Respimat® Combivent Trial in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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The primary objective of this study is to compare the effect of ipratropium bromide/salbutamol inhalation spray combination administered by the Respimat® inhaler (20 mcg/100 mcg), ipratropium bromide inhalation spray administered by the Respimat® inhaler (20 mcg), and COMBIVENT® MDI administered q.i.d on FEV1 at intervals over a treatment period of 12 weeks in patients with COPD. Specifically, non-inferiority of Combivent Respimat® to COMBIVENT® MDI in FEV1 AUC from 0 to 6 hours , superiority of Combivent Respimat® to Atrovent Respimat® monotherapy in FEV1 AUC from 0 to 4 hours, and non-inferiority of Combivent Respimat® to Atrovent Respimat® monotherapy in FEV1 AUC from 4 to 6 hours will be analyzed. In addition, steady state pharmacokinetics over one dosing interval following 4 weeks of therapy will be characterized in a subgroup of patients.

Official Title
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Safety and Efficacy of Combivent Respimat in Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Atrovent Respimat (20 mcg)
* Drug: COMBIVENT MDI (36/206 mcg)
* Drug: Combivent Respimat (20 mcg/100 mcg)
* Drug: Placebo via corresponding inhaler for blinding purposes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients of either sex, 40 years or older, with a diagnosis of COPD (FEV1 65% predicted normal and FEV1/FVC 70%). Exclusion Criteria: Patients with significant diseases other than COPD that may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study, with a history of asthma or allergic rhinitis, who regularly use daytime oxygen therapy for more than 1 hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy or using oral corticosteroid me dication at unstable doses (i.e., less than 6 weeks on a stable dose) or at a dose in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day will be excluded.

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: COMBIVENT Respimat 20/100 mcg<br> | Drug: Combivent Respimat (20 mcg/100 mcg)<br> <br> Drug: Placebo via corresponding inhaler for blinding purposes<br> <br> |
| Experimental: COMBIVENT CFC-MDI 36/206 mcg<br> | Drug: COMBIVENT MDI (36/206 mcg)<br> <br> Drug: Placebo via corresponding inhaler for blinding purposes<br> <br> |
| Experimental: Ipratropium Respimat 20 mcg<br> | Drug: Atrovent Respimat (20 mcg)<br> <br> Drug: Placebo via corresponding inhaler for blinding purposes<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-6 at Day 85 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 85 | Before drug administration to 6 hours after drug administration on Day 85 | 
| FEV1 AUC0-4 at Day 85 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 85 | Before drug administration to 4 hours after drug administration on Day 85 | 
| FEV1 AUC4-6 at Day 85 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 85 | Between 4 hours and 6 hours after drug administration on Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-6 at Day 1 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 1 | Before drug administration to 6 hours after drug administration on Day 1 | 
| FEV1 AUC0-6 at Day 29 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 29 | Before drug administration to 6 hours after drug administration on Day 29 | 
| FEV1 AUC0-6 at Day 57 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 57 | Before drug administration to 6 hours after drug administration on Day 57 | 
| FEV1 AUC0-4 at Day 1 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 1 | Before drug administration to 4 hours after drug administration on Day 1 | 
| FEV1 AUC0-4 at Day 29 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 29 | Before drug administration to 4 hours after drug administration on Day 29 | 
| FEV1 AUC0-4 at Day 57 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 57 | Before drug administration to 4 hours after drug administration on Day 57 | 
| FEV1 AUC4-6 at Day 1 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 1 | Between 4 hours and 6 hours after drug administration on Day 1 | 
| FEV1 AUC4-6 at Day 29 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 29 | Between 4 hours and 6 hours after drug administration on Day 29 | 
| FEV1 AUC4-6 at Day 57 | Area between the test-day baseline FEV1 and the FEV1 change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 57 | Between 4 hours and 6 hours after drug administration on Day 57 | 
| Peak FEV1 Response at Day 1 | Maximum change in recorded FEV1 value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 1 | Within the first 2-hour post-treatment interval on Day 1 | 
| Peak FEV1 Response at Day 29 | Maximum change in recorded FEV1 value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 29 | Within the first 2-hour post-treatment interval on Day 29 | 
