Safety of Exercise and High-dose Salbutamol in Patients With Chronic Obstructive Pulmonary Disease (COPD) Receiving Therapeutic Doses of Indacaterol (QAB 149) and Salmeterol

Study Overview
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Brief Summary
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This study investigated the effect of exercise and high-dose salbutamol on the maximum heart rate in patients with chronic obstructive pulmonary disease (COPD) receiving therapeutic doses of indacaterol, salmeterol and placebo.

Official Title
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A Double-blind, Randomized, Cross-over, Placebo-controlled, 2-part Study to Compare the Effect of Exercise and High-dose Salbutamol on Maximal Heart-rate in Patients With COPD Following Therapeutic Doses of Inhaled QAB149 and Salmeterol

Conditions
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Chronic Obstructive Pulmonary Disease

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients between 40 and 75 years of age diagnosed with chronic obstructive pulmonary disease (COPD). Female patients must be surgically sterilized, postmenopausal or using a double-barrier method of contraception. Body mass index (BMI) must be within the range of 18 to 32. Exclusion Criteria: Participation in any clinical investigation with experimental drug therapy within four weeks prior to dosing or longer as required by local regulation. Donation or loss of 400 mL or more of blood within two months prior to dosing. Significant illness (other than respiratory) within two weeks prior to dosing. A past medical history of, or a family history (grandparents, parents and siblings) of a prolonged QT-interval syndrome or a prolonged QT-interval at screening. Any clinically significant medical abnormalities (excluding COPD) limiting ability to perform standardized exercise protocol on cycle ergometer will exclude the patient. For example, arthritis. History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug. History of immunocompromise, including a positive HIV, Hepatitis B or C test result. History of drug or alcohol abuse within the 12 months prior to dosing Any conditions that in the opinion of the investigator may compromise patient safety, interfere with evaluations, or preclude the completion of the trial. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 40 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Sequence A, Part 2: Sequence A<br>Part 1: Sequence 'A' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'A' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | Drug: Indacaterol<br>* Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).<br>Drug: Placebo<br>* Single dose indacaterol matching placebo via Concept 1 device<br>Drug: Salmeterol<br>* Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.<br>|
| Experimental: Part 1 : Sequence B, Part 2: Sequence B<br>Part 1: Sequence 'B' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'B' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | Drug: Indacaterol<br>* Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).<br>Drug: Placebo<br>* Single dose indacaterol matching placebo via Concept 1 device<br>Drug: Salmeterol<br>* Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.<br>|
| Experimental: Part 1: Sequence C, Part 2: Sequence C<br>Part 1: Sequence 'C' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus DPI. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'C' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device . In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | Drug: Indacaterol<br>* Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).<br>Drug: Placebo<br>* Single dose indacaterol matching placebo via Concept 1 device<br>Drug: Salmeterol<br>* Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.<br>|
| Experimental: Part 1; Sequence D, Part 2: Sequence D<br>Part 1: Sequence 'D' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'D' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | Drug: Indacaterol<br>* Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).<br>Drug: Placebo<br>* Single dose indacaterol matching placebo via Concept 1 device<br>Drug: Salmeterol<br>* Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.<br>|
| Experimental: Part 1: Sequence E, Part 2: Sequence E<br>Part 1: Sequence 'E' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'E' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | Drug: Indacaterol<br>* Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).<br>Drug: Placebo<br>* Single dose indacaterol matching placebo via Concept 1 device<br>Drug: Salmeterol<br>* Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.<br>|
| Experimental: Part 1: Sequence F, Part 2: Sequence F<br>Part 1: Sequence 'F' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'F' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | Drug: Indacaterol<br>* Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).<br>Drug: Placebo<br>* Single dose indacaterol matching placebo via Concept 1 device<br>Drug: Salmeterol<br>* Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Maximum Heart Rate Increase During Exercise in Part 1 of the Study | The percentage of patients with an increase of more than 10 beats per minute (bpm) in their heart rate following treatment with indacaterol and salmeterol compared to treatment with placebo was determined. | 24-hours post-dose on Day 1 (of each treatment) | 
| Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | The percentage of patients with an increase of >= 10 beats per minute (bpm) in their heart rate (HR) following treatment with indacaterol and salmeterol compared to treatment with placebo over 24 hours in Part 2 was determined. 0-12 hours: post first dose measurements up to second dose 12-24 hours: post second dose measurement up to and including the 24 hour measurement 0-24 hours: all post dose measurements up to and including the 24 hour measurement | 24 hours post dose on Day 1 | 
| Maximum Heart Rate During Exercise in Part 1 | Maximum heart rate was generally taken from the continuous ECG monitoring. Analysis based on mixed effects analysis using model with treatment and period as fixed effects and subject as random effect. | 2 hour post-dose on Day 1 | 
| Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | Maximum HR (0-12 hours): maximum (max) of post dose measurement up to second administration. Maximum HR (12-24 hours): max of the post second administration of salbutamol measurements. Maximum HR (0-24 hours): max of all post dose measurements up to and including the 24 hour measurement. Mixed effects analysis model used period baseline HR as the covariate. The maximum HR for 0-24 hours (h) is the maximum of the maximum HR for the two 12h periods and thus the average (LS means) of the maximum HRs for 0-24h will be equal to or greater than the average of the maximum for the two periods. | 24 hours post dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heart Rate During Exercise in Part 1 | Change in heart rate is calculated from the 1.5 hour post dose to the maximum heart rate during exercise. Analysis of covariance included treatment and period as fixed effects, subject as random effect and 1.5 hour pre-exercise/post dose heart rate as a covariate. | 1.5 hour post dose to max heart rate during exercise | 
| Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hours 30 minutes and 24 hours post morning dose FEV1 measurements. Analysis of covariance included pre-dose FEV1 as covariate. | 23 hours 30 minutes and 24 hours post-dose at Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, cycle ergometry, exercise testing, spirometry, cardiovascular, salbutamol, indacaterol, chronic obstructive pulmonary disease