A Multicenter Randomized 52 Week Treatment Double-blind, Triple Dummy Parallel Group Study to Assess the Efficacy and Safety of QMF149 Compared to Mometasone Furoate in Participants With Asthma

Study Overview
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Brief Summary
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The purpose of the trial is to evaluate the efficacy and safety of two different doses of QMF149 (QMF149 150/160 µg and QMF149 150/320 µg via Concept1) over two respective MF doses (MF 400 µg and MF 800 µg via Twisthaler® (total daily dose)) in poorly controlled asthmatic participants as determined by pulmonary function testing, and effects on asthma control

Official Title
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A Multicenter Randomized 52 Week Treatment Double-blind, Triple Dummy Parallel Group Study to Assess the Efficacy and Safety of QMF149 Compared to Mometasone Furoate in Patients With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Indacaterol acetate/Mometasone furoate
* Drug: Mometasone furoate
* Drug: Salmeterol xinafoate/fluticasone propionate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a diagnosis of asthma, for a period of at least 1 year prior to Visit 1 (Screening) Participants who have used medium or high dose inhaled corticosteroids (ICS) or low dose of long acting beta-2 agonist (LABA)/ICS combinations for asthma for at least 3 months and at stable doses for at least 1 month prior to Visit 1 Participants must have ACQ-7 score ≥ 1.5 at Visit 101 and at Visit 102 (prior to double-blind treatment) and qualify for treatment with medium or high dose LABA/ICS Pre-bronchodilator ≥ 50% Forced expiratory volume in 1 second (FEV1) of < 85 % of the predicted normal value for the participants after withholding bronchodilators at both Visit 101 and 102, according to American Thoracic Society/European Respiratory Society (ATS/ERS) criteria. Withholding period of bronchodilators prior to spirometry: short acting beta-2 agonist (SABA) for ≥ 6 hours and FDC or free combinations of ICS/LABA for ≥ 48 hours, short acting anticholinergics (SAMA) for ≥ 8 hours, xanthines >=07 days A one-time repeat/re-testing of percent predicted FEV1 (prebronchodilator FEV1) is allowed at Visit 101 and at Visit 102. Spacer devices are permitted for reversibility testing only. -Participants who demonstrate an increase in FEV1 of 12% and 200 mL within 30 minutes after administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at Visit 101 All participants must perform a reversibility test at Visit 101 If reversibility is not demonstrated at Visit 101: Reversibility should be repeated once- Participants may be permitted to enter the study with historical evidence of reversibility that was performed according to ATS/ERS guidelines within 2 years prior to Visit 1 Alternatively, participants may be permitted to enter the study with a historical positive bronchoprovocation test that was performed within 2 years prior to Visit 1. Exclusion Criteria: Participants who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years. This includes use of nicotine inhalers such as e-cigarettes at the time of Visit 1 Participants who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening) Participants who have ever required intubation for a severe asthma attack/exacerbation. Participants who have a clinical condition which is likely to be worsened by ICS administration (e.g. glaucoma, cataract and fragility fractures) who are according to investigator's medical judgment at risk participating in the study). Participants who have had a respiratory tract infection or asthma worsening as determined by the investigator within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. Participants may be re-screened 4 weeks after recovery from their respiratory tract infection or asthma worsening. Participants with a history of chronic lung diseases other than asthma, including (but not limited to) Chronic Obstructive Pulmonary Disease (COPD), sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant bronchiectasis and active tuberculosis. Participants with severe narcolepsy and/or insomnia. Participants who have a clinically significant electrocardiogram (ECG) abnormality at Visit 101 (Start of Run- In epoch) and at any time between Visit 101 and Visit 102 (including unscheduled ECG). ECG evidence of myocardial infarction at Visit 101 (via central reader) should be clinically assessed by the investigator with supportivedocumentation Participants with a history of hypersensitivity to lactose, any of the study drugs or to similar drugs within the class including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof Participants who have not achieved an acceptable spirometry results at Visit 101 in accordance with ATS/ERS criteria for acceptability and repeatability (rescreening allowed only once). Repeat spirometry may be allowed once in an ad-hoc visit if the spirometry did not qualify due to ATS/ERS criteria. If the participant fails the repeat assessment, the participant may be rescreened once Participants on Maintenance Immunotherapy (desensitization) for allergies or less than 3 months prior to Visit 101 or participants on Maintenance Immunotherapy for more than 3 months prior to Visit 101 but expected to change throughout the course of the study. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment and for 30 days after stopping of study treatment. Long acting muscarinic antagonist (LAMA) use within 3 months prior to Visit 101

