| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
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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.1.3 | 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 characterize the pharmacokinetics (i.e. systemic exposure to tiotropium and salmeterol) of the once-daily Tiotropium/Salmeterol (7.5 µg/25 µg) Inhalation Powder in comparison with the free combination therapy of Tiotropium (18 µg) Inhalation Powder once-daily plus Salmeterol (50 µg) Inhalation Powder twice daily in separate devices as well as the single-agent therapies Tiotropium (18 µg) Inhalation Powder once-daily or Salmeterol (50 µg) Inhalation Powder twice daily in their marketed formulations and approved daily dose regimens following 4-week treatment periods in patients with chronic obstructive pulmonary disease (COPD). |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to compare the safety, tolerability (adverse events, 12-lead ECG recordings) and efficacy (FEV1, FVC) of tiotropium and salmeterol when administered as Tiotropium/Salmeterol (7.5 µg/25 µg) Inhalation Powder, single-agent therapy or as free combination of the single agents in separate devices. |
|
| 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 and post-bronchodilator FEV1 < 70% of post-bronchodilator FVC at Visit 1 (according to GOLD criteria).
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.
6. Patients must be able to inhale medication in a competent manner from the HandiHaler devices and the multi-dose powder inhaler.
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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. Hospitalisation 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 systems.
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. Treatment with theophylline within 48 hours prior to Screening Visit (Visit 1) or during the 2-week run-in period.
23. Patients who are currently participating in another study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The pharmacokinetics of tiotropium and salmeterol will primarily be characterized with the following parameters:
Tiotropium
• Area under the concentration-time curve of tiotropium in plasma over the time interval from 0 extrapolated to infinity; if the data do not allow for the calculation of AUC0-inf, the area under the concentration-time curve of tiotropium in plasma over an appropriate time interval will be calculated and used for comparison,
• Cmax (maximum measured concentration of tiotropium in plasma),
and
• Amount of tiotropium that is eliminated in urine (Ae0-8) from time point 0 to 8 hours post-inhalation.
Salmeterol
• Area under the concentration-time curve of salmeterol in plasma over the time interval from 0 extrapolated to infinity; if the data do not allow for the calculation of AUC0-inf, the area under the concentration-time curve of salmeterol in plasma over an appropriate time interval will be calculated and used for comparison.
• Cmax (maximum measured concentration of salmeterol in plasma).
• Amount of salmeterol that is eliminated in urine (Ae0-8) from time point 0 to 8 hours post-inhalation.
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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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 1 |
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