A Dose Ranging Trial of 4 Doses of Indacaterol Delivered Via TWISTHALER® Device in Adult and Adolescent Patients With Persistent Asthma

Study Overview
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Brief Summary
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This study will evaluate the dose response relationship among four doses of indacaterol as well as placebo delivered via the TWISTHALER® device.

Official Title
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A Randomized, Multi-center, Parallel Group, Double Blind, Placebo and Formoterol Controlled 14 Day Dose Ranging Trial of 4 Doses of Indacaterol Delivered Via TWISTHALER® Device in Adult and Adolescent Patients With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: indacaterol
* Drug: formoterol
* Drug: placebo to indacaterol
* Drug: placebo to formoterol
* Drug: short acting β2-agonist


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adult and adolescent patients aged 12-75 years inclusive (or ≥18-75 years depending upon regulatory and/or Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/Research Ethics Board (REB) approval), who have signed an Informed Consent Form prior to initiation of any study-related procedure, including any adjustments to asthma medication prior to Visit 1. Patients below the legal age of consent are required to have the Informed Consent Form signed by the patient's parent / guardian. Patients with 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 package leaflet, in a stable regimen for the month prior to Visit 1. Patients with a Forced Expiratory Volume in one second (FEV1) at Visit 1 of ≥50% of the predicted normal value for the patient. This criterion for FEV1 will have to be demonstrated after a washout period of at least 6 hours during which no short acting β2-agonist has been inhaled, and a minimum of 48 hours for a long acting β2-agonist. Patients who demonstrate an increase of ≥12% and ≥200 mL in FEV1 over their pre-bronchodilator value within 30 minutes after inhaling a total of 200 µg/180 µg of salbutamol/albuterol Metered Dose Inhaler (MDI) (or equivalent dose of Dry Powder Inhaler [DPI]) (the reversibility test). Reversibility will have to be demonstrated after an appropriate washout period of at least 6 hrs prior to the evaluation for a short-acting β2-agonist. The administration of salbutamol/albuterol for the reversibility test is to be within 30 minutes after pre bronchodilator spirometry. Reversibility has to be demonstrated at Visit 1 or between Visits 1 and 2, in order for patients to be included in the trial. 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 with Chronic Obstructive Pulmonary Disease (COPD), or current smokers, or patients who have used tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years. Patients: who's asthma is likely to deteriorate during the study (including seasonal allergy), hospitalized for an acute asthma attack/asthma exacerbation within 6 months prior to Visit 1, who have had an emergency room visit for an asthma attack/asthma exacerbation within 6 weeks prior to Visit 1 who have had a respiratory tract infection or emergency room treatment for an asthma attack/asthma exacerbation within 4 weeks prior to Visit 1 Patients who require the use of ≥8 inhalations per day of short acting B2-agonist (100 µg/ 90 µg salbutamol/albuterol MDI or equivalent dose of DPI) on any 2 consecutive days from Screening to Randomization. Other protocol-defined inclusion/exclusion criteria may apply

