Asthma
Conditions
Brief summary
The primary goal of this trial is to compare the efficacy and safety of COMBIVENT CFC MDI with albuterol HFA MDI, the current standard reliever medication in asthma. In the first cross-over part of the study (Treatment Phases 1 and 2) the marketed product, COMBIVENT CFC MDI will be used. In the second, parallel group part of the trial (Treatment Phase 3) COMBIVENT RESPIMAT will be tested for acute bronchodilator efficacy in a blinded manner at the clinic visits. During the third 4-week treatment phase open label COMBIVENT RESPIMAT will be used for symptom relief as needed.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. All patients must sign and date an Informed Consent consistent with International Conference on Harmonization Good Clinical Practices (ICH GCP) guidelines and local regulations prior to participation in the trial (i.e., prior to any study procedures, including washout of any medication) at Visit 1. 2. Male or female patients greater to or equal to 18 years of age. 3. Physician diagnosis of moderate-to-severe asthma (GINA Guidelines) existing for \>1 year. 4. Reversible airway obstruction (more than or equal to 12 % or at least 200 mL improvement in FEV1 post bronchodilator after 4 puffs of albuterol HFA MDI). 5. Pre-bronchodilator clinic measured FEV1 ≤80% of predicted normal value (measured greater to or equal to 6 hours of the last use of short acting bronchodilator and greater to or equal to 12 hours after the last use of LABA if applicable). 6. Continuous treatment with inhaled corticosteroids (ICS) with or without long-acting beta agonists (LABA) and other controller medication(s) for at least 6 weeks prior to screening (GINA 2007 Treatment Steps 3 to 5). 7. No change in dos or regimen of ICS and LABA or other controller medications (including oral corticosteroids \[OCS\] if applicable), for at least 2 weeks prior to Visit 2. 8. Use of short acting bronchodilator at least three times a week for symptom relief in the 2 weeks prior to Visit 1. 9. Score of ≥1.5 points on the Asthma Control Questionnaire (ACQ) (see Appendix 10.6). 10. Able to perform technically acceptable pulmonary function tests at the clinic and peak flow measurements with the eDiary/Peak Expiratory Flow Meter. 11. Able to perform all necessary recordings (symptoms and as needed medication use) in the electronic diary, which is a part of the eDiary/Peak Expiratory Flow Meter. 12. Investigator assessment of patients ability to inhale medication from a metered dose inhaler and RESPIMAT inhaler.
Exclusion criteria
1. Significant disease other than asthma not limited to diagnosis of COPD, such as, active tuberculosis, cystic fibrosis, alpha 1 antitrypsin deficiency, clinically significant bronchiectasis, interstitial lung disease, allergic bronchopulmonary aspergillosis, or constrictive bronchiolitis. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, or (ii) influence the results of the study, or (iii) cause concern regarding the patient ability to participate in the study. 2. History of thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion 1. 3. History of life-threatening asthma attack. 4. Worsening of asthma that required treatment with an addition or increase in OCS dose (steroid burst) in the 4- week period prior to Visit 2. 5. Current or ex-smokers who quit \<1 year before enrollment. Ex-smokers who quit less than 1 year from enrollment must have a cigarette smoking history of less than 10 pack years. Pack years = Number of cigarettes/day x years of smoking 20 6. Use of oral beta-adrenergic agents within 4 weeks prior to screening. 7. Treatment with inhaled ipratropium, ipratropium/albuterol combination, or nasal ipratropium within 1week of Visit 2. 8. Treatment with inhaled tiotropium within 4 weeks of Visit 2. 9. Known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetracetic acid (EDTA) or any other components of the tiotropium inhalation solution or MDI. 10. Known narrow-angle glaucoma. 11. Clinically relevant abnormal hematology or blood chemistry at screening if the abnormality defines a significant disease as defined in exclusion criterion 1. 12. Recent history (i.e., one year less) of myocardial infarction. Cardiac arrhythmias, newly diagnosed arrhythmias and/or any arrhythmia requiring an intervention (i.e., hospitalization, cardio version, pacemaker placement, and automatic implantable cardiac defibrillator placement) or a change in drug therapy during the last year. 13. Hospitalization for cardiac failure during the past year. 14. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years, with the exception of treated basal cell carcinoma. 15. Unwillingness or inability to use a highly effective method of birth control by women of childbearing potential. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap is used together with spermicides (e.g., foam or gel). Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. 16. Pregnancy or nursing. 17. Any investigational drug taken within 30 days or six half-lives (whichever is greater) prior to Visit 2. 