Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
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
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.
Interventions
DRUGAlbuterol/salbutamol
Albuterol/salbutamol (daily)
DRUGIpratropium
Ipratropium (daily)
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Variability in Daily FEV1, Estimated by Coefficient of Variation | up to 10 days | 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. |
| Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | up to 10 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | up to 35 days | 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). |
| The Maximal Bronchodilator Response for the First Administered Agent | up to 10 days | 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. |
| Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | up to 10 days | 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. |
| Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | up to 10 days | 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. |
| Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | up to 35 days | 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). |
Countries
United Kingdom, United States
Participant flow
Pre-assignment details
This was a randomized, open-label, two-period cross-over study to evaluate the daily bronchodilator response to albuterol/salbutamol and ipratropium individually and in combination in participants with chronic obstructive pulmonary disease.
Participants by arm
| Arm | Count |
|---|---|
| All Randomized Participants All participants randomized to receive a sequence of either salbutamol (4 puffs; 100 µg per puff) via an MDI and albuterol (4 puffs; 90 µg per puff) followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in TP1 and the same dose of each bronchodilator given in the opposite order in TP2, or ipratropium followed by albuterol/salbutamol in TP1 and the same dose of each bronchodilator given in the opposite order in TP2 | 56 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 2 | Adverse Event | 0 | 1 |
| Treatment Period 2 | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | All Randomized Participants |
|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 7.42 |
| Race/Ethnicity, Customized African American/African Heritage | 4 participants |
| Race/Ethnicity, Customized White | 52 participants |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 56 |
| serious Total, serious adverse events | 1 / 56 |
Outcome results
Primary
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.
Time frame: up to 10 days
Population: Efficacy Population: participants in the Intent-to-Treat Population (all participants who were randomized and received at least one bronchodilator in the treatment period) who completed pre- and post- bronchodilator assessments for at least 17 visits, with no more than 3 consecutive missing days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Coefficient of Variation | Pre-dose/non-bronchodilator | 0.081 Liters | Standard Error 0.0394 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Coefficient of Variation | Ipratropium alone, 1 hour | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Coefficient of Variation | Albuterol/Salbutamol (A/S) alone, 1 hour | 0.059 Liters | Standard Error 0.0276 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Coefficient of Variation | Ipratropium followed by A/S, 2 hours | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Coefficient of Variation | A/S followed by ipratropium, 2 hours | 0.054 Liters | Standard Error 0.0232 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Coefficient of Variation | Ipratropium followed by A/S, 2 hours | 0.063 Liters | Standard Error 0.0327 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Coefficient of Variation | Albuterol/Salbutamol (A/S) alone, 1 hour | NA Liters | — |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Coefficient of Variation | A/S followed by ipratropium, 2 hours | NA Liters | — |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Coefficient of Variation | Ipratropium alone, 1 hour | 0.072 Liters | Standard Error 0.0406 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Coefficient of Variation | Pre-dose/non-bronchodilator | 0.079 Liters | Standard Error 0.0372 |
95% CI: [0.049, 0.067]
95% CI: [0.062, 0.08]
95% CI: [0.044, 0.062]
95% CI: [0.053, 0.071]
Primary
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.
Time frame: up to 10 days
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Ipratropium followed by A/S, 2 hours | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Albuterol/Salbutamol (A/S) alone, 1 hour | 0.125 Liters | Standard Error 0.0525 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | A/S followed by ipratropium, 2 hours | 0.122 Liters | Standard Error 0.0542 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Ipratropium alone, 1 hour | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Pre-dose/non-bronchodilator | 0.136 Liters | Standard Error 0.0627 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Ipratropium alone, 1 hour | 0.145 Liters | Standard Error 0.0805 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Pre-dose/non-bronchodilator | 0.135 Liters | Standard Error 0.078 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Ipratropium followed by A/S, 2 hours | 0.137 Liters | Standard Error 0.0726 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | A/S followed by ipratropium, 2 hours | NA Liters | — |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values) | Albuterol/Salbutamol (A/S) alone, 1 hour | NA Liters | — |
95% CI: [0.049, 0.067]
95% CI: [0.062, 0.08]
95% CI: [0.044, 0.062]
95% CI: [0.053, 0.071]
Secondary
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).
Time frame: up to 35 days
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | Ipratropium followed by A/S, 2 hours | NA percentage of days | — |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | Albuterol/Salbutamol (A/S) alone, 1 hour | 58.4 percentage of days | Standard Deviation 38.26 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | A/S followed by ipratropium, 2 hours | 71.7 percentage of days | Standard Deviation 35.51 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | Ipratropium alone, 1 hour | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | Ipratropium alone, 1 hour | 55.4 percentage of days | Standard Deviation 39.34 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | Ipratropium followed by A/S, 2 hours | 69.1 percentage of days | Standard Deviation 36.82 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | A/S followed by ipratropium, 2 hours | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1 | Albuterol/Salbutamol (A/S) alone, 1 hour | NA percentage of days | — |
Secondary
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).
