Efficacy, Safety, Tolerability, and Pharmacokinetics of Indacaterol Salts in Patients With Asthma

Study Overview
=================
Brief Summary
-----------------
This study assessed the efficacy, safety, and pharmacokinetics of indacaterol salts (maleate, xinafoate and acetate) in patients with asthma.

Official Title
-----------------
A Multi-centre, Randomized, Double-blind, Placebo-controlled, Multiple-dose, 4-way Crossover Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Orally Inhaled Indacaterol Salts (Maleate, Xinafoate, and Acetate) in Patients With Persistent Asthma

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Indacaterol maleate 400 μg
* Drug: Indacaterol acetate 400 μg
* Drug: Indacaterol xinafoate 400 μg
* Drug: Placebo to indacaterol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-smoker 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, including any adjustments to asthma medication prior to screening. Patients with asthma, receiving daily treatment with inhaled corticosteroid. Patients with a forced expiratory volume in 1 second (FEV1) during screening of ≥ 50% of the predicted normal value for the patient. Body mass index (BMI) must be within the range 18-32 kg/m^2 (inclusive). Able to communicate well with the investigator and comply with the requirements of the study. Exclusion criteria: A urine cotinine level greater than the local laboratory lowest level of quantification (LOQ of 500 ng/ml or lower). Patients who have had a severe asthma attack/exacerbation requiring hospitalization in the 6 months prior to screening. Patients who have had an emergency room visit for an asthma attack/exacerbation within 6 weeks prior to screening or any time between screening and pre-dose on day 1 of the study. Patients who have had a respiratory tract infection within 4 weeks prior to screening or any time between screening and pre-dose on day 1 of the study. Patients who require the use of ≥ 8 inhalations per day of the short-acting β2-agonist salbutamol/albuterol (100 μg/90 μg salbutamol/albuterol metered dose inhaler [MDI] or equivalent dose of a dry-powder inhaler [DPI]) on any 2 consecutive days from screening to randomization. Patients diagnosed with chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (2008). Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation. Previous participation in a study with either the investigational or comparator drugs does not exclude a patient from participation in this study. Significant illness. History of being immunocompromised, including a positive human immunodeficiency virus (HIV) test result (ELISA and Western blot). A positive hepatitis B surface antigen (HBsAg) or hepatitis C test result. Patients who are considered vulnerable as per ICH GCP guidelines. Patients with a history of hypersensitivity to indacaterol or to similar drugs including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof. Treatments for asthma and allied conditions: The following treatments should not be used unless they have been stabilized prior to screening: antihistamines, inhaled nasal cromolyn, inhaled nasal corticosteroids, and maintenance immunotherapy. Other protocol-defined inclusion/exclusion criteria applied to the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indacaterol (ind) maleate-placebo-ind xinafoate-ind acetate<br>In treatment period 1, patients received indacaterol maleate 400 μg; in treatment period 2, patients received placebo to indacaterol; in treatment period 3, patients received indacaterol xinafoate 400 μg; and in treatment period 4, patients received indacaterol acetate 400 μg. Patients received each treatment once daily for 7 days via the Concept1 single-dose dry-powder inhaler. There was a washout period of at least 7 days between each treatment period. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Indacaterol maleate 400 μg<br>* Indacaterol maleate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol acetate 400 μg<br>* Indacaterol acetate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol xinafoate 400 μg<br>* Indacaterol xinafoate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Placebo to indacaterol<br>* Placebo to indacaterol was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler.<br>|
| Experimental: Indacaterol (ind) xinafoate-ind maleate-ind acetate-placebo<br>In treatment period 1, patients received indacaterol xinafoate 400 μg; in treatment period 2, patients received indacaterol maleate 400 μg; in treatment period 3, patients received indacaterol acetate 400 μg; and in treatment period 4, patients received placebo to indacaterol 400 μg. Patients received each treatment once daily for 7 days via the Concept1 single-dose dry-powder inhaler. There was a washout period of at least 7 days between each treatment period. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Indacaterol maleate 400 μg<br>* Indacaterol maleate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol acetate 400 μg<br>* Indacaterol acetate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol xinafoate 400 μg<br>* Indacaterol xinafoate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Placebo to indacaterol<br>* Placebo to indacaterol was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler.<br>|
