Efficacy and Safety Assessment of Budesonide, Glycopyrronium, and Formoterol Fumarate MDI in Severe Asthma Uncontrolled by Standard Therapy

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 severe and inadequately controlled asthma. This is clinically relevant as improving lung function is crucial for managing asthma symptoms and reducing the risk of exacerbations in patients who do not achieve adequate control with standard treatments.

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 effect 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 **1759 participants** diagnosed with **severe and inadequately controlled asthma**. The study population includes both male and female subjects, ranging in age from **12 to 80 years**. Participants were selected based on specific criteria, including a **BMI** of less than 40 kg/m² and compliance with a 14-day electronic diary during the screening phase. The trial population is characterized by individuals who have a documented history of physician-diagnosed asthma for at least one year and are regularly using a stable daily regimen of inhaled corticosteroids and long-acting beta-agonists. Participants must not have had a respiratory infection or asthma exacerbation requiring systemic corticosteroids in the four weeks prior to randomization. The study also considers lifestyle factors such as the ability to adjust current asthma therapy and demonstrate proper metered-dose inhaler administration technique. Both genders are included, and the trial acknowledges the inclusion of a vulnerable population. The selection process ensures that participants are willing and able to comply with the study requirements, including the use of specific asthma medications during the trial period.

The clinical trial is designed as a **randomized**, **double-blind**, **double-dummy**, parallel-group, multicenter study with a variable length ranging from 24 to 52 weeks. The primary objective is to assess the efficacy and safety of Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhaler (MDI) compared to Budesonide and Formoterol Fumarate MDI and Symbicort® Pressurized MDI in adult and adolescent participants with severe and inadequately controlled **asthma**. The trial will evaluate changes in lung function and the rate of severe asthma exacerbations as primary endpoints, with secondary endpoints including the onset of action, changes in FEV1, and quality of life assessments over 24 weeks.

Participants will be involved in the study for a period of up to 52 weeks, with the trial estimated to conclude by March 2025. The study includes several key visits: an initial screening visit to determine eligibility based on criteria such as age, asthma history, and current treatment regimen; multiple follow-up visits to monitor lung function, medication adherence, and any adverse events; and an end-of-study visit to assess overall outcomes and gather final data. Participants are required to demonstrate compliance with the study protocol, including the use of an electronic diary and proper inhaler technique.

Inclusion criteria specify that participants must be between 12 to 80 years of age, have a documented history of physician-diagnosed asthma, and be on a stable inhaled corticosteroid/long-acting beta-agonist regimen. Exclusion criteria include recent respiratory infections or asthma exacerbations requiring systemic corticosteroids. Participants may be withdrawn from the study if they fail to adhere to the protocol, experience significant adverse events, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the comparative efficacy and safety of the investigational inhaler therapy in managing severe asthma.

The clinical trial involves several treatments, including both experimental and non-experimental medications. The **experimental medication** is Budesonide, Glycopyrronium, and Formoterol Fumarate, administered as a pressurised inhalation suspension. This medication is delivered via inhalation, with a maximum daily dose of 4 dosage forms, and a maximum treatment period of 52 weeks. The medication is designed to assess its efficacy and safety in participants with inadequately controlled asthma.

Another experimental treatment is Budesonide and Formoterol Fumarate, also administered as a pressurised inhalation suspension. This treatment is similarly delivered via inhalation, with the same dosing schedule as the previous medication. It serves as a comparator to evaluate the relative effectiveness of the experimental medication.

Symbicort, containing Budesonide and Formoterol Fumarate Dihydrate, is used as a comparator treatment. It is provided as a pressurised inhalation suspension, with a maximum daily dose of 4 dosage forms. This treatment is also administered via inhalation and is used to compare its effects with the experimental medication over a 52-week period.

**Prednisolone** is included as a non-experimental treatment, administered in tablet form. It is taken orally, with a maximum daily dose of 50 mg. Prednisolone or equivalent corticosteroid dose therapy is used for severe acute exacerbations in participants.

Salbutamol, a short-acting selective beta-2-adrenoreceptor agonist, is used as an auxiliary treatment. It is administered as a pressurised inhalation suspension, with a maximum daily dose of 200 micrograms. This medication is used for inhalation to provide relief from acute asthma symptoms.

Placebo treatments are also utilized in the trial. A placebo pressurised metered-dose inhaler (pMDI) is used to match Budesonide/Formoterol Fumarate pMDI, and another placebo MDI is used to match Budesonide, Glycopyrronium, and Formoterol Fumarate/Budesonide and Formoterol Fumarate MDI. These placebos are employed to maintain the double-blind nature of the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to provide a comprehensive assessment of the efficacy and safety of the experimental medication in comparison to standard treatments and placebos in managing inadequately controlled asthma.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the change from baseline in morning pre-dose trough **FEV1** over 24 weeks, as well as the rate of severe asthma exacerbations. Secondary endpoints include 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 evaluated, with a decrease of ≥0.5 indicating a response. The St. George's Respiratory Questionnaire (SGRQ) will also be used, with a decrease of ≥4.0 units indicating a response at Week 24.

The trial will also assess the rate of severe asthma exacerbations over the treatment period, time to first severe asthma exacerbation, and rate of moderate/severe asthma exacerbations. Specific subgroups, such as participants with a percent predicted **FEV1** ≤ 55% at baseline or those with ≥1 severe exacerbation in the 12 months prior to Visit 1, will be analyzed for their rate of severe asthma exacerbations. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on inadequately controlled asthma.