| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 evaluate the safety and tolerability of single doses of GW642444M with magnesium stearate (25, 50 and 100 mcg) in COPD patients |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the pulmonary and extra-pulmonary pharmacodynamic effects of single doses of GW642444M (25, 50 and 100 mcg) in COPD patients
To evaluate the systemic pharmacokinetics of GW642444, GI179710 (triphenylacetate counterion) and the metabolites, GW630200 and GSK 932009 following single doses of GW642444M (25, 50 and 100 mcg) in COPD patients
To assess the safety and tolerability, PK and PD parameters of a single inhaled dose of GW642444H (100 mcg) and obtain an estimate of the difference between inhaled dose of GW642444H (100 mcg) and a single inhaled dose GW642444M (100 mcg) in COPD patients
To characterise lung dose-response and systemic exposure-response relationships
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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. Male subjects or female subjects of non child bearing potential (i.e. post-menopausal or surgically sterile) between 40 and 75 years of age at screening
Post-menopausal females are defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. However if indicated this should be confirmed by oestradiol and FSH levels consistent with menopause (according to laboratory ranges) at screening.
Surgically sterile females are defined as those with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy or tubal ligation.
2. Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004]:
COPD is a preventable and treatable disease characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
3. Body weight equal or greater than 50 kg and BMI within the range 18 - 32 kg/m2.
4. Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). A former smoker is defined as a subject who has not smoked for equal or greater than 12 months at screening.
5. Subjects with a post-bronchodilator FEV1 to FVC ratio (FEV1/FVC) < 0.7 at screening visit.
6. Subjects with a post-bronchodilator FEV1 equal or greater than 40% and < 80% of predicted normal (according to ECCS guidelines) for height, age and gender at screening.
7. Subject is able and willing to give written informed consent to take part in the study.
8. Subject is available to complete all study measurements and procedures.
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| E.4 | Principal exclusion criteria |
1. Subjects who have a past or present disease, which may affect the outcome of this study.
2. Women who are pregnant or lactating or of child bearing potential.
3. Subjects with a primary diagnosis of asthma. (Subjects with a prior history of asthma are eligible if COPD is currently their primary diagnosis).
4. Subjects with alpha-1 antitrypsin deficiency as the underlying cause of COPD.
5. Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary disease.
6. Subjects with lung volume reduction surgery within the 12 months prior to screening.
7. Subject has had an upper respiratory tract infection in the 4 weeks prior to the screening visit and throughout the duration of the study.
8. Subjects with hypoxaemia, or subjects receiving treatment with long-term oxygen therapy (LTOT). All subjects must have an Oxygen (O2) saturation of greater or equal than 88% on room air.
9. Subjects with a positive Hepatitis B surface antigen or positive hepatitis C antibody pre-study or at screening.
10. Subjects with poorly controlled COPD:
• acute worsening of COPD that is managed by subject at home with oral corticosteroids or antibiotics in the 6 weeks prior to screening, or
• more than two exacerbations in the previous 12 months prior to screening that required a course of oral corticosteroids or antibiotics, or, for which the subject was hospitalised.
11. Subjects with a blood potassium level <3.5 mmol/L at screening.
12. Subjects with clinically important cardiovascular, neurological, psychiatric, renal, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled.
13. Uncontrolled hypertension defined as a mean supine blood pressure equal to or higher than 160/90 mmHg at screening in subjects not receiving medication for hypertension.
Or
Uncontrolled hypertension defined as a mean supine blood pressure equal to or higher than 150/90 mmHg at screening in subjects receiving medication for hypertension (please refer to exclusion criteria for prohibited medications).
14. A mean heart rate outside the range 50 – 90 beats per minute (bpm) at screening.
15. Subjects with carcinoma that has not been in complete remission for at least 5 years.
16. Subjects with a history of hypersensitivity to any beta-agonist or to ipratropium bromide. In addition patients with a history of milk protein allergy will also be excluded.
17. Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
Abuse of alcohol is defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females)..
18. Subjects who are predicted to be medically unable to withhold their rescue medication for the 6 hour period required prior to spirometry testing at each study visit would be ineligible for the study.
19. The subjects must not have used the medications listed in Section 9.2 prior to screening for the required interval.
20. Subjects receiving treatment with tricyclic antidepressants, Monoamine Oxidase Inhibitors (MAOI), or beta-adrenergic antagonist would be ineligible for the study.
21. Subjects receiving treatment with long term or short-term oxygen therapy or who require nocturnal positive pressure ventilation for sleep apnea.
22. Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Programme within 4 weeks prior to screening or who will enter the acute phase of a Pulmonary Rehabilitation Programme during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation programme are not excluded.
23. The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
24. Where participation in the study would result in donation of blood in excess of 500 mL within a 56 day period.
25. Subjects unable to comply with study procedures.
26. Any of the following abnormalities, identified on any of the resting 12-Lead ECGs at screening :
• A mean QTc(B) value > 450 msec (male and female) or any of the 3 screening QTc(B) values not within 10% of the mean.
• Ventricular rate < 40 beats per minute
• Evidence of second or third degree atrioventricular (AV) block
• Pathological Q waves (> 40 msec duration and > 2 mm in depth) when associated with a current clinically relevant history of ischaemic heart disease
• Evidence of arrhythmias
• ST-T wave abnormalities, with the exception of “early repolarisation” which is acceptable
• Left complete bundle branch block
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| General safety and tolerability, including adverse events, laboratory safety tests (haematology, clinical chemistry and urinalysis), vital signs, 12-lead ECG and, Holter monitoring. |
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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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 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) | 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| 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 | 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
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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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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