18. Previous randomization in this study or current participation in another study. 19. Symptomatic prostate hypertrophy or bladder neck obstruction. Patients with symptomatically controlled prostate hypertrophy on medications may be included and should continue their medications. 20. Use of monoamine oxidase inhibitors or tricyclic antidepressants. Examples include but are not limited to the following for monoamine oxidase inhibitors nardil, parnate, marplan and for tricyclic antidepressants: amitriptyline, norpramine, and pamelor. 21. History of and/or active alcohol or drug abuse. 22. Patient who have been treated with beta-blocker medication during the screening of the study. Topical cardio-selective beta-blocker eye medications for treatment of acute angle glaucoma are allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 AUC0-6 Response (Crossover Part of the Study) | Test day baseline and test day FEV1 AUC 0-6, after 4 weeks | Change from baseline after 4 weeks in Forced Expiratory Volume Area Under (FEV1 AUC) the Curve from 0 to 6 hours. |
| Peak FEV1 Response (Crossover Part of the Study) | Test day baseline and test day peak FEV1, after 4 weeks | Change from baseline after 4 weeks in peak Forced Expiratory Volume response |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Asthma Control Questionnaire (Crossover Part of the Study) | Baseline, 4 weeks | Change from baseline after 4 weeks in ACQ score. Worst score - 6(most severe), best score - 0 (no symptoms) |
| Puffs Study Medication Used During Night (Crossover Part of the Study) | Baseline, 4 weeks | Change from baseline in weekly mean of puffs of blinded study medication (albuterol HFA or combivent CFC) used during night |
| Puffs Open-label Albuterol Used During Day (Crossover Part of the Study) | Baseline, 4 weeks | Change from baseline in weekly mean of puffs of open-label albuterol used during day |
| Puffs Study Medication Used During Day (Crossover Part of the Study) | Baseline, 4 weeks | Change from baseline in weekly mean of puffs of blinded study medication (albuterol HFA or combivent CFC) used during day |
| FEV1 AUC0-6 Response (Parallel Part of the Study) | Test day baseline and test day FEV1 AUC 0-6, after 4 weeks | Change from baseline after 4 weeks in Forced Expiratory Volume Area Under the Curve from 0 to 6 hours |
| Peak FEV1 Response | Test day baseline and test day peak FEV1, after 4 weeks | Change from baseline after 4 weeks in peak Forced Expiratory Volume response |
| Puffs Open-label Albuterol Used During Night (Crossover Part of the Study) | Baseline, 4 weeks | Change from baseline in weekly mean of puffs of open-label albuterol used during night |
| Mini Asthma Quality of Life Questionnaire (Crossover Part of the Study) | Baseline, 4 weeks | Change from baseline after 4 weeks in Mini-AQLQ score. Worst score - 1 (most severe), best score - 7 (less severe) |
Countries
United States
Participant flow
Recruitment details
* Crossover Part of the Study (Treatment Period 1) * Crossover Part of the Study (Washout Period of 1 Week) * Crossover Part of the Study (Treatment Period 2) * Parallel Part of the Study Following Second Randomization (Treatment Period 3)
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Participants randomized to crossover part at randomization 1 | 226 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 1 | 0 | 0 |
| Treatment Period 1 | Other | 3 | 0 | 0 | 0 |
| Treatment Period 2 | Other | 2 | 1 | 0 | 0 |
| Treatment Period 3 | Adverse Event | 0 | 0 | 0 | 1 |
| Washout Period of 1 Week | Adverse Event | 1 | 1 | 0 | 0 |
| Washout Period of 1 Week | Other | 1 | 2 | 0 | 0 |
| Washout Period of 1 Week | Protocol Violation | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 47.1 Years STANDARD_DEVIATION 13.7 |
| Alcohol history Drinks - no interference | 150 Participants |
| Alcohol history Drinks - possible interference | 0 Participants |
| Alcohol history Non drinker | 76 Participants |
| Body mass index | 31.1 Kilograms per square meter STANDARD_DEVIATION 6.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 215 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 169.9 Centimeters STANDARD_DEVIATION 11 |
| Race/Ethnicity, Customized Amer. Ind./Alaska Nat | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black/African Amer. | 44 Participants |
| Race/Ethnicity, Customized Hawaiian/Pacif. Isle | 5 Participants |
| Race/Ethnicity, Customized White | 174 Participants |
| Sex: Female, Male Female | 130 Participants |
| Sex: Female, Male Male | 96 Participants |
| Smoking history Currently smokes | 0 Participants |
| Smoking history Ex-smoker | 63 Participants |
| Smoking history Never smoked | 163 Participants |
| Weight | 89.9 Kilograms STANDARD_DEVIATION 21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 222 | 11 / 219 | 0 / 26 | 0 / 139 |
| serious Total, serious adverse events | 1 / 222 | 1 / 219 | 0 / 26 | 0 / 139 |
Outcome results
Primary
FEV1 AUC0-6 Response (Crossover Part of the Study)
Change from baseline after 4 weeks in Forced Expiratory Volume Area Under (FEV1 AUC) the Curve from 0 to 6 hours.
