Safety and Tolerability of QVA149 (Indacaterol/Glycopyrrolate) Compared to Placebo and to Indacaterol in Patients With Moderate to Severe Stable Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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An investigational inhalation product (QVA149) for the treatment of patients with Chronic Obstructive Pulmonary Disease (COPD) is being developed. This 14 day study will investigate the effect on heart rate and cardiovascular effects to ensure the product is safe.

Official Title
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A Randomized, Double Blind, Placebo Controlled, Multicenter Study to Determine the Effect of QVA149 on Mean 24-hours Heart Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: indacaterol/glycopyrrolate
* Drug: indacaterol
* Drug: glycopyrrolate
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consented male or female adults aged ≥40 years Moderate to severe stable Chronic Obstructive Pulmonary Disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines (2006) Patients who have smoking history of at least 10 pack years Patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥30% and <80% of the predicted normal and post-bronchodilator FEV1/Forced vital capacity (FVC) <0.70 at Visit 1 and Visit 3 Exclusion Criteria: Pregnant or nursing (lactating) women Patients requiring long term oxygen therapy (> 15 hours a day) on a daily basis for chronic hypoxemia, or who have been hospitalized or visited an emergency room for a COPD exacerbation in the 6 weeks prior to screening (Visit 1) or during the screening period Patients who had a respiratory tract infection within 6 weeks of Visit 1 or at screening Concomitant pulmonary disease, pulmonary tuberculosis (TB) (unless chest x-ray confirms no longer active) or clinically significant bronchiectasis Any history of asthma Patients who have clinically relevant lab abnormalities / conditions such as (but not limited to) long term prednisone therapy, unstable ischemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding stable atrial fibrillation [AF]), uncontrolled hypertension, narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment, uncontrolled hypo- and hyperthyroidism, hypokalemia, hyperadrenergic state or any condition which might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study Patients with a history of cardiac failure, life threatening arrhythmias (screening Holter) and acute ischemic changes (screening ECG) Patients with a history of long QT syndrome or whose QTc (Fridericia method) interval measured at screening (Visit 1) is prolonged (>450 ms for males or >470 for females) History of malignancy of any organ system, treated or untreated within the past 5 years Uncontrolled Type I / Type II Diabetes or blood glucose outside the normal range or Hemoglobin A1C (HbA1c) >8.0% of total hemoglobin measured at Visit 1 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: indacaterol/glycopyrrolate 600/100 μg<br>Two capsules indacaterol/glycopyrrolate 300/50 μg delivered via a single dose dry powder inhaler in the morning for 14 days. The use of salbutamol/albuterol as rescue medication was permitted throughout the study. | Drug: indacaterol/glycopyrrolate<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>* Other names: QVA149;|
| Experimental: indacaterol/glycopyrrolate 300/100 μg<br>One capsule indacaterol/glycopyrrolate 300/100 μg and one placebo capsule delivered via a single dose dry powder inhaler in the morning for 14 days. The use of salbutamol/albuterol as rescue medication was permitted throughout the study. | Drug: indacaterol/glycopyrrolate<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>* Other names: QVA149;Drug: placebo<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>|
| Experimental: indacaterol/glycopyrrolate 150/100 μg<br>One capsule indacaterol/glycopyrrolate 150/50 μg and one capsule 50 μg glycopyrrolate delivered via a single dose dry powder inhaler in the morning for 14 days. The use of salbutamol/albuterol as rescue medication was permitted throughout the study. | Drug: indacaterol/glycopyrrolate<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>* Other names: QVA149;Drug: glycopyrrolate<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>|
| Active Comparator: indacaterol 300 μg<br>One capsule indacaterol 300 μg and one placebo capsule delivered via s single dose dry powder inhaler in the morning for 14 days. The use of salbutamol/albuterol as rescue medication was permitted throughout the study. | Drug: indacaterol<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>* Other names: QAB149;Drug: placebo<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>|
