Efficacy and Safety Evaluation of Fluticasone Propionate/Salbutamol Sulfate Combination in Asthma Patients Aged 12 and Older: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to evaluate the **efficacy** of the Fluticasone Propionate/Albuterol Sulfate (Fp/ABS) combination delivered via an electronic Multidose Dry Powder Inhaler (eMDPI) in participants aged 12 years and older with **asthma**. This assessment is clinically relevant as it aims to determine the therapeutic potential of the Fp/ABS combination in managing asthma symptoms, which could lead to improved treatment options for patients.

Secondary objectives include:

• Evaluating the efficacy of Fp/ABS eMDPI when administered four times daily (QID).
• Assessing the safety and tolerability of Fp/ABS eMDPI administered QID over a 4-week period.
• Investigating the pharmacokinetics of Fp/ABS eMDPI, ABS eMDPI, and Fp eMDPI following a single dose administration.

The clinical trial involves a total of **813 participants** diagnosed with **asthma**. The study population includes both male and female subjects aged 12 years and older, with a specific focus on individuals who have had a diagnosis of asthma for at least six months. Participants are required to have a pre-bronchodilator FEV1 of 50 to 85% predicted normal for adults and 50 to 90% for those aged 12 to 17 years. The trial includes individuals who are currently using a beta-agonist as rescue medication, with or without asthma controller medication, and who have been on stable maintenance therapy for at least 30 days prior to the trial. The selection process ensures that participants are capable of performing necessary lung function tests and demonstrate proper inhaler technique. The trial population was selected based on their ability to comply with trial restrictions and attend follow-up visits. Key lifestyle considerations include the use of medically accepted birth control methods for females of childbearing potential. The trial does not include pregnant or breastfeeding females, and participants must not be attempting to become pregnant during the study period.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of a combination of **fluticasone propionate** and **salbutamol sulfate** in participants aged 12 years and older with **asthma**. The trial will be conducted over a period of four weeks, with participants randomly assigned to receive either the combination therapy, individual components, or a placebo, all delivered via a multidose dry powder inhaler. The primary objective is to assess the baseline-adjusted post-dose forced expiratory volume in one second (FEV1) area under the effect curve from time zero to 6 hours over the four-week period. Secondary endpoints include time to improvement in FEV1, duration of FEV1 increase, and changes in asthma control scores.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, asthma diagnosis, and lung function. This will be followed by a run-in period where participants demonstrate proper inhaler technique and compliance with trial procedures. Subsequent visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will involve final assessments of lung function and overall health status.

The expected length of participant involvement is approximately four weeks, with conditions for early termination including non-compliance with trial procedures, adverse events, or withdrawal of consent. Participants must be willing to comply with trial restrictions and attend all scheduled visits. The trial aims to provide valuable data on the efficacy and safety of the combination therapy in managing asthma symptoms, contributing to the broader understanding of treatment options for this condition.

The clinical trial involves the administration of several treatments, including an experimental medication and comparator treatments. The **experimental medication** is a combination of **fluticasone propionate** and **salbutamol sulfate**, delivered as an **inhalation powder**. This combination is identified by the sponsor product code TEV-56248 and is also known as ICS/SABA Digihaler. The maximum daily dose is 440 µg, with a total treatment period of 4 weeks. The medication is administered via inhalation, and participant compliance is monitored throughout the study.

One of the **comparator treatments** is ArmonAir® Digihaler®, which contains **fluticasone propionate** as the active substance. This treatment is also delivered as an **inhalation powder**. The maximum daily dose for ArmonAir® Digihaler® is 220 µg, with a treatment duration of 4 weeks. Administration is through inhalation.

Another **comparator treatment** is ProAir® Digihaler®, which contains **salbutamol sulfate**. This medication is provided as an **inhalation powder** with a maximum daily dose of 936 µg, administered over a 4-week period. The route of administration is inhalation.

Additionally, Albuterol Sulfate HFA is used as a **comparator treatment**. It contains **salbutamol sulfate** and is delivered as a **pressurised inhalation**. The maximum daily dose is 1080 µg, with a treatment period of 4 weeks. This medication is also administered via inhalation.

A **placebo** treatment, identified as Placebo TEV-56248, is included in the study. It is administered in a manner consistent with the other treatments, although specific details regarding its pharmaceutical form are not applicable. The placebo is used to maintain the double-blind nature of the trial.

The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the baseline-adjusted post-dose forced expiratory volume in one second (**FEV1**) area under the effect curve from time zero to 6 hours (AUEC0-6hr) over 4 weeks, and the baseline-adjusted trough **FEV1** at week 4. These measurements will provide insights into the respiratory function improvements in participants with asthma.

Secondary endpoints will further evaluate the treatment's efficacy and include the time to 15% and 12% improvement from baseline **FEV1** post-dose on day 1, and the duration of a 15% increase in **FEV1** from baseline post-dose on day 1. Additionally, patient-reported outcomes will be assessed using the Asthma Control Questionnaire-6 (ACQ-6) and the Asthma Control Test (ACT) at week 4. The ACQ-6 response is defined as achieving a decrease in score from baseline value of at least 0.5 for participants with a baseline ACQ-6 score of ≥1.5, while the ACT score response is defined as achieving an increase in score from baseline value of at least 3.

Other secondary endpoints include the occurrence of adverse events, serious adverse events, treatment withdrawal due to treatment-emergent adverse events, and plasma concentration of fluticasone propionate and albuterol sulfate at specified timepoints. These endpoints will be measured and collected at various timepoints throughout the trial to ensure comprehensive evaluation of the treatment's efficacy and safety profile.