| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
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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 |
Part A
To assess the safety and tolerability of repeat doses of GSK2269557 administered as a dry powder to COPD patients.
Part B
To characterise the dose-response relationship of repeat doses of GSK2269557 administered as a dry powder to COPD patients using inflammatory cytokine biomarker. |
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| E.2.2 | Secondary objectives of the trial |
To determine the pharmacokinetic profile of repeat doses of GSK2269557 administered as a dry powder to COPD patients.
To determine the effect on recue medication usage of repeat doses of GSK2269557 administered as a dry powder to COPD patients.
Part B only: To assess the safety and tolerability of repeat doses of GSK2269557 administered as a dry powder to COPD patients |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has a confirmed and established diagnosis of COPD, as defined by the GOLD guidelines (see Appendix 4).
2. Male or female of non-child bearing potential between 40 and 75 years of age inclusive, at the time of signing the informed consent.
3.The subject has a post-bronchodilator (400 μg salbutamol) FEV1/FVC < 0.7 and FEV1 ≥ 40 % to ≤ 80 % of predicted (Predictions should be according to the European Community of Coal and Steel (ECCS) equations).
4.Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (pack years = (cigarettes per day smoked/20) x number of years smoked)).
5.The subject is able to produce > 100 mg of sputum at screening.
6.Body weight ≥ 45 kg and BMI within the range 17 – 32 kg/m2 (inclusive).
7.A female subject is eligible to participate if she is of:
- Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy, salpingo-oophrectomy or oophrectomy [for this definition, “documented” refers to the outcome of the investigator's/designee’s review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 4.3.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.]
OR
- Has only same-sex partners, when this is her preferred and usual lifestyle.
8.Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 4.3.1. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.
9.Based on averaged QTcF values of triplicate ECGs obtained over a brief recording period (e.g. 5 minutes):
-[QTcF] < 450 msec; or
-QTcF < 480 msec in subjects with Right Bundle Branch Block.
10.Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
11.A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included if the Investigator [in consultation with the GSK Medical Monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
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| E.4 | Principal exclusion criteria |
1. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome, asymptomatic gallstones and cholecystectomy).
2. Subjects who have a past or current medical conditions or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions (e.g. hypertension) ARE permitted to be entered into the study).
3. Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the Investigator, compromise the safety of the subject or affect the interpretation of the results.
4. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >28 units for males or >21 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
5. History of sensitivity to any of the study medications, or components (such as lactose) thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
6. A positive test for HIV antibody - tested according to local policies.
7. The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include cannabinoids, amphetamines, barbiturates, cocaine and opiates. The detection of drugs (e.g. benzodiazepines, opiates) taken for a legitimate medical purpose would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
8. A positive pre-study Hepatitis B surface antigen (HBs-Ag) or positive total hepatitis B core antibody (anti-HBc) or positive Hepatitis C antibody result within 3 months.
9. Pregnant females as determined by positive urine hCG test at screening or prior to dosing.
10. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
11. Lactating females.
12. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
13. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
14. Subject has poorly controlled or unstable COPD, defined as the occurrence of any of the following:
- Either: acute worsening of COPD (an exacerbation) that is managed by the subject at home requiring treatment with corticosteroids and/or antibiotics in the 4 weeks prior to the screening visit.
- Or: more than two exacerbations in the previous 2 months prior to the screening visit that required a course of oral corticosteroids and/or antibiotics, or for which the subject was hospitalised.
15. Subject has had a respiratory tract infection treated with antibiotics in the 4 weeks prior to first dose.
16. Subject requires regular treatment with oral corticosteroids or has received oral or parenteral corticosteroids within 4 weeks of screening.
17. Vulnerable subject (e.g., person kept in detention).
18. The subject is not able to understand and communicate in German or native language.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A
• Adverse events (AEs)
• Hematology and Clinical Chemistry
• Vital signs
• 12-lead ECG
• Pulmonary Function Tests (FEV1)
Part B
•Induced Sputum cytokine concentrations on Day 7 and Day 15 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
Adverse events (AEs): from start of study treatment until follow-up
contact; Hematology and Clinical Chemistry: screening, Day 1 predose,
Day 7 predose, Day 15 and follow-up visit; Vital signs: Screening, Day 1
(predose, 30 min postdose, 6h postdose), Day 7 predose, Day 15 and
follow-up visit; 12-lead ECG: Screening, Day 1 (predose, 30 min
postdose, 6h postdose), Day 7 predose, Day 15 and follow-up visit;
Pulmonary Function Tests (FEV1): Screening, Day 1 (predose, 1h
postdose), Day 7 (predose, 1h postdose), Day 15 and follow-up visit
Part B:
Cytokine concentration: Day -7, Day 1, Day 7 and Day 15
|
|
| E.5.2 | Secondary end point(s) |
Part A
• Day 1 plasma exposure up to 6 hours post dose
• Maximum observed plasma drug concentration: Cmax on Day 7.
• Trough concentration (Cτ) on Day 6/7 and on Day 15
• Rescue medication usage
Part B only
•Adverse events (AEs)
•Hematology and Clinical Chemistry
•Vital signs
•12-lead ECG
•Pulmonary Function Tests (FEV1)
|
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A&B:
PK samples collected at Day 1 (predose, 5m, 30m, 1h, 2h, 4h, 6h), Day 7
(predose, 5m postdose), Day 15 (24h post last dose)
Part B only:
Adverse events (AEs): from start of study treatment until follow-up
contact; Hematology and Clinical Chemistry: screening, Day 1 predose,
Day 7 predose, Day 15 and follow-up visit; Vital signs: Screening, Day 1
(predose, 30 min postdose, 6h postdose), Day 7 predose, Day 15 and
follow-up visit; 12-lead ECG: Screening, Day 1 (predose, 30 min
postdose, 6h postdose), Day 7 predose, Day 15 and follow-up visit;
Pulmonary Function Tests (FEV1): Screening and follow-up visit
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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 | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| 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 | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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