| Peak FEV1 Response at Day 57 | Maximum change in recorded FEV1 value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 57 | Within the first 2-hour post-treatment interval on Day 57 | 
| Peak FEV1 Response at Day 85 | Maximum change in recorded FEV1 value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 85 | Within the first 2-hour post-treatment interval on Day 85 | 
| Time to Onset of Therapeutic FEV1 Response at Day 1 | Achievement of recorded FEV1 measurement of at least 1.15 times of the corresponding test-day baseline value at any time during the first 2 hours of observation after drug administration at Day 1 | Within the first 2-hour post-treatment interval at Day 1 | 
| Time to Onset of Therapeutic FEV1 Response at Day 29 | Achievement of recorded FEV1 measurement of at least 1.15 times of the corresponding test-day baseline value at any time during the first 2 hours of observation after drug administration at Day 29 | Within the first 2-hour post-treatment interval at Day 29 | 
| Time to Onset of Therapeutic FEV1 Response at Day 57 | Achievement of recorded FEV1 measurement of at least 1.15 times of the corresponding test-day baseline value at any time during the first 2 hours of observation after drug administration at Day 57 | Within the first 2-hour post-treatment interval at Day 57 | 
| Time to Onset of Therapeutic FEV1 Response at Day 85 | Achievement of recorded FEV1 measurement of at least 1.15 times of the corresponding test-day baseline value at any time during the first 2 hours of observation after drug administration at Day 85 | Within the first 2-hour post-treatment interval at Day 85 | 
| Duration of Therapeutic FEV1 Response at Day 1 | The time interval between the onset and the the termination of a therapeutic FEV1 response (at least 1.15 times the corresponding test-day baseline value) during the 6-hour observation period at Day 1 | During the 6-hour observation period after drug administration at Day 1 | 
| Duration of Therapeutic FEV1 Response at Day 29 | The time interval between the onset and the the termination of a therapeutic FEV1 response (at least 1.15 times the corresponding test-day baseline value) during the 6-hour observation period at Day 29 | During the 6-hour observation period after drug administration at Day 29 | 
| Duration of Therapeutic FEV1 Response at Day 57 | The time interval between the onset and the the termination of a therapeutic FEV1 response (at least 1.15 times the corresponding test-day baseline value) during the 6-hour observation period at Day 57 | During the 6-hour observation period after drug administration at Day 57 | 
| Duration of Therapeutic FEV1 Response at Day 85 | The time interval between the onset and the the termination of a therapeutic FEV1 response (at least 1.15 times the corresponding test-day baseline value) during the 6-hour observation period at Day 85 | During the 6-hour observation period after drug administration at Day 85 | 
| Time to Peak FEV1 Response at Day 1 | The first time point at which the maximum change in recorded FEV1 data from the corresponding test-day baseline occurred during the 6-hours observation period after drug administration at Day 1 | Within the 6-hour post-treatment observation period at Day 1 | 
| Time to Peak FEV1 Response at Day 29 | The first time point at which the maximum change in recorded FEV1 data from the corresponding test-day baseline occurred during the 6-hours observation period after drug administration at Day 29 | Within the 6-hour post-treatment observation period at Day 29 | 
| Time to Peak FEV1 Response at Day 57 | The first time point at which the maximum change in recorded FEV1 data from the corresponding test-day baseline occurred during the 6-hours observation period after drug administration at Day 57 | Within the 6-hour post-treatment observation period at Day 57 | 
| Time to Peak FEV1 Response at Day 85 | The first time point at which the maximum change in recorded FEV1 data from the corresponding test-day baseline occurred during the 6-hours observation period after drug administration at Day 85 | Within the 6-hour post-treatment observation period at Day 85 | 
| FVC AUC0-6 at Day 1 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 1 | Before drug administration to 6 hours after drug administration at Day 1 | 
| FVC AUC0-6 at Day 29 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 29 | Before drug administration to 6 hours after drug administration at Day 29 | 
| FVC AUC0-6 at Day 57 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 57 | Before drug administration to 6 hours after drug administration on Day 57 | 
| FVC AUC0-6 at Day 85 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 6 hours divided by 6 at Day 85 | Before drug administration to 6 hours after drug administration on Day 85 | 
| FVC AUC0-4 at Day 1 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 1 | Before drug administration to 4 hours after drug administration on Day 1 | 
