| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To assess the systemic pharmacokinetics of GSK961081 DPI after single inhaled doses in healthy male subjects and
• To investigate the pulmonary pharmacodynamic profile of 2 doses determined from Part 1 of GSK961081 DPI versus placebo and versus Tiotropium plus Salmeterol given for 14 days in patients with COPD. |
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| E.2.2 | Secondary objectives of the trial |
• To investigate the safety and tolerability of single inhaled doses of GSK961081 DPI in healthy male subjects.
• To assess the systemic pharmacodynamics of GSK961081 DPI as measured by heart rate, serum potassium, blood glucose, 12-lead ECG including QTc(b) and (f) and blood pressure in healthy male subjects.
• To investigate the safety and tolerability of 2 doses of GSK961081 DPI given for 14 days in patients with COPD.
• To investigate the systemic pharmacodynamics of 2 doses of GSK961081 DPI given for 14 days as measured by serum potassium, blood glucose, 12- lead ECG, including QTc(b) and (f) , heart rate and blood pressure in patients with COPD.
• To assess the systemic pharmacokinetics of GSK961081 DPI given for 14 days in patients with COPD.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria Part 1
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Healthy adult males aged between 18 and 60 years.
Healthy as judged by the Investigator means- no clinically significant abnormality identified on the medical or laboratory evaluation, including 12-lead ECG, and other tests. A subject with a clinical abnormality or laboratory parameters outside the reference range for this age group may be included only if the Investigator and medical monitor consider the finding will not constitute an additional risk to the subject and will not interfere with the study procedures or objectives.
2. Body mass index within the range 18.5-29.9 kilograms/metre2 (kg/m2).
3. Forced Expiratory Volume in 1 second (FEV1) 80% predicted and a FEV1/ Forced Vital Capacity (FVC) ratio greater than 0.7
4. Signed and dated written informed consent is obtained from the subject
5. The subject is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions.
6. Subjects who are current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit and have a pack history of 10 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years smoked]Subject is male or female of non child bearing potential over 40 years of age and under 75 years of age.
5.2.3. Inclusion Criteria Part 2
A subject will be eligible for inclusion 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.
2. 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 ie age, history of vasomotor symptoms-estrodial and FSH levels may be checked if indicated) and females who are surgically sterile (hysterectomy, tubal ligation or bilateral oophorectomy.
3. Subject diagnosed with COPD (stage II) in accordance with ATS/ERS guidelines (see Appendix 2: COPD Guidelines).
4. 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)
5. Subject has FEV1/FVC < 0.7 post - bronchodilator (salbutamol)
6. Subject has FEV1 < 80 % of predicted normal for height, age, gender after inhalation of salbutamol
7. Response to ipatropium bromide defined as:
Either an increase in FEV1 of > 12 % and > 150 mLwithin 2 hour following inhalation of 80 µcg ipratopium bromide at the screening visit
Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hour following inhalation of 80 µcg ipratopium bromide within 6 months of screening and an increase in FEV1 of > 6 % and > 100 mL within 2 h following inhalation of 80 mcg ipratopium bromide at the screening visit (in order to allow for potential fluctuations in the response to ipatropium bromide in patients known to be responders to ipratropium bromide)
8. Response to salbutamol defined as:
Either an increase in FEV1 of > 12 % and > 150 mL within 2 hour following inhalation of 400 mcg salbutamol at the screening visit
Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hour following inhalation of 400 mcg salbutamol within 6 months of screening and an increase in FEV1 of > 6 % and >100 mL within 2 h following inhalation of 400 mcg salbutamol at the screening visit (in order to allow for potential fluctuations in the response to salbutamol in patients known to be responders to salbutamol)
9. Body mass index within the range 18-35 kilograms/metre2 (kg/m2).
10. Subject is able and willing to give written informed consent to take part in the study.
11. Subject is available to complete all study measurements
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| E.4 | Principal exclusion criteria |
Exclusion Criteria Part 1
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Any clinically relevant abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or ECG (12-lead or Holter).
2. A history of respiratory disease (i.e. history of asthmatic symptoms).
3. QTc(B) and QTc(F) value at screening >450msec on an individual ECG, the 3 screening ECGs are not within 10% of the mean, a PR interval outside the range 120-210 msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave).
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. Strict vegetarians;
6. Shift-worker unable to comply with the study;
7. Inability to understand the protocol requirements, instructions and study-related restrictions; the nature, scope and possible consequences of the study;
Exclusion Criteria Part 2
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. Women who are pregnant or lactating
3. 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
4. The subject has a positive urine drug screen. A minimum list of drugs that will be screened for include Amphetamines, Barbituates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.
5. The subject has a positive alcohol test (breath or urine) predose.
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 a 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 or intends to donate within 56 days after completing the study.
10. The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet.
11. Subject has an FEV1 < 50 % of predicted for age, height and gender after inhalation of salbutamol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1- To assess the systemic pharmacokinetics of GSK961081 DPI after single inhaled doses in healthy male subjects.
Part 2 - To investigate the pulmonary pharmacodynamic profile of 2 doses determined from Part 1 of GSK961081 DPI versus placebo and versus Tiotropium plus Salmeterol given for 14 days in patients with COPD. |
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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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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
| Information not present in EudraCT |
| 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 | 3 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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