A Study to Look at Day to Day Changes in Lung Function in COPD Subjects Taking Albuterol/Salbutamol and Ipratropium

Study Overview
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Brief Summary
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The objective of this study is to assess the daily variation in bronchodilator response to an inhaled short acting beta2-agonist (albuterol/salbutamol) and an inhaled short acting anticholinergic (ipratropium) individually and when used in combination in subjects with COPD.

Detailed Description
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Beta2-agonist and anticholinergics are a principle component of the pharmacologic management of chronic obstructive pulmonary disease COPD. It has been demonstrated that the combination of a short acting beta2-agonist and a short acting anticholinergic yields greater efficacy as measured by FEV1 when compared with the response to the individual short acting bronchodilators. However, daily bronchial response to these agents is poorly understood. It is also poorly understood how the variation in magnitude of the response to the individual agents and how the variation in response for one agent coincides with the variation in response to the other agent. This study will seek to define the pattern of response of each individual agent and the relationship between them. The study will also explore if the combination of the two agents leads to less variation in response compared to the individual agents. This is a randomized, open label, two period cross-over study. Eligible subjects will be randomized to a sequence of either albuterol/salbutamol via metered-dose inhaler (MDI) followed by ipratropium via MDI or the same dose of each bronchodilator given in the opposite order. Each study period will consist of 10 clinic visits to be conducted over 10 to 14 days.

Official Title
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A 4-Week Randomized Cross-Over Study to Evaluate Daily Lung Function Following the Administration of Albuterol/Salbutamol and Ipratropium in Subjects With Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Albuterol/salbutamol
* Drug: Ipratropium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must give their signed and dated written informed consent to participate. Subjects 40 years of age or older at Visit 1. Male or female subjects . An established clinical history of COPD. Current or former cigarette smokers with a history of cigarette smoking of >=10 pack-years at Visit 1. A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1 of >=30 and <= 70% of predicted normal values at Visit 1 calculated using NHANES III reference equations . Exclusion Criteria: A current diagnosis of asthma Women who are pregnant of lactating or are planning on becoming pregnant during the study. Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1. Participation in pulmonary rehabilitation

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Albuterol/salbutamol followed by ipratropium<br>Subjects will recieve daily albuterol/salbutamol followed by ipratropium which will be adminstered one hour after adminstration of albuterol/salbutamol | Drug: Albuterol/salbutamol<br>* Albuterol/salbutamol (daily)<br>|
| Active Comparator: Ipratropium followed by albuterol/salbutamol<br>Subjects will recieve daily ipratropium followed by albuterol/salbutamol which will be adminstered one hour after adminstration of ipratropium | Drug: Ipratropium<br>* Ipratropium (daily)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability in Daily FEV1, Estimated by Coefficient of Variation | FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum FEV1 values. | up to 10 days | 
| Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum FEV1 values. | up to 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximal Bronchodilator Response for the First Administered Agent | The maximal bronchodilator response for the first administered agent is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) 1 hour post-dose of the first bronchodilator minus the pre-dose. The maximal bronchodilator response for the second agent is defined as the FEV1 1 hour post-dose of the second bronchodilator minus the FEV1 at 1 hour post-dose of the first bronchodilator. The maximal bronchodilator response for the combination is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) at 1 hour post-administration of the second bronchodilator minus the corresponding pre-dose FEV1. Derived FEV1 response is FEV1 change from 0 hours (0H) for the first agent assessment (at 1 hour [1H]); change from 1H for the second agent assessment (at 2 hours [2H]); and change from 0H for the combination assessment (at 2H). Data were adjusted for FEV1, smoking status, and center. | up to 10 days | 
| Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). | up to 35 days | 
| Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). | up to 35 days | 
| Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum IC values. | up to 10 days | 
| Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum IC values. | up to 10 days |