Time frame: up to 35 days
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S alone, 1 hour, 200 mL | 59.2 percentage of days | Standard Deviation 38.2 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S alone, 1 hour, 100 mL | 81.6 percentage of days | Standard Deviation 31.35 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S followed by ipratropium, 2 hours, 100 mL | 85.2 percentage of days | Standard Deviation 29.92 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium alone, 1 hour, 100 mL | NA percentage of days | — |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium followed by A/S, 2 hours, 100 mL | NA percentage of days | — |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S followed by ipratropium, 2 hours, 200 mL | 72.7 percentage of days | Standard Deviation 35.25 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium alone, 1 hour, 200 mL | NA percentage of days | — |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium followed by A/S, 2 hours, 200 mL | NA percentage of days | — |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S alone, 1 hour, 250 mL | 45.9 percentage of days | Standard Deviation 38.85 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S followed by ipratropium, 2 hours, 250 mL | 64.0 percentage of days | Standard Deviation 39.08 |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium alone, 1 hour, 250 mL | NA percentage of days | — |
| Albuterol/Salbutamol Followed by Ipratropium | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium followed by A/S, 2 hours, 250 mL | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium followed by A/S, 2 hours, 250 mL | 59.6 percentage of days | Standard Deviation 38.19 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium followed by A/S, 2 hours, 200 mL | 70.5 percentage of days | Standard Deviation 36.23 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S followed by ipratropium, 2 hours, 250 mL | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S followed by ipratropium, 2 hours, 200 mL | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S alone, 1 hour, 100 mL | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S alone, 1 hour, 250 mL | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S followed by ipratropium, 2 hours, 100 mL | NA percentage of days | — |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium alone, 1 hour, 200 mL | 56.0 percentage of days | Standard Deviation 39.54 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium alone, 1 hour, 100 mL | 72.9 percentage of days | Standard Deviation 38.06 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium alone, 1 hour, 250 mL | 45.8 percentage of days | Standard Deviation 36.94 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | Ipratropium followed by A/S, 2 hours, 100 mL | 81.2 percentage of days | Standard Deviation 33.46 |
| Ipratropium Followed by Albuterol/Salbutamol | Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL | A/S alone, 1 hour, 200 mL | NA percentage of days | — |
Secondary
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.
Time frame: up to 10 days
Population: Efficacy Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | The Maximal Bronchodilator Response for the First Administered Agent | Second agent, A/S | 0.094 Liters | Standard Error 0.0123 |
| Albuterol/Salbutamol Followed by Ipratropium | The Maximal Bronchodilator Response for the First Administered Agent | First agent, albuterol/salbutamol (A/S) | 0.269 Liters | Standard Error 0.0174 |
| Albuterol/Salbutamol Followed by Ipratropium | The Maximal Bronchodilator Response for the First Administered Agent | First agent, ipratropium | 0.243 Liters | Standard Error 0.0174 |
| Albuterol/Salbutamol Followed by Ipratropium | The Maximal Bronchodilator Response for the First Administered Agent | Second agent, ipratropium | 0.094 Liters | Standard Error 0.0123 |
| Albuterol/Salbutamol Followed by Ipratropium | The Maximal Bronchodilator Response for the First Administered Agent | A/S followed by ipratropium | 0.363 Liters | Standard Error 0.02 |
| Albuterol/Salbutamol Followed by Ipratropium | The Maximal Bronchodilator Response for the First Administered Agent | Ipratropium followed by A/S | 0.337 Liters | Standard Error 0.02 |
Secondary
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.
Time frame: up to 10 days
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | A/S followed by ipratropium, 2 hours | 0.233 Liters | Standard Deviation 0.1132 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Albuterol/Salbutamol (A/S) alone, 1 hour | 0.229 Liters | Standard Deviation 0.1004 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Ipratropium alone, 1 hour | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Ipratropium followed by A/S, 2 hours | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Pre-dose/non-bronchodilator | 0.225 Liters | Standard Deviation 0.1017 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Ipratropium followed by A/S, 2 hours | 0.221 Liters | Standard Deviation 0.1066 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Pre-dose/non-bronchodilator | 0.236 Liters | Standard Deviation 0.1166 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Albuterol/Salbutamol (A/S) alone, 1 hour | NA Liters | — |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | A/S followed by ipratropium, 2 hours | NA Liters | — |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum) | Ipratropium alone, 1 hour | 0.235 Liters | Standard Deviation 0.1026 |
95% CI: [0.2, 0.255]
95% CI: [0.203, 0.258]
95% CI: [0.204, 0.259]
95% CI: [0.19, 0.245]
Secondary
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.
Time frame: up to 10 days
Population: Efficacy Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | A/S followed by ipratropium (A+I), 2 hours | 0.070 Liters | Standard Deviation 0.0373 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Ipratropium alone, 1 hour | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Albuterol/Salbutamol (A/S) alone, 1 hour | 0.069 Liters | Standard Deviation 0.031 |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Ipratropium followed by A/S (I+A), 2 hours | NA Liters | — |
| Albuterol/Salbutamol Followed by Ipratropium | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Pre-dose/non-bronchodilator | 0.078 Liters | Standard Deviation 0.0305 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Ipratropium followed by A/S (I+A), 2 hours | 0.066 Liters | Standard Deviation 0.0307 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Pre-dose/non-bronchodilator | 0.083 Liters | Standard Deviation 0.0374 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Albuterol/Salbutamol (A/S) alone, 1 hour | NA Liters | — |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | Ipratropium alone, 1 hour | 0.072 Liters | Standard Deviation 0.0353 |
| Ipratropium Followed by Albuterol/Salbutamol | Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation | A/S followed by ipratropium (A+I), 2 hours | NA Liters | — |
95% CI: [0.058, 0.076]
95% CI: [0.061, 0.079]
95% CI: [0.06, 0.078]
95% CI: [0.055, 0.073]