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QMF149 150/160 µg<br>QMF149 (Indacaterol acetate/Mometasone furoate) 150/160 μg was delivered once daily (o.d) via Concept1 inhaler in the evening. | Drug: Indacaterol acetate/Mometasone furoate<br> <br> * Other names: QMF149;|
| Experimental: QMF149 150/320 µg<br>QMF149 (Indacaterol acetate/Mometasone furoate) 150/320 μg was delivered o.d via Concept1 inhaler in the evening. | Drug: Indacaterol acetate/Mometasone furoate<br> <br> * Other names: QMF149;|
| Active Comparator: MF 400 µg<br>Mometasone furoate (MF) 400 μg was delivered o.d via Twisthaler® in the evening | Drug: Mometasone furoate<br> <br> |
| Active Comparator: Salmeterol /fluticasone 50/500 μg<br>Salmeterol xinafoate/fluticasone propionate 50/500 μg was delivered twice daily (in the morning and in the evening) via Accuhaler®. | Drug: Salmeterol xinafoate/fluticasone propionate<br> <br> |
| Active Comparator: MF 800 μg<br>MF 800 μg of total daily dose (400 μg twice daily, in the morning and in the evening) was delivered via Twisthaler®. | Drug: Mometasone furoate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Forced Expiratory Volume in One Second (Trough FEV1) at Week 26 | Trough FEV1 was assessed by performing spirometric assessment. It is defined as average of the two FEV1 measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. 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. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Control Questionnaire (ACQ-7) at Weeks 4, 12, 26 and 52 | The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue bronchodilator use and 1 on airway calibre (FEV1 % predicted). All 7 questions of the ACQ-7 were equally weighted. Items 1-5 were scored along a 7-point response scale, where 0 = totally controlled and 6 = severely uncontrolled. Item 6 is scored between 0 = no rescue medication and 6 = More than 16 puffs/inhalations most days. The 7th item was scored by the investigator based on the FEV1 % predicted from the masterscope at the site (i.e., Score = 0 means > 95% of predicted FEV1, 1 = 90 - 95%, 2 = 80 - 89%, 3 = 70 - 79%, 4 = 60 - 69%, 5 = 50 - 59%, and Score = 6 means < 50% of predicted FEV1). The total score was calculated as the mean of all questions. | Weeks 4, 12, 26 and 52 | 
| Trough FEV1 at Week 52 | Trough FEV1 was assessed by performing spirometric assessment. It is defined as average of the two FEV1 measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. 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. | Week 52 | 
| Pre-dose FEV1 at Weeks 4 and 12 | Pre-dose trough FEV1 is defined as average of the two FEV1 measurements taken 45 min and 15 min pre evening dose. It was assessed by performing spirometric assessment. 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. | Weeks 4 (Day 30) and 12 (Day 86) | 
| Post Dose FEV1 (5 Minutes-1 Hour) | Post-dose FEV1 measurements were analyzed at 5 minutes, 15 minutes, 30 minutes and 1 hour. 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. | Up to Week 52 (Day 364) | 
| Trough Forced Vital Capacity (FVC) | FVC is the total amount of air exhaled during the FEV test. Trough FVC is defined as average of the two FVC measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. It was assessed by performing spirometric assessment. | Up to Week 52 (Day 365) | 
| Trough Forced Expiratory Flow (FEF)Between 25% and 75% of FVC (FEF25-75) | FEF is the flow (or speed) of air coming out of the lung during the middle portion of a forced expiration. Trough FEF25-75% is defined as average of the two FEF25-75% measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. It was assessed by performing spirometric assessment. | Up to Week 52 (Day 365) | 
| Change From Baseline in Morning and Evening Peak Expiratory Flow Rate (PEF) Over 26 and 52 Weeks of Treatment | PEF is a person's maximum speed of expiration. All the participants were instructed to record PEF twice daily using a mini Peak Flow Meter device, once in the morning (before taking the morning dose) and once approximately 12 h later in the evening (before taking the evening dose). At each timepoint, the participant was instructed to perform 3 consecutive manoeuvres within 10 minutes. These PEF values were captured in the e-PEF/diary. The best of 3 values were used. | Up to Weeks 26 and 52 | 
| Percentage of Participants Achieving the Minimal Important Difference (MID) ACQ ≥ 0.5 at Weeks 26 and 52 | Change from baseline in ACQ-7 scores of ≤ 0.5 was defined as minimal clinically important difference and were considered clinically meaningful. The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue bronchodilator use and 1 on airway calibre (FEV1 % predicted). All 7 questions of the ACQ-7 were equally weighted. Items 1-5 were scored along a 7-point response scale, where 0 = totally controlled and 6 = severely uncontrolled. Item 6 is scored between 0 = no rescue medication and 6 = More than 16 puffs/inhalations most days. The 7th item was scored by the investigator based on the FEV1 % predicted from the masterscope at the site (i.e., Score = 0 means > 95% of predicted FEV1, 1 = 90 - 95%, 2 = 80 - 89%, 3 = 70 - 79%, 4 = 60 - 69%, 5 = 50 - 59%, and Score = 6 means < 50% of predicted FEV1). The total score was calculated as the mean of all questions | Weeks 26 (Day 183) and 52 (Day 364) | 
| Change From Baseline in Percentage of Asthma Symptoms Free Days | All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. Asthma symptoms free days are days with no daytime symptoms, no night-time awakenings and no symptoms on awakening. The daytime asthma symptom score was based on the daily e-diary recordings by participants with respect to shortness of breath, wheeze, cough, chest tightness, and impact on usual daily activities due to symptoms. | Up to Week 52 | 