| Placebo Comparator: placebo<br>Two placebo capsules delivered via a single dose dry powder inhaler in the morning for 14 days. The use of salbutamol/albuterol as rescue medication was permitted throughout the study. | Drug: placebo<br>* Inhalation capsule delivered via a single dose dry powder inhaler in the morning for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean 24 Hour Heart Rate at Day 14 | Heart rate was assessed by Holter monitoring and was measured over a 24 hour period at day 14. Heart rate was defined as the average value over the 24 hour monitoring period. The baseline measurement was the average heart rate taken from the 24 hour Holter monitoring period performed at screening or the last 24-hour period before taking the first dose of study drug. Least square means are based on the analysis of covariance: 24 hours mean heart rate = center + treatment + baseline value + Forced Expiratory Volume in one second (FEV1) before inhalation of salbutamol/albuterol + FEV1 30 min post salbutamol/albuterol + error. | Baseline, Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean 24 Hour Heart Rate at Day 1 | Heart rate was assessed by Holter monitoring and was measured over a 24 hour period at day 1. Heart rate was defined as the average value over the 24 hour monitoring period. The baseline measurement was the average heart rate taken from the 24 hour Holter monitoring period performed at screening or the last 24-hour period before taking the first dose of study drug. Least squares means are based on the analysis of covariance: 24 hours mean heart rate = center + treatment + baseline value + Forced Expiratory Volume in one second (FEV1) before inhalation of salbutamol/albuterol + FEV1 30 min after inhalation of salbutamol/albuterol + error. | Baseline, Day 1 | 
| Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Day 14 | Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 was defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline is defined as the mean of the two values taken at 45 minutes and 15 minutes prior to dosing at day 1. Least square means are based on the analysis of covariance: response variable=center + treatment + baseline value + Forced Expiratory Volume in one second (FEV1) before inhalation of salbutamol/albuterol + FEV1 30 minutes post inhalation of salbutamol/albuterol. | Day 1, Day 14 | 
| Trough Forced Vital Capacity (FVC) at Day 1 and Day 14 | Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FVC was defined as the mean of two measurements at 23 hours 15 minutes and the 23 hours 45 minutes post dosing. Baseline was defined as the mean of the two values taken at 45 minutes and 15 minutes prior to dosing at day 1. Analysis of covariance: FVC parameter = center + treatment + baseline FVC + FEV1 before inhalation of salbutamol/albuterol + FEV1 30 min after inhalation of salbutamol/albuterol + error. | Day 1 and Day 14 | 
| Change From Baseline in QTc (Fridericia's Formula) at Day 1 | The change from baseline in QTc at 30 minutes, 4 hours and 23 hours 45 minutes post dose on day 1. QT calculated (QTc) was calculated from the QT interval and RR (in seconds) using Fridericia's formula: QTc = QT / 3√ RR. Least square means are based on the analysis of covariance: response variable = center + treatment + baseline value + FEV1 before inhalation of salbutamol/albuterol + FEV1 30 min post inhalation of salbutamol/albuterol. | Baseline, Day 1 | 
| Change From Baseline in QTc (Fridericia's Formula) at Day 7 | The change from baseline in QTc at 30 minutes and 2 hours post dose on day 7. QT calculated (QTc) was calculated from the QT interval and RR (in seconds) using Fridericia's formula: QTc = QT / 3√ RR. Least square means are based on the analysis of covariance: response variable = center + treatment + baseline value + FEV1 before inhalation of salbutamol/albuterol + FEV1 30 min post inhalation of salbutamol/albuterol. | Baseline, Day 7 | 
| Change From Baseline in QTc (Fridericia's Formula) at Day 14 | The change from baseline in QTc at 30 minutes, 4 hours and 23 hours 45 minutes post dose on day 14. QT calculated (QTc) was calculated from the QT interval and RR (in seconds) using Fridericia's formula: QTc = QT / 3√ RR. Least square means are based on the analysis of covariance: response variable = center + treatment + baseline value + FEV1 before inhalation of salbutamol/albuterol + FEV1 30 minutes post inhalation of salbutamol/albuterol. | Baseline, Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Chronic Obstructive Pulmonary Disease, Indacaterol, QVA149