| FVC AUC0-4 at Day 29 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 29 | Before drug administration to 4 hours after drug administration on Day 29 | 
| FVC AUC0-4 at Day 57 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 57 | Before drug administration to 4 hours after drug administration on Day 57 | 
| FVC AUC0-4 at Day 85 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 0 to 4 hours divided by 4 at Day 85 | Before drug administration to 4 hours after drug administration on Day 85 | 
| FVC AUC4-6 at Day 1 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 1 | Between 4 hours and 6 hours after drug administration on Day 1 | 
| FVC AUC4-6 at Day 29 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 29 | Between 4 hours and 6 hours after drug administration on Day 29 | 
| FVC AUC4-6 at Day 57 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 57 | Between 4 hours and 6 hours after drug administration on Day 57 | 
| FVC AUC4-6 at Day 85 | Area between the test-day baseline FVC and the FVC change from the test-day baseline curve from 4 to 6 hours divided by 2 at Day 85 | Between 4 hours and 6 hours after drug administration on Day 85 | 
| Peak FVC Response at Day 1 | Maximum change in recorded FVC value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 1 | Within the first 2-hour post-treatment interval at Day 1 | 
| Peak FVC Response at Day 29 | Maximum change in recorded FVC value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 29 | Within the first 2-hour post-treatment interval at Day 29 | 
| Peak FVC Response at Day 57 | Maximum change in recorded FVC value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 57 | Within the first 2-hour post-treatment interval at Day 57 | 
| Peak FVC Response at Day 85 | Maximum change in recorded FVC value from the corresponding test-day baseline within the first 2 hours after drug administration on Day 85 | Within the first 2-hour post-treatment interval at Day 85 | 
| Rescue Medication Use on Pulmonary Test Day 1 | Number of patients used rescue medication during the 6-hour pulmonary function testing after drug administration on Day 1 | During the 6-hour pulmonary function testing after drug administration on Day 1 | 
| Rescue Medication Use on Pulmonary Test Day 29 | Number of patients used rescue medication during the 6-hour pulmonary function testing after drug administration on Day 29 | During the 6-hour pulmonary function testing after drug administration on Day 29 | 
| Rescue Medication Use on Pulmonary Test Day 57 | Number of patients used rescue medication during the 6-hour pulmonary function testing after drug administration on Day 57 | During the 6-hour pulmonary function testing after drug administration on Day 57 | 
| Rescue Medication Use on Pulmonary Test Day 85 | Number of patients used rescue medication during the 6-hour pulmonary function testing after drug administration on Day 85 | During the 6-hour pulmonary function testing after drug administration on Day 85 | 
| Night-time Rescue Medication Use | The mean number of puffs of rescue medication used during the night-time per week during the entire study (including baseline and on-treatment period) | During the 2-week baseline washout period and the 12-week treatment period | 
| Daytime Rescue Medication Use | The mean number of puffs of rescue medication used during the daytime per week during the entire study (including baseline and on-treatment period) | During the 2-week baseline washout period and the 12-week treatment period | 
| Night-time Symptom Score | The weekly mean night-time symptom score per week during the entire study (including baseline and on-treatment period). Night-time COPD symptoms: 0=none 1=some - slept well 2=woke once 3=woke several times 4=woke most of night | During the 2-week baseline washout period and the 12-week treatment period | 
| Daytime Symptom Score | The weekly mean daytime symptom score per week during the entire study (including baseline and on-treatment period). Daytime COPD symptoms: 0=none 1=occasional 2=frequent, no interference with activities 3=most of day, interference with activities 4=prevent working and activities | During the 2-week baseline washout period and the 12-week treatment period | 
| Trough Peak Expiratory Flow Rate (PEFR) | The weekly mean trough PEFR during the entire study (including baseline and on-treatment period) | During the 2-week baseline washout period and the 12-week treatment period and PEFR taken before administration of study medication | 
| Physician's Global Evaluation Score on Pulmonary Function Testing Day 29 | Physician's Global Evaluation score is based on the need for concomitant medication, number and severity of exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, etc. Score: 1,2 = poor; 3,4 = fair; 5,6 =good; 7,8 = excellent. | Prior to pulmonary function test on Day 29 | 
