Evaluation of the Efficacy and Safety of Fluticasone Propionate/Salbutamol Sulfate in Reducing Severe Asthma Exacerbations in Asthma Patients

The primary objective of this study is to assess the **efficacy** of high dose (HD) and low dose (LD) fluticasone propionate (Fp)/albuterol sulfate (ABS) eMDPI compared to ABS eMDPI in decreasing severe clinical asthma exacerbations (CAEs) when used as a rescue medication. This is clinically relevant as reducing the frequency and severity of asthma exacerbations can significantly improve patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the efficacy of Fp/ABS eMDPI 2 inhalations taken as needed (prn) compared to ABS eMDPI 2 inhalations prn and the effect on systemic corticosteroid (SCS) exposure.
• Evaluating the safety and tolerability of Fp/ABS eMDPI 2 inhalations prn over 24 weeks.

The clinical trial involves a total of **1337 participants** diagnosed with **asthma**, aiming to evaluate the efficacy of high and low doses of fluticasone propionate/albuterol sulfate eMDPI as a rescue medication. The study population includes both male and female subjects, aged 4 years and older, with a documented diagnosis of asthma for at least one year. Participants are required to have a history of at least one severe clinical asthma exacerbation within the past 12 months and must be on a stable dose of prescribed inhaled asthma controller medication for at least one month prior to the screening visit. The trial includes a vulnerable population, with age ranges spanning from children to adults. Participants' general health status is characterized by their asthma condition, and they must meet specific lung function criteria based on their age group. The selection process ensures that participants are capable of providing informed consent or assent, with written consent obtained from a parent or legally acceptable representative for minors. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, active-controlled, parallel-group study to evaluate the efficacy and safety of a fixed-dose combination of **fluticasone propionate** and **salbutamol sulfate** in patients with **asthma**. The primary objective is to assess the efficacy of high-dose and low-dose fluticasone propionate/albuterol sulfate eMDPI compared to albuterol sulfate eMDPI in reducing severe clinical asthma exacerbations when used as a rescue medication. The trial is expected to commence on March 1, 2024, and conclude by December 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented asthma diagnosis, and specific lung function parameters. Following successful screening, participants will be randomized into treatment groups. The trial will include multiple follow-up visits to monitor efficacy and safety endpoints, including the time to first severe clinical asthma exacerbation and secondary endpoints such as the annualized severe exacerbation rate and changes in asthma control and quality of life questionnaires. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of treatment outcomes and any adverse events.

The expected duration of participant involvement is up to 35 days, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. Participants will be required to adhere to the study protocol, including the use of inhalation powder as the route of administration for the investigational products. The trial will ensure rigorous monitoring to maintain the integrity of the double-blind design and the reliability of the collected data.

The clinical trial involves the administration of an **experimental medication** consisting of a fixed-dose combination of **fluticasone propionate** and **salbutamol sulfate**. This medication is provided in the form of an **inhalation powder** and is identified by the sponsor product code TEV-56248. The medication is administered via the **inhalation route**. The maximum daily dose is 660 µg, with a total maximum dose of 660 µg over a treatment period of up to 35 days. The medication is intended for use as a rescue treatment in patients with asthma to evaluate its efficacy in reducing severe clinical asthma exacerbations.

In addition to the experimental medication, the study includes the use of a **comparator treatment** known as ProAir® RespiClick®, which contains **salbutamol sulfate** as the active ingredient. This comparator is also provided in the form of an **inhalation powder** and is administered via the **inhalation route**. The maximum daily dose for this treatment is 1404 µg, with a total maximum dose of 1404 µg over a treatment period of up to 35 days. ProAir® RespiClick® serves as a standard-of-care therapy to compare the efficacy and safety of the experimental medication.

Another non-experimental treatment used in the study is ProAir® Digihaler®, which also contains **salbutamol sulfate**. Similar to the comparator, this treatment is provided as an **inhalation powder** and administered via the **inhalation route**. The dosing schedule and maximum dose are identical to those of ProAir® RespiClick®, with a maximum daily dose of 1404 µg and a total maximum dose of 1404 µg over a 35-day period. ProAir® Digihaler® is utilized to monitor participant compliance through its digital inhaler technology, which records usage data to ensure adherence to the dosing regimen.

The efficacy of the investigational product in the clinical trial will be assessed primarily by evaluating the **time to first severe clinical asthma exacerbation (CAE)**, which is defined as a worsening of asthma symptoms. This primary endpoint will provide a direct measure of the treatment's impact on preventing severe exacerbations in patients with asthma. Secondary efficacy endpoints include the annualized severe CAE rate and the total annualized systemic corticosteroid (SCS) exposure over the treatment period. Additionally, patient-reported outcomes will be measured using the Asthma Control Questionnaire-5 (ACQ-5) and the Asthma Quality of Life Questionnaire + 12 (AQLQ+12). The ACQ-5 response at week 24 is defined as achieving a decrease in score from baseline of at least 0.5, while the AQLQ+12 response is defined as achieving an increase from baseline of at least 0.5.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the study, including at week 24. The use of validated scales such as the ACQ-5 and AQLQ+12 ensures the reliability and accuracy of patient-reported outcomes. The study is designed to compare the efficacy of high dose (HD) and low dose (LD) fluticasone propionate/albuterol sulfate eMDPI against albuterol sulfate eMDPI when used as a rescue medication. The trial will be conducted in a randomized, double-blind, multicenter, active-controlled, parallel-group format to ensure robust and unbiased results.