E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease |
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MedDRA Classification |
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 |
To investigate the pulmonary pharmacodynamic profile of single doses of GSK961081 alone and in combination with cumulative doses of short acting bronchodilators (salbutamol and ipratropium bromide) in COPD patients. |
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E.2.2 | Secondary objectives of the trial |
To assess the systemic pharmacodynamics of single doses of GSK961081 in combination with cumulative doses of short acting bronchodilators (salbutamol and ipratropium bromide) as measured by heart rate, 12-lead ECG including QTc(B) and QTc (F), blood pressure, serum potassium and blood glucose in COPD patients.
To assess the systemic pharmacokinetics of single doses of GSK961081 in combination with cumulative doses of short acting bronchodilators (salbutamol and ipratropium bromide) in COPD patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Subject is male or female (of non-child bearing potential) ≥ 40 years of age and ≤ 75 years of age. Non- child bearing potential is defined as physiologically incapable of becoming pregnant, including females who are post-menopausal (more than 2 years without menses with appropriate clinical history i.e. age, history of vasomotor symptomsestradiol and FSH levels may be checked if indicated) and females who are surgically sterile (hysterectomy, tubal ligation or bilateral oophorectomy). 2. Subject diagnosed with COPD in accordance with ATS/ERS guidelines. 3. Subject is a smoker or an ex-smoker with a history of at least 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent) 4. Subject has FEV1/FVC < 0.7 post-bronchodilator (salbutamol) 5. Subject has FEV1 < 80 % of predicted normal for height, age, gender after inhalation of salbutamol 6. Response to ipatropium bromide defined as: Either an increase in FEV1 of > 12 % and > 150 mL within 2 hours following inhalation of 80 μg ipratopium bromide (Atrovent MDI via spacer) at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following inhalation of 80 μg ipratopium bromide within 6 months of screening and an increase in FEV1 of > 6 % and > 100 mL within 2h following inhalation of 80 μg ipratopium bromide (Atrovent MDI via spacer) at the screening visit (in order to allow for potential fluctuations in the response to ipratropium bromide in patients known to be responders to ipratropium bromide) 7. Response to salbutamol defined as: Either an increase in FEV1 of > 12 % and > 150 mL within 2 hours following inhalation of 400 μg salbutamol MDI (via spacer) at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following inhalation of 400 μg salbutamol MDI within 6 months of screening and an increase in FEV1 of > 6 % and >100 mL within 2h following inhalation of 400 μg salbutamol MDI (via spacer) at the screening visit (in order to allow for potential fluctuations in the response to salbutamol in patients known to be responders to salbutamol) 8. Body mass index (BMI) within the range 18-35 kg/m2 9. Subject is able and willing to give written informed consent to take part in the study. 10. Subject is available to complete all study assessments |
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E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. Subjects who have a past or present disease, which as judged by the Investigator and medical monitor may affect the outcome of the study or the safety of the subject 2. Subjects with clinically relevant findings on laboratory safety tests. 3. Women who are pregnant or lactating 4. An unwillingness of subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as IUD, diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants or tubal ligation if the woman could become pregnant from the time of the first dose study medication until 90 days post-dose 5. The subject has a positive urine drugs of abuse screen. 6. A history, or suspected history, of alcohol abuse within the 6 months before the screening visit. 7. A positive test for hepatitis C antibody, hepatitis B surface antigen, or HIV. 8. The subject has participated in a clinical study with another New Chemical Entity within the past 2 months or participated in a clinical study with any other drug during the previous month. 9. The subject has donated a unit of blood within the 56 days of dosing or intends to donate within 56 days after completing the study. 10. Subject has an FEV1 < 40 % of predicted for age, height and gender after inhalation of salbutamol. 11. The subject has a diagnosis of active tuberculosis, lung cancer, sarcoidosis, bronchiectasis, lung fibrosis, pulmonary hypertension or with a primary diagnosis of asthma 12. The subject has a known allergy or hypersensitivity to ipratropium bromide, salbutamol, or lactose 13. A subject in whom ipratropium bromide or salbutamol is contraindicated 14. Subjects with lung volume reduction surgery within 12 months of screening 15. Poorly controlled COPD as defined in the protocol 16. Subject has had a respiratory tract infection in the 4 weeks before screening 17. Subject requires treatment with inhaled cromolyn sodium, theophyline, oral ß2- agonists, nebulised anticholinergics or leukotriene antagonists 18. Subject is unable to abstain from long acting ß2-agonist from 72 hours before screening and throughout the dosing period 19. Subject is unable to abstain from tiotropium bromide from 28 days before screening and throughout the dosing period 20. Subject is predicted to be unable to abstain from short acting inhaled ß2-agonists or short acting antimuscarinics for 6 hours before screening and for 6 hours before dosing with GSK961081 until all post-dose lung function tests have been completed for a given study day. 21. Subject has received oral corticosteroids within the 6 weeks before screening 22. Subject is receiving > 1000 μg FP (or equivalent) a day of inhaled corticosteroid or has changed dose within the 6 weeks before screening or is predicted not to be able to maintain a constant dose during the study 23. Subject is receiving oxygen therapy or nocturnal positive pressure treatment 24. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study investigator would prevent use of an inhaled anticholinergic 25. The subject is unable to use the dosing devices (MDPI/ MDI/ spacer) correctly. 26. Subject with carcinoma that has not been in complete remission for at least 5 years (with the exception of carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma if the subject is considered cured) 27. A history of congestive heart failure, coronary insufficiency or cardiac arrhythmia or a finding on screening 24h Holter monitor that would contraindicate the subject’s participation in the study 28. 12- lead ECG abnormality which is either clinically significant or may interfere with QTc measurement or QTc > 450 msec or PR interval outside the range 120 to 220 msec. 29. A supine mean heart rate outside the range 40-90 bpm at screening. 30. Persistently elevated supine blood pressure higher than 160/95 at screening. 31. Subject is receiving a high-dose diuretic and/ or ß2-adrenergic antagonist 32. Subject has a serum potassium level below the reference range at screening. 33. Inability to understand the protocol requirements, instructions and study-related restrictions; the nature, scope and possible consequences of the study. 34. Unlikely to complete the study; e.g., uncooperative attitude, inability to return for follow-up visits |
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E.5 End points |
E.5.1 | Primary end point(s) |
Maximal increase from pre-dose short-acting bronchodilator (salbutamol or ipratropium bromide) in FEV1 after inhalation of short-acting bronchodilator at 1h, 12h and 24h. |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Information not present in EudraCT |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
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 | 2 |
E.8.9.1 | In the Member State concerned days | 22 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 22 |