| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adults with Chronic Obstructive Pulmonary Disease (COPD) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to compare the long-term (12-week) bronchodilator efficacy and safety of ipratropium bromide/salbutamol combination administered by the Respimat® 20 mcg/100 mcg (one inhalation q.i.d.) to ipratropium bromide delivered by the Respimat® (20 mcg) (one inhalation q.i.d.) and COMBIVENT® Inhalation Aerosol (two inhalations q.i.d ) in patients with COPD. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary: FEV1 (peak, onset, duration and time to peak response); FVC (same as FEV1); rescue medication use |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All patients must have a diagnosis of COPD and must meet the following spirometric criteria at Visit 1 (Screening) and Visit 2: Patients must have relatively stable, moderate to severe airway obstruction with pre-bronchodilator FEV1 65% of predicted normal and FEV1 70% of FVC. Predicted normal values will be calculated according to ECSC [R94-1408]
2.Male or female patients 40 years of age or older.
3.Patients must have a smoking history of more than ten pack-years. A pack-year is defined as the equivalent of smoking one pack of 20 cigarettes per day for a year.
4.Patients must be able to perform pulmonary function tests and maintain records during the study period as required in the protocol.
5.Patients must be able to be trained in the proper use of an MDI and the Respimat® inhaler.
6.All patients must sign an Informed Consent Form prior to participation in the trial
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| E.4 | Principal exclusion criteria |
1. Patients with significant diseases other than COPD will be excluded. A significant disease is defined as a disease which in the opinion of the investigator 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.
2Patients with clinically relevant abnormal baseline hematology, blood chemistry or urinalysis. If the abnormality defines a disease listed as an exclusion criterion, the patient is excluded.
3.All patients with an AST (SGOT) >80 IU/L, ALT (SGPT) >80 IU/L, Bilirubin >2.0 mg/dL or Creatinine >2.0 mg/dL will be excluded regardless of the clinical condition. Repeat laboratory evaluation will not be conducted in these subjects.
4.Patients who have a total blood Eosinophil count ≥600/mm3. A repeat Eosinophil count will not be conducted in these patients.
5.Patients with a recent history (i.e., one year or less) of myocardial infarction.
6.Patients with a recent history (i.e., three years or less) of heart failure or patients with any cardiac arrhythmia requiring drug therapy.
7.Patients with a history of cancer, other than treated basal cell carcinoma, within the last five years.
8.Patients with a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
9.Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of a thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1.
10.Patients with a history of asthma or allergic rhinitis.
11.Patients with a history of and/or active alcohol or drug abuse.
12.Patients with known active tuberculosis.
13.Patients with an upper or lower respiratory tract infection or COPD exacerbation in the 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period.
14.Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction.
15.Patients with known narrow-angle glaucoma.
16.Patients with current significant psychiatric disorders.
17.Patients 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.
18.Use of cromolyn sodium or nedocromil sodium less than 30 days prior to the baseline period or during the treatment period.
19.Patients who are being treated with antihistamines for any excluded allergic conditions.
20.Patients using oral corticosteroid medication 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.
21.Initiation of inhaled steroid use, or new dosage, less than 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period.
22.Use of beta-blocker medications, MAO inhibitors or tricyclic antidepressants less than 30 days prior to the baseline period or during the treatment period . Beta blocker eye medications for treatment of non-narrow angle glaucoma are allowed.
23.Patients who have had changes in their therapeutic plan within the last 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period.
24.Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (i.e., oral contraceptives, intrauterine devices or diaphragm with spermicide, or Norplant®).
25.Patients with known hypersensitivity to anticholinergic drugs, any other component of the ipratropium bromide/salbutamol Respimat® solution including BAC and EDTA or the ipratropium bromide/salbutamol MDI components.
26.Previous participation in this study. (The patient cannot re-enrol into this study)
27.Patients who are currently participating in another study.
28.Patients who have taken an investigational drug within 1 month or 6 half lives (whichever is greater) prior to screening
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The three primary efficacy endpoints are:
1.) Area between test-day baseline FEV1 (forced expiratory volume in one second) and the FEV1 change from test day baseline curve from 0 to 6 hours divided by six (FEV1 AUC0-6) at Day 85 the end of the treatment period (for comparison of Combivent Respimat® to COMBIVENT® MDI)
2.) Area between test-day baseline FEV1 (forced expiratory volume in one second) and the FEV1 change from test-day baseline curve from 0 to 4 hours divided by four (FEV1 AUC0-4) at Day 85 the end of the treatment period (for comparison of Combivent Respimat® to Atrovent Respimat®)
3.) Area between test-day baseline FEV1 (forced expiratory volume in one second) and the FEV1 change from test-day baseline curve from 4 to 6 hours divided by two (FEV1 AUC4-6) at Day 85 the end of the treatment period (for comparison of Combivent Respimat® to Atrovent Respimat®)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
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