asthma therapy as required by the protocol. Participants must demonstrate an acceptable metered dose inhaler (MDI) administration technique and have no respiratory infection or asthma exacerbation treated with systemic corticosteroids in the four weeks prior to randomization. The study population is characterized by a compliance rate of at least 70% with the electronic diary during the screening period. Both genders are included, and the trial considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, double-dummy, parallel group, multicenter study** to evaluate the efficacy and safety of a **budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler (MDI)** compared to a budesonide and formoterol fumarate MDI and Symbicort® pressurized MDI in participants with severe and inadequately controlled asthma. The trial will span a variable length of 24 to 52 weeks, with the estimated end date set for March 21, 2025. The study aims to assess the effect of the investigational product on lung function and asthma exacerbations.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, asthma history, and current treatment regimen. Following successful screening, participants will be randomized and commence the treatment phase. Regular follow-up visits will be scheduled to monitor lung function, adherence to the treatment protocol, and any adverse events. The primary endpoint is the change from baseline in morning pre-dose trough FEV1 over 24 weeks, while secondary endpoints include the rate of severe asthma exacerbations and various quality of life measures. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

Participant involvement is expected to last between 24 to 52 weeks, depending on individual response and study progression. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial is structured to ensure rigorous data collection and analysis, maintaining the integrity and scientific validity of the study outcomes.

The clinical trial involves several treatments, including both experimental and non-experimental medications. **PREDNISOLONE** is utilized as a comparator treatment in the study. It is administered in the form of a tablet, with a maximum daily dose of 50 mg. The route of administration is oral, and the treatment period can extend up to 52 weeks. Prednisolone or an equivalent corticosteroid dose therapy is used for severe acute exacerbations.

**Symbicort**, containing **BUDESONIDE** and **FORMOTEROL FUMARATE DIHYDRATE**, is administered as a pressurised inhalation suspension. The maximum daily dose is 4 dosage forms, with the route of administration being inhalation. The treatment period is up to 52 weeks. Symbicort is used as a test treatment to assess its efficacy and safety in participants with inadequately controlled asthma.

**Trixeo Aerosphere** is another test treatment, consisting of **BUDESONIDE**, **GLYCOPYRRONIUM BROMIDE**, and **FORMOTEROL FUMARATE DIHYDRATE**. It is also administered as a pressurised inhalation suspension, with a maximum daily dose of 4 dosage forms. The inhalation route is used, and the treatment period is up to 52 weeks. This combination is evaluated for its effect on lung function and asthma exacerbations.

The study includes a placebo treatment, designed to match the Budesonide/Formoterol Fumarate pMDI and Budesonide, Glycopyronium, and Formoterol Fumarate/Budesonide and Formoterol Fumarate MDI. These placebos are used to maintain the double-blind nature of the trial and are administered via inhalation.

**SALBUTAMOL** is used as an auxiliary treatment in the study. It is administered as a pressurised inhalation suspension, with a maximum daily dose of 200 µg. The route of administration is inhalation, and the treatment period can last up to 52 weeks. Salbutamol serves as a short-acting selective beta-2-adrenoreceptor agonist, providing relief for asthma symptoms.

Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment protocols. The trial aims to assess the efficacy and safety of these treatments in adult and adolescent participants with inadequately controlled asthma.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the change from baseline in morning pre-dose trough **FEV1** over 24 weeks and the rate of severe asthma exacerbations. Secondary endpoints will evaluate various aspects such as the onset of action on Day 1, measured by the absolute change in **FEV1** at 5 minutes, and the change from baseline in **FEV1** AUC0-3 over 24 weeks. Additionally, the percentage of responders in the Asthma Control Questionnaire (ACQ-7 and ACQ-5) and the Asthma Quality of Life Questionnaire (AQLQ(s)+12) will be assessed, with specific criteria for response defined as a decrease or increase in scores over 24 weeks. The St. George's Respiratory Questionnaire (SGRQ) will also be used to determine the percentage of responders at Week 24.

The trial will also measure the rate of severe asthma exacerbations over the treatment period and the time to first severe asthma exacerbation. For pooled studies, additional secondary endpoints include the rate and time to first moderate/severe asthma exacerbations, and the rate of severe asthma exacerbations for participants with specific baseline characteristics, such as percent predicted **FEV1** ≤ 55% or those with ≥ 1 severe exacerbation in the 12 months prior to the study. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, which ranges from 24 to 52 weeks.