Study of Indacaterol Dosed in the Evening in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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This study was conducted to provide detailed information on the efficacy of indacaterol (in terms of the spirometry assessment forced expiratory volume in 1 second [FEV1]) over the full 24-h time period

Official Title
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A Phase III Randomized, Double Blind, Double Dummy, Placebo Controlled, Multicenter, 4 Treatments, 3 Period Incomplete Block Crossover Study to Assess the Efficacy and Safety of Indacaterol 300 µg o.d. Dosed in the Evening in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD), Using Salmeterol 50 µg b.i.d. as Active Control

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: Indacaterol
* Drug: Salmeterol
* Drug: Placebo to Indacaterol
* Drug: Placebo to Salmeterol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female adults aged ≥ 40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure Co-operative outpatients with a diagnosis of chronic obstructive pulmonary disease (COPD) (moderate to severe as classified by the Global initiative for chronic obstructive lung disease (GOLD) Guidelines, 2006) and: Smoking history of at least 20 pack years Post-bronchodilator FEV1 < 80% and ≥30% of the predicted normal value Post-bronchodilator FEV1/forced vital capacity (FVC) < 70% Exclusion criteria: Pregnant or lactating females Patients who have been hospitalized for a COPD exacerbation in the 6 weeks prior to Visit 1 or during the run-in period Patients requiring long term oxygen therapy (>15 h a day) Patient who have had a respiratory tract infection 6 weeks prior to V2 (with further criteria) Patients with concomitant pulmonary disease, pulmonary tuberculosis, or clinically significant bronchiectasis Patients with history of asthma (with further criteria) Patients with Type I or uncontrolled type II diabetes. Patients who have clinically relevant laboratory abnormalities or a clinically significant abnormality Any patient with active cancer or a history of cancer with less than 5 years disease free survival time Patient with a history with long QT syndrome or whose QTc interval is prolonged Patients with a hypersensitivity to any of the study drugs or drugs with similar chemical structure Patients who have had treatment with an investigational drug (with further criteria) Patients who have had live attenuated vaccination within 30 days prior to Visit 2, or during run-in period Patients with known history of non compliance to medication Patients unable to satisfactorily use a dry powder inhaler device or perform spirometry measurements Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 40 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indacaterol Morning,Indacaterol Evening, Salmeterol<br>In period I, indacaterol 300 μg once a day in the morning delivered via single dose dry powder inhaler (SDDPI) with a placebo to salmeterol delivered via dry powder inhaler (DPI). Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. In period II, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. In period III, Salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and second dose in the evening along with placebo matching indacaterol delivered by SDDPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Indacaterol Evening,Indacaterol Morning, Placebo<br>In period I, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. In period II, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. In period III, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Salmeterol, Placebo, Indacaterol Morning<br>In period I, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose was in the evening along with placebo matching indacaterol delivered by SDDPI. In period II, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. In period III, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Placebo, Salmeterol, Indacaterol Evening<br>In period I, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. In period II, salmeterol 50 μg twice daily delivered via dry powder inhaler (DPI). One of the two daily doses of salmeterol was administered in the morning and the second dose was in the evening along with placebo matching indacaterol delivered by SDDPI. In period III, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via dry DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Indacaterol Morning, Placebo, Indacaterol Evening<br>In period I, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. In period II, During morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. In period III, Patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Indacaterol Evening,Salmeterol, Indacaterol Morning<br>In period I, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. In period II, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose in evening along with placebo matching indacaterol delivered by SDDPI. In period III, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Salmeterol, Indacaterol Evening, Placebo<br>In period I, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose in evening along with placebo matching indacaterol delivered by SDDPI. In period II, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. In period III, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Placebo, Indacaterol Morning, Salmeterol<br>In period I, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. In period II, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via dry powder inhaler DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. In period III, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose in evening along with placebo matching indacaterol delivered by SDDPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Indacaterol Morning, Salmeterol, Placebo<br>In period I, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. In period II, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose in evening along with placebo matching indacaterol delivered by SDDPI. In period III, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Indacaterol Evening, Placebo, Salmeterol<br>In period I, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via dry powder inhaler DPI. In period II, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. In period III, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose in evening along with placebo matching indacaterol delivered by SDDPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Salmeterol, Indacaterol Morning, Indacaterol Evening<br>In period I, salmeterol 50 μg twice daily delivered via DPI. One of the two daily doses of salmeterol was administered in the morning and the second dose in evening along with placebo matching indacaterol delivered by SDDPI. In period II, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. In period III, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Salmeterol<br>* 50 µg twice daily delivered via dry powder inhaler (DPI)<br>* Other names: Serevent®;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<br>|
| Experimental: Placebo, Indacaterol Evening, Indacaterol Morning<br>In period, during morning and evening, placebo matching indacaterol was delivered via SDDPI and placebo matching salmeterol was delivered via DPI. In period II, patients were instructed to take morning doses of a placebo to indacaterol delivered via SDDPI and placebo to salmeterol delivered via DPI. Indacaterol 300 μg once a day in the evening delivered via SDDPI with placebo to salmeterol delivered via DPI. In period III, indacaterol 300 μg once a day in the morning delivered via SDDPI with a placebo to salmeterol delivered via DPI. Patients were also instructed to take evening doses of a placebo to indacaterol via SDDPI and placebo to salmeterol via DPI. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) was available for rescue use throughout the study. | Drug: Indacaterol<br>* 300 µg dosed in the morning/evening via single dose dry powder inhaler (SDDPI)<br>* Other names: QAB149;Drug: Placebo to Indacaterol<br>* Placebo matching indacaterol was delivered via SDDPI.<br>Drug: Placebo to Salmeterol<br>* Placebo matching salmeterol was delivered via DPI<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 (FEV1) Following 14 Days of Evening Dosing of Indacaterol Versus Placebo | Trough FEV1 was assessed by performing spirometry measurements in the clinic for each treatment period. For the primary efficacy variable, trough FEV1 is the mean of two measurements taken at 23h 10 min and 23h 45 min post dose. The primary variable was analyzed using an analysis of covariance (ANCOVA) model with the (period) baseline FEV1 as covariate. The (period) baseline FEV1 was defined as the value measured before the study drug administration in that treatment period. | After 14 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Assessed After 14 Days of Dosing for All Other Treatment Comparisons | Trough FEV1 was assessed by performing spirometry measurements in the clinic for each treatment period. On the morning and evening of Day 15 trough FEV1 (i.e. mean of measurements performed 23 h 10 min and 23 h 45 min post-dose) were assessed. An analysis of covariance (ANCOVA) model was used with the (period) baseline FEV1 as covariate. The (period) baseline FEV1 was defined as the value measured before the study drug administration in that treatment period. | After 14 days of dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, bronchodilator, long acting beta agonist, LABA