Bronchodilatory Efficacy of a Single Dose QMF149 (Indacaterol Maleate/Mometasone Furoate) Via the Twisthaler® Device in Adult Patients With Asthma

Study Overview
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Brief Summary
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This study is designed to evaluate the bronchodilatory efficacy of indacaterol maleate 500 μg/mometasone furoate 400 μg via the Twisthaler® device in adult patients with persistent asthma.

Official Title
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An Exploratory, Multi-centre, Double-blind, Placebocontrolled Crossover Study, to Investigate the Bronchodilatory Efficacy of a Single Dose of Indacaterol in Fixed Combination With Mometasone Furoate Delivered Via a MDDPI (Twisthaler®) in Adult Patients With Persistent Asthma Using Open Label Seretide® Accuhaler® (50/250 Mcg b.i.d.) as an Active Control

Conditions
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Asthma

Intervention / Treatment
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* Drug: indacaterol maleate/mometasone furoate
* Drug: placebo to indacaterol maleate/mometasone furoate
* Drug: fluticasone proprionate / salmeterol xinafoate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adult patients aged 18-75 years with persistent asthma Patients with persistent asthma, diagnosed according to the Global Initiative for Asthma guidelines (GINA) and who additionally met the following criteria: Patients receiving daily treatment with inhaled corticosteroid up to the maximum dose per day indicated in the package leaflet, in a stable regimen for the month prior to Visit 1. Patients with a forced expiratory volume in 1 second (FEV1) at Visit 1 of ≥ 50% of the predicted normal value. This criterion for FEV1 had to be demonstrated after a washout period of at least 6 hours during which no short acting β2-agonist had been inhaled, and a minimum of 48 hours for a long acting β2-agonist. Patients who demonstrated an increase of ≥12% and ≥200 mL in FEV1 over their pre-bronchodilator value 30 minutes after inhaling a total of 200 μg of salbutamol (or albuterol) via metered dose inhaler (MDI) (the reversibility test). Reversibility had to be demonstrated after an appropriate washout period of at least 6 hrs prior to the evaluation for a shortacting β2-agonist. The administration of salbutamol (or albuterol) for the reversibility test was to be within 30 minutes after pre-bronchodilator spirometry. Reversibility had to be demonstrated at Visit 1 or between Visits 1 and 2, in order for patients to be included in the trial. For each patient, the smaller value of the Visit 1 FEV1 or the Visit 2 FEV1 pre-dose value had to be at least 85% of the larger value. Body mass index (BMI) between 18 and 32 kg/m^2 and weight >50 kg. patients using local contraception Exclusion Criteria: Pregnant or nursing women Recent use of tobacco or history of smoking > 10 pack years Patients diagnosed with chronic obstructive pulmonary disease (COPD) Patients with recent experience of severe asthma attack/exacerbation within 6-months of study start Patients with frequent rescue medication (>8 puffs/day for two consecutive days) Clinically relevant laboratory abnormality or a clinically significant condition Active cancer or a history of cancer with less than 5 years disease free survival time History of long QT syndrome or with long QTc interval prior to dosing History of hypersensitivity to the study drugs or to drugs with similar chemical structures Use of certain medications Use of other investigational drugs A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result History of immunodeficiency diseases, including a positive human immumodeficiency virus (HIV) test result. History of drug or alcohol abuse or evidence of such abuse Other protocol-defined inclusion/exclusion criteria may apply.

