Investigation of the 24 Hour Forced Expiratory Flow in 1 Second (FEV1) Profile of a Single Dose of Indacaterol/Mometasone Delivered Via the TWISTHALER® Device in Adult Patients With Persistent Asthma

Study Overview
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Brief Summary
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This study is designed to provide data about the 24 hours FEV1 profile, safety and tolerability of indacaterol/mometasone TWISTHALER device compared to placebo and using fluticasone/salmeterol as an active control.

Official Title
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A Multi-center, Randomized, Double-blind, Double Dummy, Placebo and Active Controlled Crossover Study, to Investigate the 24 Hour FEV1 Profile of a Single Dose of QMF TWISTHALER Device in Adult Patients With Persistent Asthma

Conditions
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Asthma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adult patients aged 18-75 years (inclusive), who have signed an Informed Consent Form prior to initiation of any study-related procedure, Patients with persistent asthma, diagnosed according to Global Initiative for Asthma (GINA) guidelines (National Institute of Health, National Heart, Lung and Blood Institute, 2006) and who additionally meet the following criteria: Patients receiving daily treatment with inhaled corticosteroid up to the maximum dose per day indicated in the product label, in a stable regimen for the month prior to Visit 1. Patients with an FEV1 at Visit 1 ≥50% of predicted normal. Patients who demonstrate an increase of ≥ 12% and ≥ 200 mL in FEV1 over their pre-bronchodilator. Exclusion Criteria: Pregnant women, nursing mothers, or females of childbearing potential, regardless of whether or not sexually active, if they are not using a reliable form of contraception. Patients who have used tobacco products within the 6 months period prior to Visit 1, or who have a smoking history of greater than 10 pack years. Patients diagnosed with Chronic Obstructive Pulmonary disease (COPD) as defined by the GOLD guidelines (Global Initiative for Chronic Obstructive Lung Disease 2006). Patients with seasonal allergy whose asthma is likely to deteriorate during the study period. Patients who have had an acute asthma attack/exacerbation requiring hospitalization in the 6 months prior to Visit 1. Patients who have had an acute asthma attack / exacerbation requiring an emergency room visit within 6 weeks prior to Visit 1 or at any time between Visit 1 and Visit 2. Patients who have had a respiratory tract infection within 4 weeks prior to Visit 1 or at any time between Visit 1 and Visit 2. Patients with a history of long QT interval syndrome or whose QT interval corrected for heart rate (QTc) interval (Bazett's) measured at Visit 1 or Visit 2 is prolonged: > 450 ms (males) or > 470 ms (females). Other clinically significant conditions which may interfere with the study conduct or patient safety as specified in the protocol. 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: Ind/M - FP/Salm - Pbo<br>In Treatment Period 1 (Days 1 & 2) participants received indacaterol/mometasone (Ind/M) 500/400 μg via the TWISTHALER device (2 inhalations of 250/200 μg) in the evening and placebo to fluticasone/salmeterol via multi-dose dry powder inhaler (MDDPI), one inhalation in the evening and one inhalation the following morning. In Treatment Period 2 (Days 8 & 9) participants received 2 inhalations of placebo to indacaterol/mometasone via the TWISTHALER device in the evening and fluticasone/salmeterol (FP/Salm) 250/50 μg via MDDPI, one inhalation in the evening and one inhalation the following morning. In Treatment Period 3 (Days 15 & 16) participants received 2 inhalations of placebo (Pbo) to indacaterol/mometasone via the TWISTHALER device in the evening and placebo to fluticasone/salmeterol via MDDPI, one inhalation in the evening and one inhalation the following morning. Each treatment period was separated by a 6-day washout period. | Drug: fluticasone propionate/salmeterol<br>* Fluticasone propionate/salmeterol 250/50 μg twice daily delivered via MDDPI.<br>* Other names: Seretide®;Drug: indacaterol maleate / mometasone furoate<br>* Indacaterol maleate / mometasone furoate 500/400 μg once daily delivered via the TWISTHALER device.<br>* Other names: QMF149;Drug: placebo to indacaterol/mometasone<br>* Placebo to indacaterol maleate/mometasone furoate delivered via the TWISTHALER device.<br>Drug: placebo to fluticasone propionate/salmeterol<br>* Placebo to fluticasone propionate / salmeterol delivered via MDDPI.<br>|
| Experimental: FP/Salm - Pbo - Ind/M<br>In Treatment Period 1 (Days 1 & 2) participants received 2 inhalations of placebo to indacaterol/mometasone via the TWISTHALER device in the evening and fluticasone/salmeterol (FP/Salm) 250/50 μg via MDDPI, one inhalation in the evening and one inhalation the following morning. In Treatment Period 2 (Days 8 & 9) participants received 2 inhalations of placebo to indacaterol/mometasone via the TWISTHALER device in the evening and placebo to fluticasone/salmeterol via MDDPI, one inhalation in the evening and one inhalation the following morning. In Treatment Period 3 (Days 15 & 16) participants received indacaterol/mometasone (Ind/M) 500/400 μg via the TWISTHALER device (2 inhalations of 250/200 μg) in the evening and placebo to fluticasone/salmeterol via MDDPI, one inhalation in the evening and one inhalation the following morning. Each treatment period was separated by a 6-day washout period. | Drug: fluticasone propionate/salmeterol<br>* Fluticasone propionate/salmeterol 250/50 μg twice daily delivered via MDDPI.<br>* Other names: Seretide®;Drug: indacaterol maleate / mometasone furoate<br>* Indacaterol maleate / mometasone furoate 500/400 μg once daily delivered via the TWISTHALER device.<br>* Other names: QMF149;Drug: placebo to indacaterol/mometasone<br>* Placebo to indacaterol maleate/mometasone furoate delivered via the TWISTHALER device.<br>Drug: placebo to fluticasone propionate/salmeterol<br>* Placebo to fluticasone propionate / salmeterol delivered via MDDPI.<br>|
| Experimental: Pbo - Ind/M - FP/Salm<br>In Treatment Period 1 (Days 1 & 2) participants received 2 inhalations of placebo (Pbo) to indacaterol/mometasone via the TWISTHALER device in the evening and placebo to fluticasone/salmeterol via MDDPI, one inhalation in the evening and one inhalation the following morning. In Treatment Period 2 (Days 8 & 9) participants received indacaterol/mometasone (Ind/M) 500/400 μg via the TWISTHALER device (2 inhalations of 250/200 μg) in the evening and placebo to fluticasone/salmeterol via MDDPI, one inhalation in the evening and one inhalation the following morning. In Treatment Period 3 (Days 15 & 16) participants received 2 inhalations of placebo to indacaterol/mometasone via the TWISTHALER device in the evening and fluticasone/salmeterol (FP/Salm) 250/50 μg via MDDPI, one inhalation in the evening and one inhalation the following morning. Each treatment period was separated by a 6-day washout period. | Drug: fluticasone propionate/salmeterol<br>* Fluticasone propionate/salmeterol 250/50 μg twice daily delivered via MDDPI.<br>* Other names: Seretide®;Drug: indacaterol maleate / mometasone furoate<br>* Indacaterol maleate / mometasone furoate 500/400 μg once daily delivered via the TWISTHALER device.<br>* Other names: QMF149;Drug: placebo to indacaterol/mometasone<br>* Placebo to indacaterol maleate/mometasone furoate delivered via the TWISTHALER device.<br>Drug: placebo to fluticasone propionate/salmeterol<br>* Placebo to fluticasone propionate / salmeterol delivered via MDDPI.<br>|

