Assessment of Efficacy and Safety of Budesonide and Formoterol Fumarate Inhalation in Patients with Inadequately Controlled Asthma

The primary objective of this study is to evaluate the effect of **BFF MDI 320/9.6 µg** relative to **BD MDI 320 µg** on lung function in participants with inadequately controlled asthma, with a focus on demonstrating superiority. This is clinically relevant as it aims to improve the management of asthma, a condition characterized by chronic inflammation and airway obstruction, by potentially offering a more effective treatment option.

Secondary objectives include:

• Assessing the effect of BFF MDI 320/9.6 µg relative to BD MDI 320 µg on lung function, further supporting the primary objective.
• Evaluating the impact of BFF MDI 320/9.6 µg relative to BD MDI 320 µg on symptoms and patient-reported outcomes, which are crucial for understanding the overall benefit and patient satisfaction with the treatment.

The clinical trial involves a total of **470 participants** diagnosed with **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 documented history of physician-diagnosed asthma for at least six months prior to the initial visit, and a stable use of inhaled corticosteroids (ICS) or an ICS/long-acting beta-agonist (LABA) regimen for a minimum of eight weeks before the trial commencement. The trial includes individuals with a body mass index (BMI) of less than 40 kg/m², and females are required to be either not of childbearing potential or using a highly effective form of birth control. Participants must demonstrate an acceptable metered-dose inhaler (MDI) administration technique and maintain a minimum eDiary compliance of 70% during the screening phase. The trial population is characterized by a pre-bronchodilator/pre-dose forced expiratory volume in one second (FEV1) of less than 90% of the predicted normal value at specific visits, with a requirement for asthma stability during the run-in period as assessed by the investigator. The study does not provide specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group, multicenter study with a duration of 24 weeks. The primary objective is to assess the efficacy and safety of a **budesonide** and **formoterol fumarate** metered dose inhaler (MDI) compared to a **budesonide** MDI and an open-label **Symbicort** Turbuhaler in participants with inadequately controlled **asthma**. The trial will involve participants aged 12 to 80 years who meet specific inclusion criteria, such as a documented history of physician-diagnosed asthma and a stable daily inhaled corticosteroid (ICS) or ICS/long-acting beta-agonist (LABA) regimen. The primary endpoint is the change from baseline in morning pre-dose trough forced expiratory volume in one second (FEV1) over 24 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, asthma history, and lung function tests. Following randomization, participants will attend regular follow-up visits to monitor lung function, medication adherence, and any adverse events. The end-of-study visit will occur at the conclusion of the 24-week treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints, including changes in FEV1 and rescue medication use.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including significant protocol deviations, adverse events, or withdrawal of consent. Participants are required to demonstrate acceptable MDI administration technique and maintain a minimum eDiary compliance of 70% during the screening phase. The trial aims to provide comprehensive data on the comparative efficacy and safety of the investigational products in managing inadequately controlled asthma.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The **experimental medication** "Symbicort" is a pressurised inhalation suspension containing **budesonide** and **formoterol fumarate dihydrate**. It is administered via inhalation at a dosage of 160 micrograms of budesonide and 4.5 micrograms of formoterol per puff. The maximum daily dose is four puffs, and the treatment period extends up to 24 weeks. This medication is produced by AstraZeneca AB and is used in the management of obstructive airway diseases.

Another experimental treatment, "BFF (PT009)", is also a pressurised inhalation suspension containing **formoterol fumarate** and **budesonide**. It is administered via inhalation with a maximum daily dose of four puffs, similar to Symbicort, and is used for a maximum treatment period of 24 weeks. This formulation is also developed by AstraZeneca AB and is intended for use in combination with anticholinergics and corticosteroids.

The comparator treatment "BD (PT008)" is a pressurised inhalation suspension containing **budesonide**. It is administered via inhalation with a maximum daily dose of four puffs over a 24-week period. This treatment is also produced by AstraZeneca AB and serves as a corticosteroid therapy in the trial.

The non-experimental treatment "Salbutamol" is a pressurised inhalation suspension containing **salbutamol**. It is administered via inhalation with a maximum daily dose of 1200 micrograms, and the treatment period is up to 24 weeks. Salbutamol acts as a short-acting selective beta-2-adrenoreceptor agonist and is used as an auxiliary treatment in the trial.

A placebo metered-dose inhaler (MDI) and empty TBH devices are included in the study for training purposes. These do not contain any active substances and are not intended for therapeutic use. The placebo is used to maintain the double-blind nature of the trial.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed treatment regimens. The trial aims to assess the efficacy and safety of these treatments in participants with inadequately controlled asthma over a 24-week period.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in morning pre-dose trough **FEV1** (Forced Expiratory Volume in one second) over a 24-week period. This parameter is crucial for evaluating lung function improvement in participants with inadequately controlled asthma.

Secondary endpoints include several measures: the change from baseline in **FEV1** AUC0-3 over 24 weeks, the change from baseline in the mean number of puffs of rescue medication use per day over 24 weeks, and the percentage of responders in the Asthma Control Questionnaire (ACQ-7 and ACQ-5) with a decrease of ≥ 0.5 indicating a response over 24 weeks. Additionally, the percentage of responders in the Asthma Quality of Life Questionnaire (AQLQ(s)+12) with an increase of ≥ 0.5 indicating a response over 24 weeks, and specifically from 12 to 24 weeks, will be evaluated. The onset of action on Day 1 will also be assessed by measuring the absolute change in **FEV1** at 5 minutes post-dose.

These efficacy parameters will be measured and collected at specified time points throughout the trial, using validated scales and instruments to ensure accuracy and reliability. The analysis will focus on comparing the effects of the Budesonide and Formoterol Fumarate Metered Dose Inhaler (BFF MDI) relative to the Budesonide Metered Dose Inhaler (BD MDI) and open-label Symbicort® Turbuhaler® in the study population.