| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Study is in COPD patients |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
|
| 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 estimate the bronchodilatory effect of GSK233705 (20 or 50 μg bid) when administered concurrently with salmeterol 50 μg bid for 7 days in subjects with COPD, compared with placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To estimate the bronchodilatory effect of salmeterol 50 μg bid alone and tiotropium 18 μg od alone, compared with that of placebo and of concurrent treatment with GSK233705 (20 or 50 μg bid) plus salmeterol 50 μg bid, when administered for 7 days in subjects with COPD.
To assess the safety and tolerability of concurrent treatment with GSK233705 (20 or 50 μg bid) plus salmeterol 50 μg bid, as well as salmeterol 50 μg bid alone and tiotropium 18 μg od alone, when administered for 7 days in subjects with COPD.
To assess the pharmacokinetics of GSK233705 (20 or 50 μg bid) when administered concurrently with salmeterol 50 μg bid, and of salmeterol 50 μg bid administered concurrently with GSK233705 (20 or 50 μg bid) or alone, in COPD subjects dosed for 7 days.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects aged 40 – 75 y inclusive at the Screening Visit 1.
2. Female subjects must be of non-childbearing potential including pre-menopausal
females with documented (medical report verification) hysterectomy or double
oophrectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or
6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or
6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
3. Male subjects must agree to abstain from or use a condom during sexual intercourse
with pregnant or lactating females. Male subjects must also agree to use a
condom/spermicide in addition to having their female partner use another form of
contraception such as an IUD, diaphragm with spermicide, oral contraceptives,
injectable progesterone, subdermal implants or a tubal ligation if engaging in sexual
intercourse with a female partner who could become pregnant. This criterion must
be followed from the time of the first dose of study medication until 84 days after the
last dose of study medication.
4. An established clinical history of COPD at Screening Visit 2, in accordance with the
following definition by the American Thoracic Society/European Respiratory
Society (ATS/ERS) [Celli, 2004]
Chronic obstructive pulmonary disease (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.
5. Post-bronchodilator FEV1 of ≥ 40% to ≤ 75% of predicted normal at Screening
Visit 2. Subjects who do not have FEV1 values within this range at Visit 2 may have
one repeat assessment at Visit 2A to establish eligibility before randomisation (Visit
3). Subjects who do not have FEV1 values within this range will not be eligible for
the study.
6. Subject has post-bronchodilator FEV1/FVC ratio ≤ 70% at Screening Visit 2.
7. Subject must be responsive to ipratropium bromide defined as:
Either: an increase in FEV1 of ≥ 12% and ≥ 150 mL at 2 h following inhalation
of 80 μg of ipratropium bromide at Screening Visit 1,
or: a documented increase in FEV1 of ≥ 12% and ≥ 150 mL at 2 h following
inhalation of 80 μg of ipratropium bromide within 6 months of the Screening
Visit 1 and an increase in FEV1 of >6% and >100 mL 2 h following inhalation of
80 μg of ipratropium bromide at Screening Visit 1 (in order to allow for potential fluctuations in the response to ipratropium bromide in patients known to be
responders to ipratropium bromide).
Subjects who do not demonstrate the required increase in FEV1 in response to
ipratropium at Screening Visit 1 may have the assessment repeated once at
Visit 1A, before randomisation (Visit 3). Subjects who do not demonstrate the
required increase in FEV1 are not eligible to enter the study.
8. Subjects must be responsive to salbutamol defined as:
Either: an increase in FEV1 of ≥ 12% and ≥ 150 mL at 30 mins following
inhalation of 400 μg of salbutamol at Screening Visit 2, or
or: a documented increase in FEV1 of ≥ 12% and ≥ 150 mL at 30 mins following
inhalation of 400 μg of salbutamol within 6 months of Screening Visit 1 and an
increase in FEV1 of >6% and >100 mL 30 mins following inhalation of
salbutamol 400 μg at Screening Visit 2 (in order to allow for potential fluctuations
in the response to salbutamol in patients known to be responders to salbutamol).