Time frame: Test day baseline and test day FEV1 AUC 0-6, after 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | FEV1 AUC0-6 Response (Crossover Part of the Study) | 0.167 liters | Standard Error 0.026 |
| Combivent CFC | FEV1 AUC0-6 Response (Crossover Part of the Study) | 0.252 liters | Standard Error 0.026 |
p-value: <0.0001MMRM ANCOVA
Primary
Peak FEV1 Response (Crossover Part of the Study)
Change from baseline after 4 weeks in peak Forced Expiratory Volume response
Time frame: Test day baseline and test day peak FEV1, after 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Peak FEV1 Response (Crossover Part of the Study) | 0.357 liters | Standard Error 0.031 |
| Combivent CFC | Peak FEV1 Response (Crossover Part of the Study) | 0.434 liters | Standard Error 0.031 |
p-value: <0.0001MMRM ANCOVA
Secondary
Asthma Control Questionnaire (Crossover Part of the Study)
Change from baseline after 4 weeks in ACQ score. Worst score - 6(most severe), best score - 0 (no symptoms)
Time frame: Baseline, 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Asthma Control Questionnaire (Crossover Part of the Study) | -0.25 Scores on scale | Standard Error 0.04 |
| Combivent CFC | Asthma Control Questionnaire (Crossover Part of the Study) | -0.25 Scores on scale | Standard Error 0.04 |
p-value: 0.8278MMRM ANCOVA
Secondary
FEV1 AUC0-6 Response (Parallel Part of the Study)
Change from baseline after 4 weeks in Forced Expiratory Volume Area Under the Curve from 0 to 6 hours
Time frame: Test day baseline and test day FEV1 AUC 0-6, after 4 weeks
Population: These analyses were done on FAS2. FAS2 is all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had a non-missing Visit 7 baseline value and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 7.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | FEV1 AUC0-6 Response (Parallel Part of the Study) | 0.041 liters | Standard Error 0.046 |
| Combivent CFC | FEV1 AUC0-6 Response (Parallel Part of the Study) | 0.236 liters | Standard Error 0.02 |
p-value: 0.0001Mixed Models Analysis
Secondary
Mini Asthma Quality of Life Questionnaire (Crossover Part of the Study)
Change from baseline after 4 weeks in Mini-AQLQ score. Worst score - 1 (most severe), best score - 7 (less severe)
Time frame: Baseline, 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Mini Asthma Quality of Life Questionnaire (Crossover Part of the Study) | 0.150 Scores on scale | Standard Error 0.05 |
| Combivent CFC | Mini Asthma Quality of Life Questionnaire (Crossover Part of the Study) | 0.220 Scores on scale | Standard Error 0.05 |
p-value: 0.159MMRM ANCOVA
Secondary
Peak FEV1 Response
Change from baseline after 4 weeks in peak Forced Expiratory Volume response
Time frame: Test day baseline and test day peak FEV1, after 4 weeks
Population: These analyses were done on FAS2. FAS2 is all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had a non-missing Visit 7 baseline value and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 7.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Peak FEV1 Response | 0.199 liters | Standard Error 0.053 |
| Combivent CFC | Peak FEV1 Response | 0.412 liters | Standard Error 0.023 |
p-value: 0.0003Mixed Models Analysis
Secondary
Puffs Open-label Albuterol Used During Day (Crossover Part of the Study)
Change from baseline in weekly mean of puffs of open-label albuterol used during day
Time frame: Baseline, 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Puffs Open-label Albuterol Used During Day (Crossover Part of the Study) | -2.24 Puffs | Standard Error 0.05 |
| Combivent CFC | Puffs Open-label Albuterol Used During Day (Crossover Part of the Study) | -2.28 Puffs | Standard Error 0.05 |
p-value: 0.3631MMRM ANCOVA
Secondary
Puffs Open-label Albuterol Used During Night (Crossover Part of the Study)
Change from baseline in weekly mean of puffs of open-label albuterol used during night
Time frame: Baseline, 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Puffs Open-label Albuterol Used During Night (Crossover Part of the Study) | -0.92 Puffs | Standard Error 0.02 |
| Combivent CFC | Puffs Open-label Albuterol Used During Night (Crossover Part of the Study) | -0.93 Puffs | Standard Error 0.02 |
p-value: 0.6787MMRM ANCOVA
Secondary
Puffs Study Medication Used During Day (Crossover Part of the Study)
Change from baseline in weekly mean of puffs of blinded study medication (albuterol HFA or combivent CFC) used during day
Time frame: Baseline, 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Puffs Study Medication Used During Day (Crossover Part of the Study) | -0.49 Puffs | Standard Error 0.07 |
| Combivent CFC | Puffs Study Medication Used During Day (Crossover Part of the Study) | -0.53 Puffs | Standard Error 0.07 |
p-value: 0.5098MMRM ANCOVA
Secondary
Puffs Study Medication Used During Night (Crossover Part of the Study)
Change from baseline in weekly mean of puffs of blinded study medication (albuterol HFA or combivent CFC) used during night
Time frame: Baseline, 4 weeks
Population: Full analysis set 1 (FAS1) consisted of all patients who were dispensed study medication, were documented to have taken at least one dose of investigational treatment, and had non-missing Visit 3 baseline values and non-missing responses for both peak FEV1 and FEV1 AUC0-6 at Visit 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Albuterol HFA | Puffs Study Medication Used During Night (Crossover Part of the Study) | -0.10 Puffs | Standard Error 0.05 |
| Combivent CFC | Puffs Study Medication Used During Night (Crossover Part of the Study) | -0.12 Puffs | Standard Error 0.05 |
p-value: 0.6591MMRM ANCOVA