| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010953 |
| E.1.2 | Term | COPD exacerbation |
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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 objectives of this long-term study are to assess the bronchodilator efficacy as determined by FEV1, the effect on dyspnoea as determined by the Mahler BDI and TDI, the effect on the health status as determined by the SGRQ, and the effect on COPD exacerbations. These multiple primary endpoints are proposed for inclusion in the product label. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to compare the safety of once-daily Tiotropium/Salmeterol Inhalation Powder (7.5 µg/25 µg) versus single-agent therapy of its components and versus combination therapy of Tiotropium/Salmeterol Inhalation Powder (7.5 µg/25 µg) (morning) plus salmeterol (evening). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All patients must sign an informed consent consistent with ICH-GCP guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions.
2. All patients must have a diagnosis of COPD and must meet the following criteria:
•relatively stable* airway obstruction with a post-bronchodilator FEV1 < 80% of predicted normal (ECSC criteria) and post-bronchodilator FEV1 < 70% of post-bronchodilator FVC at Visit 1 [according to GOLD criteria (P01-02794)].
Following a pre-bronchodilator measurement of FEV1 and FVC, patients will inhale 4 puffs of salbutamol 100 µg (MDI) and 45 minutes after inhalation the post-bronchodilator FEV1 and FVC will be measured.
3. Male or female patients 40 years of age or older.
4. Patients must be current or ex-smokers with a smoking history of ≥ 10 pack-years (patients who have never smoked cigarettes must be excluded).
5. Patients must be able to perform technically acceptable pulmonary function tests during the study period as required in the protocol (including the PEF and FEV1 recordings with the electronic peak flow meter AM2+).
6. Patients must be able to inhale medication in a competent manner from the HandiHaler devices
7. Patients must be able to perform all necessary recordings in the AM2+.
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| E.4 | Principal exclusion criteria |
1. Significant diseases other than COPD. A significant disease is defined as a disease or condition which, in the opinion of the investigator, may either put the patient at risk because of participation in the study or may influence either the results of the study or the patient’s ability to participate in the study.
2. Patients with clinically significant abnormal baseline haematology, blood chemistry or urinalysis, if the abnormality defines a significant disease as defined in exclusion criterion No. 1.
3. Patients with a recent history (i.e., six months or less) of myocardial infarction.
4. Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the past year.
5. Hospitalization for cardiac failure during the past year.
6. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.
7. Patients with a history of asthma or atopy, or who have a total blood eosinophil count 600/mm3. A repeat eosinophil count will not be conducted in these patients.
8. Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
9. Known active tuberculosis.
10. Patients with a history (within the past two years) of and/or active significant alcohol or drug abuse. See exclusion criterion No. 1.
11. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1.
12. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the Screening Visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program that will not be maintained throughout the duration of the study.
13. 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.
14. Patients who have taken an investigational drug within 30 days or six half-lives (whichever is greater) prior to Screening Visit (Visit 1).
15. Use of antihistamines (H1 receptor antagonists), anti-leukotrienes or leukotriene receptor antagonists for asthma or excluded allergic conditions. See exclusion criterion No 7.
16. Use of cromolyn sodium or nedocromil sodium.
17. Use of systemic corticosteroid medication at unstable doses (i.e., less than six weeks on stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day.
18. Known hypersensitivity to anticholinergic drugs, β2-adrenergic drugs, lactose or any other component of the study medication delivery system.
19. Women of childbearing potential not using a highly effective method of birth control. 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 IUDs, sexual abstinence or vasectomised partner. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.
20. Treatment with oral beta-adrenergics within 4 weeks prior to Screening Visit (Visit 1) or during the 2-week run-in period.
21. Treatment with the long-acting anticholinergic tiotropium (Spiriva®) within 4 weeks prior to Screening Visit (Visit 1) or during the 2-week run-in period.
22. Patients who are currently participating in another study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There are three co-primary endpoints in this trial: trough FEV1, FEV1 AUC0-8h, and Mahler TDI (focal score). Two additional co-primary endpoints, the SGRQ and the time to first moderate to severe COPD exacerbation, will be evaluated after combining the data from the two sister studies 1184.14 and 1184.15 to obtain adequate numbers of patients.
1.Trough FEV1 response at the end of the 12-week (once-daily FDC Tiotropium/Salmeterol versus placebo) and 24-week treatment period (once-daily FDC Tiotropium/Salmeterol versus individual components).
2. FEV1 AUC0-8h response at the end of the 12-week (once-daily FDC Tiotropium/Salmeterol versus placebo) and 24-week treatment period (once-daily FDC Tiotropium/Salmeterol versus individual components).
3. Mahler TDI focal score at the end of the 12-week treatment period (once-daily FDC Tiotropium/Salmeterol versus placebo) and 24-week (once-daily FDC Tiotropium/Salmeterol versus individual components).
On combined data from the two sister studies 1184.14 and 1184.15 to get adequate number of patients:
4. SGRQ total score at the end of the 24-week treatment period (once-daily FDC Tiotropium/Salmeterol versus individual components).
5. Time to first moderate to severe COPD exacerbation within 48 weeks (once-daily FDC Tiotropium/Salmeterol versus individual components).
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| 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 | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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