Study to Compare QVM149 and Free Triple Combination of Salmeterol/Fluticasone + Tiotropium

Study Overview
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Brief Summary
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The purpose of this trial was to demonstrate that the efficacy of two treatment arms of the fixed-dose combination product QVM149 was non-inferior to the efficacy of the free combination arm of salmeterol/ fluticasone+ tiotropium in uncontrolled moderate to severe asthmatic patients. The planned duration of treatment in this study was 24 weeks, followed up by a 7-day follow-up period.

Detailed Description
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This study used a randomized, partially-blinded, 24-week, parallel-group, non-inferiority, open-label active controlled design. The study was partially open-label. Investigators and patients had knowledge of treatment allocation between QVM149 and/or comparator, however the QVM149 strength allocation was masked. The global sponsor team responsible for data review and analysis was blinded to all treatment allocations The study consisted of a screening period of up to 1-week, run-in period of 2-weeks, randomized treatment period of 24-weeks, and a follow-up period of 1-week. At the screening visit, informed consent was obtained, and current and prohibited medications were reviewed. Rescue medication was provided to all patients who met the eligibility criteria and was to be used on an as needed basis throughout the study. At the run-in visit, inclusion and exclusion criteria were reviewed and the patients were supplied with open-label long acting β2-adrenergic agonist/inhaled corticosteroids (LABA/ICS) salmeterol/fluticasone 50/250 μg b.i.d or 50/500 μg b.i.d to match their ICS background medication dose to be stopped at randomization visit. All patients who met the eligibility criteria were randomized to 1 of 3 treatment arms with a randomization ratio of 1:1:1. The patients were stratified at randomization according to the ICS dose component of background ICS/LABA (medium or high dose) and region. Treatment period visits were scheduled every 8 weeks. The study used two doses of QVM149 (high dose [150/50/160 μg] and a medium dose [150/50/80 μg] o.d. delivered via Concept1 inhaler) and a comparator treatment (salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d delivered via Respimat®). All randomized patients were contacted (by telephone) 7 days following the last dose of study medication or last visit, whichever was later, for Safety Follow-up visit.

Official Title
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A Multicenter, Partially-Blinded, Randomized, 24-Week, Parallel-Group, Non-Inferiority, Open-Label Active Controlled Study to Compare the Efficacy and Safety of QVM149 With a Free Triple Combination of Salmeterol/Fluticasone + Tiotropium in Patients With Uncontrolled Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: QVM149
* Drug: Salmeterol/fluticasone plus tiotropium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of asthma for a period of at least 6 months prior to Visit 1 with current asthma severity ≥ step 4 (GINA 2017). Patients who had used ICS/LABA combinations for asthma for at least 3 months and at stable medium or high dose of ICS/LABA for at least 1 month prior to Visit 1. Patients were required to be symptomatic at screening despite treatment with medium or high stable doses of ICS/LABA as defined by ACQ-7 score ≥ 1.5 at visits 101 and 201 (randomization visit). Patients with history of at least one severe asthma exacerbation which required medical care from a physician, emergency room visit (or local equivalent structure) or hospitalization in the 12 months prior to Visit 1 and required systemic corticosteroid treatment for at least 3 days including physician guided self-management treatment with oral corticosteroids as part of written asthma action plan. Pre-bronchodilator FEV1 of < 85 % of the predicted normal value for the patient after withholding bronchodilators prior to spirometry at both Visit 101 and Visit 201. Patients who demonstrated an increase in FEV1 of ≥ 12% and 200 ml. Exclusion Criteria: Patients who had a smoking history of greater than 20 pack years. Patients diagnosed with Chronic Obstructive Pulmonary Disease (COPD). Patients who had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). Patients treated with a LAMA for asthma within 3 months prior to Visit 1. Patients who had a respiratory tract infection or clinical significant asthma worsening as defined by Investigator within 4 weeks prior to Visit 1 or between Visit 1 and Visit 201.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QVM149 150/50/80 μg<br>QVM149 150/50/80 μg o.d. delivered via Concept1 | Drug: QVM149<br>* Indacaterol acetate / glycopyrronium bromide / mometasone furoate<br>|
| Experimental: QVM149 150/50/160 μg<br>QVM149 150/50/160 μg o.d. delivered via Concept1 | Drug: QVM149<br>* Indacaterol acetate / glycopyrronium bromide / mometasone furoate<br>|
| Active Comparator: Salmeterol/fluticasone 50/500 μg plus tiotropium 5 μg<br>Salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d. delivered via Respimat® | Drug: Salmeterol/fluticasone plus tiotropium<br>* Free triple arm of salmeterol / fluticasone plus tiotropium<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Total Score | The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional funtion, and emotional stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. Trough FEV1 is the mean of two FEV1 values measures taken 15 minutes (min) and 45 min prior to evening dose. | Baseline, Week 8, Week 16 and Week 24 | 
| Change From Baseline in Asthma Control Questionnaire (ACQ-7) Total Score | The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on airway calibre (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control and 6 indicating poor control. The questions are equally weighted and the total score is the mean of the seven items. Higher score indicates worst symptoms. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer. A negative change from baseline indicates improvement in lung function. | Baseline, Week 16 and Week 24 | 
| Change From Baseline in AQLQ Total Score | The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional function and environmental stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. | Baseline and Week 16 | 
| Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Decrease From Baseline ACQ-7 ≥ 0.5 | The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on airway calibre (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control and 6 indicating poor control. The questions are equally weighted and the total score is the mean of the seven items. Higher score indicates worst symptoms. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer. A negative change from baseline indicates improvement in lung function. Decrease of ACQ-7 score of at least 0.5 from baseline was considered clinically meaningful. | Baseline and Week 24 | 
| Percentage of Patients Achieving the Minimally Clinically Important Difference (MCID) Change From Baseline AQLQ ≥ 0.5 | The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional function and environmental stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. An improvement of 0.5 points in AQLQ score is considered to be the minimally clinically important difference in asthma. | Baseline and Week 24 | 
| Change From Baseline in Forced Vital Capacity (FVC) | FVC is the total volume of air exhaled during a expiratory maneuvre. It was assessed by performing a spirometry assessment. | Baseline, Week 8, Week 16 and Week 24 | 
| Change From Baseline in Forced Expiratory Flow Between 25% and 75% of Forced Vital Capacity (FEF25-75) | Forced expiratory flow during the mid (25 - 75%) portion of the FVC. It was assessed by performing spirometric assessment. | Baseline, Week 8, Week 16 and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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QVM149, Asthma, Moderate Asthma, Severe Asthma, ICS/LABA/LAMA, ICS/LABA, LAMA, Adult