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: indacaterol 62.5 μg<br>Indacaterol 62.5 μg delivered by the TWISTHALER® device once a day and placebo to formoterol (placebo AEROLIZER® device) twice a day for 14 days. All participants were supplied with salbutamol/albuterol to use throughout the study as rescue medication. | Drug: indacaterol<br>* Indacaterol delivered by multiple dose dry powder inhaler (TWISTHALER® device).<br>Drug: placebo to formoterol<br>* Placebo AEROLIZER® device<br>Drug: short acting β2-agonist<br>* 100 μg/ 90 μg salbutamol/albuterol Metered Dose Inhaler (MDI) or equivalent dose of Dry Powder Inhaler (DPI).<br>|
| Experimental: indacaterol 125 μg<br>Indacaterol 125 μg delivered by the TWISTHALER® device once a day and placebo to formoterol (placebo AEROLIZER® device) twice a day for 14 days. All participants were supplied with salbutamol/albuterol to use throughout the study as rescue medication. | Drug: indacaterol<br>* Indacaterol delivered by multiple dose dry powder inhaler (TWISTHALER® device).<br>Drug: placebo to formoterol<br>* Placebo AEROLIZER® device<br>Drug: short acting β2-agonist<br>* 100 μg/ 90 μg salbutamol/albuterol Metered Dose Inhaler (MDI) or equivalent dose of Dry Powder Inhaler (DPI).<br>|
| Experimental: indacaterol 250 μg<br>Indacaterol 250 μg delivered by the TWISTHALER® device once a day and placebo to formoterol (placebo AEROLIZER® device) twice a day for 14 days. All participants were supplied with salbutamol/albuterol to use throughout the study as rescue medication. | Drug: indacaterol<br>* Indacaterol delivered by multiple dose dry powder inhaler (TWISTHALER® device).<br>Drug: placebo to formoterol<br>* Placebo AEROLIZER® device<br>Drug: short acting β2-agonist<br>* 100 μg/ 90 μg salbutamol/albuterol Metered Dose Inhaler (MDI) or equivalent dose of Dry Powder Inhaler (DPI).<br>|
| Experimental: indacaterol 500 μg<br>Indacaterol 500 μg delivered by the TWISTHALER® device once a day and placebo to formoterol (placebo AEROLIZER® device) twice a day for 14 days. All participants were supplied with salbutamol/albuterol to use throughout the study as rescue medication. | Drug: indacaterol<br>* Indacaterol delivered by multiple dose dry powder inhaler (TWISTHALER® device).<br>Drug: placebo to formoterol<br>* Placebo AEROLIZER® device<br>Drug: short acting β2-agonist<br>* 100 μg/ 90 μg salbutamol/albuterol Metered Dose Inhaler (MDI) or equivalent dose of Dry Powder Inhaler (DPI).<br>|
| Active Comparator: formoterol<br>Formoterol 12 μg delivered by the AEROLIZER® device twice a day and placebo to indacaterol (placebo TWISTHALER® device) once a day for 14 days. All participants were supplied with salbutamol/albuterol to use throughout the study as rescue medication. | Drug: formoterol<br>* Formoterol delivered by oral inhalation via AEROLIZER® inhalation device.<br>Drug: placebo to indacaterol<br>* Placebo TWISTHALER® device<br>Drug: short acting β2-agonist<br>* 100 μg/ 90 μg salbutamol/albuterol Metered Dose Inhaler (MDI) or equivalent dose of Dry Powder Inhaler (DPI).<br>|
| Placebo Comparator: placebo<br>Placebo to indacaterol (placebo TWISTHALER® device) once a day and placebo to formoterol (placebo AEROLIZER® device) twice a day for 14 days. All participants were supplied with salbutamol/albuterol to use throughout the study as rescue medication. | Drug: placebo to indacaterol<br>* Placebo TWISTHALER® device<br>Drug: placebo to formoterol<br>* Placebo AEROLIZER® device<br>Drug: short acting β2-agonist<br>* 100 μg/ 90 μg salbutamol/albuterol Metered Dose Inhaler (MDI) or equivalent dose of Dry Powder Inhaler (DPI).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Mean Change From 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 baseline to 24 hour post dose trough FEV1 after 14 days of treatment was analyzed using Analysis of Covariance (ANCOVA) adjusting for treatment and region with baseline FEV1 as a covariate. | Baseline (prior to first dose) and Day 15 (24 hours after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) Between Baseline (Predose) and 4 Hours Post-dose | FEV1 was measured on Day 14 pre-dose and up to 4 hours post-dose. The Area Under the Curve (AUC) for FEV1 was analyzed using Analysis of Covariance adjusting for treatment and region with baseline FEV1 as a covariate. | Day 14, pre-dose, 5, 20 and 30 minutes, 1, 2, 3, and 4 hours post-dose. | 
| The Mean Change From Baseline to 24 Hour Post-dose (Trough) Forced Expiratory Volume in 1 Second (FEV1) on Day 1 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Change from baseline to 24 hour post dose trough FEV1 after 1 day of treatment was analyzed using Analysis of Covariance (ANCOVA) adjusting for treatment and region with baseline FEV1 as a covariate. | Day 1 Baseline (prior to first dose) and 24 hours post-dose. | 
| Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) Between Baseline (Predose) and 4 Hours Post-dose on Day 1 | FEV1 was measured on Day 1 pre-dose and up to 4 hours post-dose. The Area Under the Curve (AUC) for FEV1 was analyzed using Analysis of Covariance adjusting for treatment and region with baseline FEV1 as a covariate. | Day 1, pre-dose, 5, 20 and 30 minutes, 1, 2, 3, and 4 hours post-dose. | 
| Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 14 | 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, which is taken as the maximum FEV1 recorded post-dose. | Day 1 and Day 14 measured pre-dose and up to 4 hours post-dose | 
| Change From Baseline in Morning and Evening Peak Expiratory Flow | The Peak Expiratory Flow (PEF) rate is the maximal rate that a person can exhale during a short maximal expiratory effort after fully inhaling. Participants measured their PEF using a peak flow meter and recorded measurements in a diary every morning and evening during the study, prior to taking study medication. Change from baseline is the difference between the mean baseline PEF recorded during the screening period until the first day of treatment, and the overall mean PEF from Days 1 to 14. | Baseline (recorded during the screening period) and Days 1-14 (treatment period) | 
| Number of Participants Using Rescue Medication | Participants recorded the use of rescue medications (salbutamol/albuterol) for treatment of asthma symptoms twice a day in a diary during the 14 days of the treatment period. | Over 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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QMF, indacaterol, Twisthaler®