| Experimental: Indacaterol (ind) acetate-ind xinafoate-placebo-ind maleate<br>In treatment period 1, patients received indacaterol acetate 400 μg; in treatment period 2, patients received indacaterol xinafoate 400 μg; in treatment period 3, patients received placebo to indacaterol; and in treatment period 4, patients received indacaterol maleate 400 μg. Patients received each treatment once daily for 7 days via the Concept1 single-dose dry-powder inhaler. There was a washout period of at least 7 days between each treatment period. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Indacaterol maleate 400 μg<br>* Indacaterol maleate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol acetate 400 μg<br>* Indacaterol acetate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol xinafoate 400 μg<br>* Indacaterol xinafoate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Placebo to indacaterol<br>* Placebo to indacaterol was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler.<br>|
| Experimental: Placebo-indacaterol (ind) acetate-ind maleate-ind xinafoate<br>In treatment period 1, patients received placebo to indacaterol; in treatment period 2, patients received indacaterol acetate 400 μg; in treatment period 3, patients received indacaterol maleate 400 μg; and in treatment period 4, patients received indacaterol xinafoate 400 μg. Patients received each treatment once daily for 7 days via the Concept1 single-dose dry-powder inhaler. There was a washout period of at least 7 days between each treatment period. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | Drug: Indacaterol maleate 400 μg<br>* Indacaterol maleate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol acetate 400 μg<br>* Indacaterol acetate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Indacaterol xinafoate 400 μg<br>* Indacaterol xinafoate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.<br>Drug: Placebo to indacaterol<br>* Placebo to indacaterol was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7) | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at Baseline and at the end of each treatment period. The analysis included period baseline FEV1 as covariate. | Baseline to the end of each treatment period (Day 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at Baseline and on Day 1. The analysis included period baseline FEV1 as covariate. | Baseline to Day 1 | 
| Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | FEV1 was measured with spirometry conducted according to internationally accepted standards at 5, 15, and 30 minutes; 1 hour, 1 hour 30 minutes; and 2, 4, and 12 hours post-dose on Day 1 and Day 7. | Day 1 and Day 7 | 
| Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period | Patients recorded use of rescue medication (salbutamol/albuterol multi-dose inhaler) as the number of puffs taken in respective preceding 12 hours morning and evening in a diary. Patient with any use of rescue medication (any number of puffs > 0) was included to calculate endpoint. | Baseline to the end of each treatment period (Day 7) | 
| Indacaterol Exposure (AUC[0-24 Hours]) at the End of Each 7 Day Treatment Period | Venous blood samples for pharmacokinetic evaluation were collected at 15 and 30 minutes; and 1, 2, 4, 12, and 24 hours post-dose at the end of each 7 day treatment period and were analyzed using a LC-MS/MS assay. Area under the concentration-time curve up to 24 hours (AUC[0-24 hours]) was calculated from concentration-time data and recorded sampling times using non-compartmental methods. | End of each treatment period (Day 7) | 
| Indacaterol Exposure (Cmax) at the End of Each 7 Day Treatment Period | Venous blood samples for pharmacokinetic evaluation were collected at 15 and 30 minutes; and 1, 2, 4, 12, and 24 hours post-dose at the end of each 7 day treatment period and were analyzed using a LC-MS/MS assay. Maximum (peak) plasma drug concentration after drug administration (Cmax) was calculated from concentration-time data and recorded sampling times using non-compartmental methods. | End of each treatment period (Day 7) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
QAB149, asthma, indacaterol salts (acetate, maleate, and xinafoate), orally inhaled indacaterol salts, persistent asthma