| Change Form Baseline in Percentage of Days With no Daytime Symptoms | All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. For days with no daytime symptoms, all 5 evening questions must have a score = 0 with respect to shortness of breath, wheeze, cough, chest tightness and impact on usual daily activities due to symptoms, each with scores from 0 (no problems) to 4 (very severe problems). | Up to Week 52 | 
| Change From Baseline in Percentage of Nights With no Night-time Awakenings | All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. The question asked for nights with no night-time awakenings was How did you sleep last night? had to be answered with I did not wake up because of any breathing problems with scores from 0 (no problem)-4 (very severe problems). | Up to Week 52 | 
| Change Form Baseline in Percentage of Mornings With no Symptoms on Awakening | All participants were provided with an electronic diary (e-Diary) to record clinical symptoms. They were instructed to routinely complete the e-Diary twice daily at the same time each morning and again approximately 12 hours later in the evening. The e-Diary was reviewed at each visit until study completion. The question asked for mornings with no symptoms on awakening was Did you have asthma symptoms upon awakening in the morning? to be answered with None with scores from 0 (no problem)-4 (very severe problems). | Up to Week 52 | 
| Rescue Medication Usage | All participants were given salbutamol/albuterol to use as rescue medication throughout the study along with e-Diary to record rescue medication use. The number of puffs of rescue medication during the past 12 hours is recorded twice (morning/evening) by the participant prior to taking study medication. The mean daily number of puffs of rescue medication use will be calculated for each participant, done separately for morning (night-time), evening (daytime), and daily (night-time plus daytime) rescue medication use | Up to Weeks 26 and 52 | 
| Time to First Asthma Exacerbation by Exacerbation Category | The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. | Up to Week 52 | 
| Time to First Hospitalization for Asthma Exacerbation | The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. | Up to Week 52 | 
| Annual Rate of Asthma Exacerbations by Exacerbation Category | The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. | Up to Week 52 | 
| Duration in Days of Asthma Exacerbations by Exacerbation Category | The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. | Up to Week 52 | 
| Percentage of Participants With at Least One Asthma Exacerbation by Exacerbation Category | The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. | Up to Week 52 | 
| Time in Days to Permanent Discontinuation of Study Medication Due to Asthma Exacerbations | The exacerbation categories were: All (mild, moderate and severe) and combination of moderate or severe and severe. | Up to Week 52 | 
| Percentage of Participants Who Permanently Discontinued Study Medication Due to Asthma Exacerbations |  | Up to Week 52 | 
| Total Amounts of Systemic Corticosteroids (in Doses) Used to Treat Asthma Exacerbations | The treatment of asthma exacerbations including the initiation of systemic corticosteroids were done according to investigator's or treating physician's medical judgement and in line with national and international recommendations. If systemic corticosteroids were required, a participant could return to the study after successfully completing a taper of approximately 7-10 days. | Up to Week 52 | 
| Change From Baseline in Percentage of Rescue Medication Free Days | All participants were given salbutamol/albuterol to use as rescue medication throughout the study along with e-Diary to record rescue medication use. Rescue medication free days is defined as any day where the participant did not use any puffs of rescue medication during daytime and night-time. | Up to Weeks 26 and 52 | 
| Asthma Quality of Life Questionnaire (AQLQ) | AQLQ is a 32-item disease 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 (1-totally limited/problems all the time, 7-not at all limited/no problems). It consists of 4 domains: Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items) Activity limitation = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items) Emotional function = Mean of Items 7, 13, 15, 21, 27 (5 items) Environmental stimuli = Mean of Items 9, 17, 23, 26 (4 items) Overall Score = Mean of Items 1 to 32 (32 items) | Up to Week 52 (Day 364) | 
| Trough FEV1 Measured After 26 Weeks of Treatment | Trough FEV1 was assessed by performing spirometric assessment. It is defined as average of the two FEV1 measurements taken 23 hr 15 min and 23 hr 45 min post-evening dose. 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. | Week 26 | 
| Percentage of Participants With Composite Endpoint of Serious Asthma Outcomes | A composite endpoint of serious asthma outcomes is defined as asthma-related hospitalization, asthma-related intubation, or asthma-related death and was reviewed by the Adjudication Committee. | Up to Week 52 | 
| Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign including abnormal laboratory findings, symptom or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant, i.e. defined as an event that jeopardizes the participants or may require medical or surgical intervention. | Approximately up to 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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QMF149, Mometasone furoate (MF), asthma