| Physician's Global Evaluation Score on Pulmonary Function Testing Day 57 | Physician's Global Evaluation score is based on the need for concomitant medication, number and severity of exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, etc. Score: 1,2 = poor; 3,4 = fair; 5,6 =good; 7,8 = excellent. | Prior to pulmonary function test on Day 57 | 
| Physician's Global Evaluation Score on Pulmonary Function Testing Day 85 | Physician's Global Evaluation score is based on the need for concomitant medication, number and severity of exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, etc. Score: 1,2 = poor; 3,4 = fair; 5,6 =good; 7,8 = excellent. | Prior to pulmonary function test on Day 85 | 
| Percentage of Patients With Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During the On-treatment Period | COPD exacerbation is defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea, and chest tightness) having a duration of three or more days requiring treatment with an antibiotic and/or systemic steroids with or without hospital admission. | During the 12-week on-treatment period | 
| COPD Exacerbation Rate During the On-treatment Period | Proportion of patients experiencing a COPD exacerbation per patient year. COPD exacerbation is defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea, and chest tightness) having a duration of three or more days requiring treatment with an antibiotic and/or systemic steroids with or without hospital admission. | During the 12-week on-treatment period | 
| COPD Exacerbation During the On-treatment Period | COPD exacerbation is defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea, and chest tightness) having a duration of three or more days requiring treatment with an antibiotic and/or systemic steroids with or without hospital admission. | During the 12-week on-treatment period | 
| Frequency Distribution of Satisfaction Rating With Inhaler Attributes |  | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Overall Feeling of Inhaling Medicine | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Feeling That the Inhaled Dose Goes to the Lung | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Telling the Amount of Medication Left | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - The Inhaler Works Reliably | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Ease of Inhaling a Dose From the Inhaler | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Instructions for Use | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - The Inhaler is Durable | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Using the Inhaler | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Speed of Medicine Coming Out of the Inhaler | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Mean Rating Scores of Satisfaction With Inhaler - Overall Satisfaction With Inhaler | Patients rated their response on a seven point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = satisfied, 7 = very satisfied. | 12 weeks | 
| Device Preference (Respimat or MDI) | Frequency of patients due to device preference | 12 weeks | 
| Rating of Action of Turning Clear Base of Respimat | Frequency of patients due to rating of action of turning clear base of Respimat | 12 weeks | 
| Noncompartmental Pharmacokinetic Parameters of Ipratropium at Steady State | Geometric mean area under the plasma drug concentration time curve over one dosing interval (AUCτ). Each patient had eight plasma samples (trough pre-dose, 5, 15, 30, and 60 minutes post-dose, as well as 2, 4, and 6 hours post-dose). | Before drug administration to 6 hours after drug administration on Day 29 | 
| Noncompartmental Parameters of Albuterol at Steady State | Geometric mean area under the plasma drug concentration time curve over one dosing interval (AUCτ). Each patient had eight plasma samples (trough pre-dose, 5, 15, 30, and 60 minutes post-dose, as well as 2, 4, and 6 hours post-dose). | Before drug administration to 6 hours after drug administration on Day 29 | 
| Cumulative Amounts of Ipratropium [μg] Excreted in Urine for 0-2 Hours | Cumulative amounts of Ipratropium [μg] excreted in urine - Planned time intervals 0-2, ss | Before drug administration to 2 hours after drug administration on Day 29 | 
| Cumulative Amounts of Albuterol [μg] Excreted in Urine for 0-2 Hours | Cumulative amounts of Albuterol [μg] excreted in urine - Planned time intervals 0-2,ss. | Before drug administration to 2 hours after drug administration on Day 29 | 
| Cumulative Amounts of Ipratropium [μg] Excreted in Urine for 0-6 Hours | Cumulative amounts of Ipratropium [μg] excreted in urine - Planned time intervals 0-6,ss | Before drug administration to 6 hours after drug administration on Day 26 | 
| Cumulative Amounts of Albuterol [μg] Excreted in Urine for 0-6 Hours | Cumulative amounts of Albuterol [μg] excreted in urine - Planned time intervals 0-6, ss | Before drug administration to 6 hours after drug administration on Day 29 |