Study to Compare the Efficacy and Safety of QVM149 With QMF149 in Patients With Asthma

Study Overview
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Brief Summary
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The purpose of the trial was to evaluate the efficacy and safety of two different doses of QVM149 (QVM149 150/50/80 μg and QVM149 150/50/160 μg via Concept1) over two respective QMF149 doses (QMF149 150/160 μg and QMF149 150/320) μg via Concept1 in poorly controlled asthmatics as determined by pulmonary function testing and effects on asthma control.

Detailed Description
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This study used a 52-week treatment, randomized, double-blind, double-dummy, parallel-group design. A total of 3092 asthma patients were randomized into the 5 treatment groups with a randomization ratio of 1:1:1:1:1 (approximately 617 patients per treatment group): QVM149 150/50/80 μg once daily (o.d.), QVM149 150/50/160 μg o.d., QMF149 150/160 μg o.d. and QMF149 150/320 μg o.d., all delivered via the Concept1 device, and salmeterol/fluticasone 50/500 μg twice daily (b.i.d.) delivered via Accuhaler. The 52 week treatment period was followed by a 30-day Follow-up. The primary objective of this study was to demonstrate superiority of either QVM149 150/50/80 μg o.d. to QMF149 150/160 μg o.d. or QVM149 150/50/160 μg o.d. to QMF149 150/320 μg o.d in terms of trough Forced Expiratory Volume in One Second (Trough FEV1) (FEV1) at Week 26, all delivered via Concept1.

Official Title
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A Multicenter, Randomized, 52-week, Double-blind, Parallelgroup, Active Controlled Study to Compare the Efficacy and Safety of QVM149 With QMF149 in Patients With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: QVM149 150/50/160
* Drug: QVM149 150/50/80
* Drug: QMF149 150/320
* Drug: QMF149 150/160
* Drug: salmeterol/fluticasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of asthma, (GINA 2015) for a period of at least 1 year prior to Visit 1 (Screening). Patients who have used medium or high dose of ICS/LABA combinations for asthma for at least 3 months and at stable medium or high doses of ICS/LABA for at least 1 month prior to Visit 1. Patients must be symptomatic at screening despite treatment with mid or high stable doses of ICS/LABA. Patients with ACQ-7 score ≥ 1.5 at Visit 101 and at Visit 102 (before randomization). Patients with documented history of at least one asthma exacerbation which required medical care from a physician, ER visit (or local equivalent structure) or hospitalization in the 12 months prior to Visit 1, and required systemic corticosteroid treatment. Pre-bronchodilator FEV1 of < 80 % of the predicted normal value for the patient according to ATS/ERS guidelines after withholding bronchodilators at both visits 101 and 102. Withholding period of bronchodilators prior to spirometry: SABA for ≥ 6 hrs, Twice daily LABA (or FDC of ICS/LABA) for ≥ 12 hrs, Once daily LABA (or FDC of ICS/LABA) for ≥ 24 hrs, SAMA for ≥ 8 hrs, Short acting xanthines for 12 hrs, Long acting xanthines for 24 hrs, . Washout period of each drug should be kept as close as possible as above and should not be longer. If longer washout period is needed due to scheduling issues, please contact Novartis Medical monitor. A one-time repeat of percentage predicated FEV1 (Pre-bronchodilator) at Visit 101 and/or Visit 102 is allowed in an ad-hoc visit. Repeat of Visit 101 spirometry should be done in an ad-hoc visit to be scheduled on a date that would provide sufficient time to receive confirmation from the spirometry data central reviewer of the validity of the assessment before randomization. Run-in medication should be dispensed once spirometry assessment met inclusion criteria (ATS/ERS quality criteria, FEV1 % predicted normal value, and reversibility) as per equipment A one-time rescreen is allowed in case the patient fails to meet the criteria at the repeat, provided the patient returned to the required treatment as per inclusion criteria 4 Patients 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 patients must perform a reversibility test at Visit 101. If reversibility is not demonstrated at Visit 101 then one of the following criteria need to be met. Reversibility should be repeated once. Patients 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, patients may be permitted to enter the study with a historical positive bronchoprovocation test that was performed within 2 years prior to Visit 1. If reversibility is not demonstrated at Visit 101 (or after repeated assessment in an ad-hoc visit) and historical evidence of reversibility/bronchoprovocation is not available (or was not performed according to the ATS/ERS guidelines patients must be screen failed Spacer devices are permitted during reversibility testing only. The Investigator or delegate may decide whether or not to use a spacer for the reversibility testing Exclusion Criteria: Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit between Visit 1 and Visit 102 they may be re-screened 6 weeks after recovery from the exacerbation. Patients who have ever required intubation for a severe asthma attack/exacerbation. Patients 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. Patients treated with a LAMA for asthma within 3 months prior Visit 1 (Screening). Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or bladder-neck obstruction or severe renal impairment or urinary retention. BPH patients who are stable on treatment can be considered). Patients who have had a respiratory tract infection or asthma worsening as determined by investigator within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. Patients may be re-screened 4 weeks after recovery from their respiratory tract infection or asthma worsening. Patients with evidence upon visual inspection (laboratory culture is not required) of clinically significant (in the opinion of investigator) oropharyngeal candidiasis at Visit 102 or earlier, with or without treatment. Patients may be re-screened once their candidiasis has been treated and has resolved. Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic sinusitis) which in the opinion of the investigator may interfere with the study evaluation or optimal participation in the study. Patients with a history of chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant bronchiectasis and active tuberculosis. Patients with Type I diabetes or uncontrolled Type II diabetes. Patients who, either in the judgment of the investigator or the responsible Novartis personnel, have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study. Patients with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blockers, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at the run-in visit (Visit 101) with a resting ventricular rate < 100/min. At Visit 101 the atrial fibrillation must be confirmed by central reading. Patients with a history of myocardial infarction (this should be confirmed clinically by the investigator) within the previous 12 months. Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia method) is prolonged (> 450 msec for males and > 460 msec for females) and confirmed by a central assessor (these patients should not be rescreened). Patients 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. Patients who have not achieved an acceptable spirometry result at Visit 101 in accordance with ATS/ERS criteria for acceptability and repeatability. A one-time repeat spirometry is allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on the same day) if the spirometry did not qualify due to ATS/ERS criteria at Visit 101 and/or Visit 102. If the patient fails the repeat assessment, the patient may be rescreened once, provided the patient returns to the required treatment as per inclusion criteria 4. Patients unable to use the Concept1 dry powder inhaler, Accuhaler or a metered dose inhaler. Spacer devices are not permitted. History of alcohol or other substance abuse. Patients with a known history of non-compliance to medication or who were unable or unwilling to complete a patient diary or who are unable or unwilling to use Electronic Peak Flow with e-diary device. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers).

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QVM149 150/50/160 µg o.d.<br>QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device | Drug: QVM149 150/50/160<br> <br> |
| Experimental: QVM149 150/50/80 µg o.d.<br>QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device | Drug: QVM149 150/50/80<br> <br> |
| Active Comparator: QMF149 150/320 µg o.d.<br>QMF149 150/320 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device | Drug: QMF149 150/320<br> <br> |
| Active Comparator: QMF149 150/160 µg o.d.<br>QMF149 150/160 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device | Drug: QMF149 150/160<br> <br> |
| Active Comparator: Salmeterol/fluticasone 50/500 μg b.i.d.<br>Salmeterol xinafoate /fluticasone propionate 50/500 μg twice daily (b.i.d.) delivered via Accuhaler® | Drug: salmeterol/fluticasone<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 1 Second (Trough FEV1) of QVM149 Versus QMF149 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. The primary endpoint considered the following 2 comparison groups: QVM149 150/50/80 μg o.d. compared with QMF149 150/160 μg o.d. both delivered via Concept1 QVM149 150/50/160 μg o.d. compared with QMF149 150/320 μg o.d. both delivered via Concept1. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Control Questionnaire (ACQ-7) at Week 26 and Week 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 ACQ-7 total score reported below was calculated as the mean of scores of all 7 items and ranged between 0 and 6, with higher scores indicating worse asthma symptom control. | 26 weeks, 52 weeks | 
| Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 Versus Salmeterol/Fluticasone 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. This secondary endpoint considered the following 2 comparison groups: QVM149 150/50/80 μg o.d. via Concept1 compared with salmeterol/fluticasone 50/500 μg b.i.d. via Accuhaler® QVM149 150/50/160 μg o.d. via Concept 1 compared with salmeterol/fluticasone 50/500 μg b.i.d. via Accuhaler® | 26 weeks | 
| 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. | 52 weeks | 
| Pre-dose Forced Vital Capacity (FVC) at Week 4 and Week 12 | Pre-dose FVC is defined as average of the two FVC measurements taken 45 min and 15 min pre evening dose. It was assessed by performing spirometric assessment. FVC is the total amount of air exhaled during the FEV test. | 4 weeks, 12 weeks | 
| Trough Forced Expiratory Flow (FEF) Between 25% and 75% of FVC (FEF25-75) at 52 Weeks | 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 | 
| 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 home. 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. | Baseline, 26 weeks, 52 weeks | 
| Change From Baseline in Percentage of Asthma Symptom-free Days Over 52 Weeks | 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. | Baseline, 52 weeks | 
| Change From Baseline in Percentage of Days With no Daytime Symptoms Over 52 Weeks | 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). | Baseline, 52 weeks | 
| Change From Baseline in Percentage of Nights With no Night-time Awakenings Over 52 Weeks | 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). | Baseline, 52 weeks | 
| Change From Baseline in Percentage of Mornings With no Symptoms on Rising Over 52 Weeks | 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). | Baseline, 52 weeks | 
| Change From Baseline in Percentage of Days Without Rescue Medication Use Over 26 and 52 Weeks | Percentage of days without rescue medication usage (100 μg salbutamol/90 μg albuterol via metered-dose inhaler) as recorded by e-diary over 26 and 52 weeks of treatment. | Baseline, 26 weeks, 52 weeks | 
| Percentage of Patients Achieving the Minimal Clinically Important Difference (MCID) ACQ ≥ 0.5 at Week 26 and Week 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. | 26 weeks, 52 weeks | 
| Time to First Hospitalization for Asthma Exacerbation | Time from start of treatment until the first event (hospitalization for asthma exacerbation) or censoring. Patients without the event were considered as censored at the date of last treatment + 1 day. For patients having the event, the start date of the hospitalization was considered to calculate the time to event (i.e., the number of days from start of treatment up to the event start date). | 52 weeks on average, up to 416 days | 
| Time to First Asthma Exacerbation by Exacerbation Category | Time from start of treatment until the first event (asthma exacerbation) or censoring. Patients without the event were considered as censored at the date of last treatment + 1 day. For patients having the event, the start date of the exacerbation was considered to calculate the time to event (i.e., the number of days from start of treatment up to the event start date). The exacerbation categories were: All (mild, moderate and severe), combination of moderate or severe and severe. | 52 weeks on average, up to 416 days | 
| 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. | 52 weeks | 
| 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 Exacerbation | Time from start of treatment until the first event (permanent discontinuation of study medication due to asthma exacerbation) or censoring. Patients without the event were considered as censored at the date of last treatment + 1 day. For patients having the event, the date of the discontinuation of study medication was considered to calculate the time to event. | 52 weeks on average, up to 416 days | 
| Total Amount of Oral Corticosteroid Used (in Prednisone-equivalent mg Doses) 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 Over 26 and 52 Weeks | 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. | Baseline, 26 weeks, 52 weeks | 
| Asthma Quality of Life Questionnaire (AQLQ) at Week 52 | 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) The overall AQLQ score reported below is the mean of all 32 responses and ranges from 1 to 7, where higher scores indicate better quality of life. | 52 weeks | 
| Pre-dose FEV1 at Weeks 4 and 12 | Pre-dose 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. | 4 weeks, 12 weeks | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, QVM149, QMF149