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 analyzed using Analysis of Covariance (ANCOVA) adjusting for treatment, period, sequence and center with period baseline as a covariate and patient nested within sequence as a random effect. | 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 |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) at Single Time Points | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was analyzed using Analysis of Covariance (ANCOVA) adjusting for treatment, period, sequence and center with period baseline as a covariate and patient nested within sequence as a random effect. | 5, 30 minutes, 1, 2, 3, 4 hours, 11 hours 10 minutes, 11 hours 45 minutes, 12 hours 30 minutes, 14, 16, 18, 20, 22 hours, 23 hours 10 minutes, and 23 hours 45 minutes post-dosing. | 
| Forced Expiratory Volume in 1 Second (FEV1) Standardized Area Under the Curve (AUC) Between Baseline (Pre-dose) and 24 Hours Post-dose | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was measured pre-dose and up to 24 hours post-dose. The FEV1 standardized area under the curve (AUC) was analyzed for four time intervals: Baseline (pre-dose) to 4 hours (hr) post-dosing; Baseline (pre-dose) to 23 hours, 45 minutes (min) post-dosing; 11 hours, 10 minutes to 12 hours, 30 minutes post-dosing; 11 hours, 10 minutes to 23 hours, 45 minutes post-dosing. AUC for FEV1 was analyzed using Analysis of Covariance adjusting for treatment, period, sequence and center with period baseline as a covariate and patient nested within sequence as a random effect. | Pre-dose, 5, 30 minutes, 1, 2, 3, 4 hours, 11 hours 10 minutes, 11 hours 45 minutes, 12 hours 30 minutes, 14, 16, 18, 20, 22 hours, 23 hours 10 minutes, and 23 hours 45 minutes post-dosing. | 
| Time to Peak 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. Time to peak FEV1 is calculated in minutes from the time of inhalation of study drug to the time of the peak FEV1 during the first 4 hours post-dose. Time to peak FEV1 is based on log-transformed analysis of variance adjusted for treatment, period, sequence and center, with patient nested within sequence as a random effect. Geometric Mean was obtained by taking anti-logs of the adjusted means from the model and standard error was calculated using the delta method. | Up to 4 hours post-dose | 
| Forced Vital Capacity (FVC) at Single Time Points | Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was analyzed using ANCOVA adjusting for treatment, period, sequence and center with period baseline as a covariate and patient nested within sequence as a random effect. | 5, 30 minutes, 1, 2, 3, 4 hours, 11 hours 10 minutes, 11 hours 45 minutes, 12 hours 30 minutes, 14, 16, 18, 20, 22 hours, 23 hours 10 minutes, and 23 hours 45 minutes post-dosing. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Indacaterol, Asthma, QMF, Mometasone