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indacaterol/mometasone - Placebo<br>In Treatment Period 1 (Day 1) participants received 2 inhalations of indacaterol maleate 250 μg / mometasone furoate 200 μg once a day in the morning via the Twisthaler device. In Treatment Period 2 (Day 8) participants received 2 inhalations of placebo via the Twisthaler device once a day in the morning. In Treatment Period 3 (Day 15) participants received fluticasone proprionate 250 μg / salmeterol xinafoate 50 μg twice a day delivered via dry-powder inhaler. Each treatment period was separated by a minimum washout period of 7 days. | Drug: indacaterol maleate/mometasone furoate<br>* Indacaterol maleate 250 μg / mometasone furoate 200 μg delivered via the Twisthaler device.<br>* Other names: QMF149;Drug: placebo to indacaterol maleate/mometasone furoate<br>* Placebo to indacaterol maleate/mometasone furoate delivered via the Twisthaler device.<br>Drug: fluticasone proprionate / salmeterol xinafoate<br>* Fluticasone proprionate 250 μg / salmeterol xinafoate 50 μg delivered via the Accuhaler® device.<br>* Other names: Seretide® Accuhaler®;|
| Experimental: Placebo - indacaterol/mometasone<br>In Treatment Period 1 (Day 1) participants received 2 inhalations of placebo in the morning via the Twistheler device. In Treatment Period 2 (Day 8) participants received 2 inhalations of indacaterol maleate 250 μg / mometasone furoate 200 μg via the Twisthaler device in the morning. In Treatment Period 3 (Day 15) participants received fluticasone proprionate 250 μg / salmeterol xinafoate 50 μg twice a day delivered via dry-powder inhaler. Each treatment period was separated by a minimum washout period of 7 days. | Drug: indacaterol maleate/mometasone furoate<br>* Indacaterol maleate 250 μg / mometasone furoate 200 μg delivered via the Twisthaler device.<br>* Other names: QMF149;Drug: placebo to indacaterol maleate/mometasone furoate<br>* Placebo to indacaterol maleate/mometasone furoate delivered via the Twisthaler device.<br>Drug: fluticasone proprionate / salmeterol xinafoate<br>* Fluticasone proprionate 250 μg / salmeterol xinafoate 50 μg delivered via the Accuhaler® device.<br>* Other names: Seretide® Accuhaler®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Period Baseline to 24 Hour Post-dose (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. Change from the period baseline to 24 hour post dose trough FEV1 after 1 day of treatment was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose FEV1 as covariate. | Pre-dose for each Treatment Period (Days 1, 8 and 15) and 24-hours post-dose for each Treatment Period (Days 2, 9 and 16). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Peak FEV1 is defined as the peak FEV1 between 0 and 4 hours post-dose. The change from baseline in peak FEV1 was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose FEV1 as covariate. | Days 1, 8 and 15, pre-dose (Baseline) and 5, 15, and 30 minutes, 1, 2, 3, and 4 hours post-dose. | 
| Change From Period Baseline in Trough Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | Trough FEV1 was measured 24 hours post-dose. The FEV1 percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 % predicted indicates improvement in lung function. Change from baseline in trough FEV1 % predicted was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose value as covariate. | Pre-dose for each Treatment Period (Days 1, 8 and 15) and 24-hours post-dose for each Treatment Period (Days 2, 9 and 16). | 
| Change From Period Baseline in Peak Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | Peak FEV1 was defined as the peak FEV1 up to 4 hours post-dose. The FEV1 percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 % predicted indicates improvement in lung function. Change from baseline in peak FEV1 % predicted was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose value as covariate. | Days 1, 8 and 15, pre-dose (Baseline) and 5, 15, and 30 minutes, 1, 2, 3, and 4 hours post-dose. | 
| Change From Period Baseline in Trough Forced Vital Capacity (FVC) | Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Trough FVC was measured 24 hours post-dose. Change form baseline in trough FVC was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose value as covariate. | Pre-dose for each Treatment Period (Days 1, 8 and 15) and 24-hours post-dose for each Treatment Period (Days 2, 9 and 16). | 
| Change From Period Baseline in Peak Forced Vital Capacity (FVC) | Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Peak FVC was measured up to 4 hours post-dose. Change from baseline in peak FVC was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose value as covariate. | Days 1, 8 and 15, pre-dose (Baseline) and 5, 15, and 30 minutes, 1, 2, 3, and 4 hours post-dose. | 
| Change From Period Baseline in Trough FEV1/FVC Ratio | The forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio represents the proportion of a person's vital capacity that they are able to expire in the first second of an expiration. Trough FEV1/FVC was calculated from measurements taken 24 hours post-dose. Change from baseline in trough FEV1/FVC ratio was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose value as covariate. | Pre-dose for each Treatment Period (Days 1, 8 and 15) and 24-hours post-dose for each Treatment Period (Days 2, 9 and 16). | 
| Change From Period Baseline in Peak FEV1/FVC Ratio | The forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio represents the proportion of a person's vital capacity that they are able to expire in the first second of an expiration. Peak FEV1/FVC was calculated from spirometry measurements taken up to 4 hours post-dose. Change from baseline in peak FEV1/FVC ratio was modeled using a linear mixed effect model fitting treatment, sequence and period as fixed factors, patient within sequence as a random factor and pre-dose value as covariate. | Days 1, 8 and 15, pre-dose (Baseline) and 5, 15, and 30 minutes, 1, 2, 3, and 4 hours post-dose. | 
| Area Under the Concentration-time Curve From Time 0 to 12 Hours Post-dose for Mometasone Furoate |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, and 12 hours post-dose. | 
| Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose for Mometasone Furoate |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, 12 and 24 hours post-dose. | 
| Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose for Indacaterol |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, 12 and 24 hours post-dose. | 
| Maximum (Peak) Plasma Concentration (Cmax) of Mometasone Furoate |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, 12 and 24 hours post-dose. | 
| Maximum (Peak) Plasma Concentration (Cmax) of Indacaterol |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, 12 and 24 hours post-dose. | 
| Time to Reach Peak or Maximum Concentration Following Drug Administration for Mometasone Furoate |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, 12 and 24 hours post-dose. | 
| Time to Reach Peak or Maximum Concentration Following Drug Administration for Indacaterol |  | Samples were taken pre-dose and at 15 and 30 minutes and 1, 2, 4, 12 and 24 hours post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, QMF149, fixed combination of indacaterol and mometasone furoate