| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary (COPD) disease |
|
| 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 |
| The primary objective of this study is to evaluate the dose response, efficacy, and safety of five dosage regimens of GSK233705B (12.5, 25, 50, 100 and 200mcg once daily), compared with placebo, in subjects with COPD to inform the selection of the optimal once daily dose of GSK233705B for subsequent development as a monotherapy product and as a component of fixed dose combination products. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives in this study are to evaluate the pharmacokinetic profile of
GSK233705B in subjects with COPD and to collect blood samples for a pharmacogenetic study. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed Consent: A signed and dated written informed consent prior to study
participation.
2. Gender: Male or female adults.
A female is eligible to enter and participate in this study if she is of:
a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal; or,
b. child-bearing potential, has a negative pregnancy test at Visit 1/Visit 1A, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study – Screening through follow-up contact):
• Complete abstinence from intercourse from Screening until 2 weeks after the
follow-up contact
• Oral contraceptive (either combined or progestogen alone) administered for at
least 1 monthly cycle prior to study medication administration
• Injectable progestogen administered for at least 1 month prior to study
medication administration and administered for 1 month following study
completion
• Implants of levonorgestrel inserted for at least 1 month prior to the study
medication administration but not beyond the third successive year following
insertion
• Estrogenic vaginal ring
• Percutaneous contraceptive patches
• Intrauterine device (IUD) or intrauterine system (IUS) with published data
showing that the highest expected failure rate is less than 1% per year
• Male partner sterilization (vasectomy with documentation of azoospermia) prior
to the female subject’s entry into the study, and this male is the sole partner for
that subject
• Double barrier method: condom or occlusive cap (diaphragm or cervical/vault
caps) plus spermicidal agent (foam/gel/film/cream/suppository)
3. Age: 40 to 80 years of age at Visit 1
4. Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004] as follows: Chronic obstructive pulmonary disease is a preventable and treatable disease state characterized 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.
5. Current or previous cigarette smokers with a history of cigarette smoking of ≥ 10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
6. Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 and a
post-albuterol/salbutamol FEV1 of ≥ 35 and ≤70% of predicted normal values
calculated using NHANES III reference equations at Visit 1/Visit 1A (Screening) [Hankinson, 1999]. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating.
2. A current diagnosis of asthma.
3. Known respiratory disorders other than COPD including but not limited to α-1 antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease.
4. Any previous lung resection surgery (e.g., lung volume reduction surgery or lobectomy).
5. Chest X-ray or computed tomography (CT) scan which reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken if a chest X-ray or CT scan is not available within 6 months prior to Visit 1. For subjects in Germany, if a chest X-ray (or CT scan) is not available in the 6 months prior to Visit 1, the subject will not be eligible for the study.
6. Use of oral corticosteroids or antibiotics for COPD within 6 weeks prior to Visit 1.
7. Hospitalization: Hospitalization for COPD or pneumonia within 3 months prior to
Visit 1.
8. Use of antibiotics for a lower respiratory tract infection within 30 days prior to Visit 1.
9. Other Diseases/Abnormalities: Clinically significant and uncontrolled
cardiovascular, neurological, psychiatric, renal, gastro-intestinal, immunological,
endocrine (including uncontrolled diabetes or thyroid disease) or hematological
abnormalities.
10. 12-Lead ECG: An abnormal and clinically significant 12-lead electrocardiogram
(ECG) that results in active medical problem. For the purposes of this study, an
abnormal ECG is defined as a 12-lead tracing which is interpreted with (but not
limited to) any of the following:
i. Clinically significant conduction abnormalities (e.g., left bundle branch block,
Wolff-Parkinson-White syndrome)
ii. Myocardial ischemia
iii. Clinically significant arrhythmias (e.g., atrial fibrillation, ventricular tachycardia)
iv. A mean QTc(B) value at screening >450msec, the QTc(B) of all 3 screening
ECGs are not within 10% of the mean, or an ECG that is not suitable for QT
measurements (e.g. poorly defined termination of the T wave)
The independent cardiologist, contracted by GSK, will determine the clinical
significance of any ECG abnormality and determine if a subject is precluded from
entering the study.
11. Hepatitis: A positive Hepatitis B surface antigen or positive hepatitis C antibody at Visit 1.
12. Cancer: A current malignancy or previous history of cancer in remission for < 5
years prior to Visit 1 (localized basal cell or squamous cell carcinoma of the skin that
has been resected is not exclusionary).
13. A history of allergy or hypersensitivity to ipratropium, tiotropium, or atropine and any of their derivatives, lactose/milk protein or magnesium stearate.
14. Diseases Preventing Use of Anticholinergic: 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 anticholingeric.
15. Medication Prior to Spirometry: Medically unable to withhold their albuterol/salbutamol for the 6 hour period required prior to spirometry testing at each study visit or to withhold ipratropium (if applicable) for the 6-hour period prior to
Visit 1/Visit 1A, Visit 2, and Visit 3.
16. Additional Medications: Unable to stop medications at the defined times prior to Visit 1 (please refer to page 24 of the protocol).
17. Use of inhaled corticosteroids at a dose greater than 1000 mcg/day of fluticasone propionate or equivalent within 30 days prior to Visit 1.
18. Use of long-term oxygen therapy (LTOT) or supplemental oxygen required for greater than 12 hours a day. Oxygen prn use is not exclusionary.
19. Subjects with clinically significant sleep apnea that requires CPAP
20. Use of regular nebulized therapy
21. Use of nocturnal positive pressure or non-invasive positive pressure ventilation (NIPPV).
22. Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
23. Affiliation with Investigator Site: Is an investigator, sub-investigator, study
coordinator, employee of a participating investigator or study site, or immediate
family member of the aforementioned that is involved in this study.
24. Questionable Validity of Consent: A history of psychiatric disease, intellectual
deficiency, poor motivation, substance abuse in the two years prior to Visit 1
(including drug and alcohol), or other conditions, which will limit the validity of
informed consent to participate in the study.
25. Use of GSK233705B in previous studies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for this study is change from baseline in clinic visit trough FEV1
on Day 29. The trough FEV1 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 28. The baseline FEV1 is the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose [time 0] on Day 1. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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