Subjects who do not demonstrate the required increase in FEV1 in response to
salbutamol at Screening Visit 2 may have the assessment repeated once at Visit 2a
before randomisation (Visit 3). Subjects who do not demonstrate the required
increase in FEV1 are not eligible to enter the study.
9. Current smoker or ex-smoker with a smoking history of > 10 pack-years (10 pack
years defined as 20 cigarettes per day for 10 years, or 10 cigarettes (or equivalent if
subject smoked cigars or a pipe) per day for 20 years). Ex-smokers are required to
have stopped smoking for at least 6 months prior to Screening Visit 2. Ex-smokers
who stopped smoking less than 6 months ago will be defined as current smokers.
10. Subject is >50kg with a body mass index within the range 19.0 to 29.9 kg/m2 at
Screening Visit 2.
11. Subject is able and willing to give written informed consent to take part in the study.
12. Subject is available to complete all study measurements and procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects with any of the following criteria must not be enrolled in the study:
1. COPD exacerbation, or changes in COPD medication (other than use of relief
VENTOLIN™) within the 4 weeks prior to Screening Visit 2 or during the run-in
period.
2. Received antibiotic therapy for either a lower respiratory tract infection or for COPD
exacerbation within the 4 weeks prior to Screening Visit 2 or during the run-in
period.
3. Hospitalised for a COPD exacerbation in the 6 months prior to Screening Visit 2 or
during the run-in period.
4. Current diagnosis of asthma or a post-salbutamol increase in lung function of
>500 mL at any reversibility assessment prior to randomisation (Visit 3).
5. Known respiratory disorders other than COPD (e.g., lung cancer, sarcoidosis,
tuberculosis, bronchiectasis, lung fibrosis).
6. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck
obstruction that in the opinion of the Investigator should prevent them from entering
the study.
7. Undergone lung surgery (e.g., lung transplant and/or lung volume reduction) which
in the opinion of the investigator may affect the outcome of the study.
8. Currently receiving pulmonary rehabilitation.
9. Had a chest X-ray indicating diagnosis other than COPD that might interfere with the
study (in the 12 months prior to the Screening Visit 2).
10. Requires regular (daily) or long term oxygen therapy (LTOT).
11. Experienced two or more COPD exacerbations requiring treatment with oral,
parenteral or depot corticosteroids in the last 6 months.
12. Received oral or parenteral corticosteroids within 4 weeks or depot corticosteroids
within the 3 months prior to Screening Visit 2 or during the run-in period.
13. Receiving inhaled corticosteroids at a dose greater than 1000 μg / day of fluticasone
propionate (FP) or equivalent during the run-in period or who changed dose within
6 weeks of Screening Visit 2 or during the run-in period.
14. Currently receiving β-blockers (except eye drops).
15. Any of the following cardiovascular criteria:
a. History of significant congestive heart failure (greater than New York Heart
Association Type I), myocardial infarction, ischaemic heart disease requiring
regular therapy with drugs other than nitrates or clinically significant cardiac
arrhythmia.
b. Mean QTc(B) at screening of > 440 msec, the QTc(B) of all three screening
ECGs at the Screening Visit 2 are not within 10% of the mean, a PR interval
outside the range 90-220 msec or an ECG that is not suitable for QT
measurements (e.g., poorly defined termination of the T wave or left bundle
branch block).
c. History of elevated supine blood pressure or mean blood pressures
≥ 160/90 mmHg at Screening Visit 2.
d. Mean heart rate outside the range 50–90 bpm at Screening Visit 2.
16. Subjects who are not considered able to tolerate three 2-week wash-out periods
according to the study schedule with all COPD medications removed apart from
relief use of VENTOLIN via metered dose inhaler (MDI) or
DISKUS/ACCUHALER (inhaled use as required) or inhaled corticosteroids at a
dose less than 1000 μg / day of fluticasone propionate (FP) or equivalent.
17. The subject has a positive drugs of abuse test at Screening Visit 2.
18. A positive alcohol test (breath or urine), including ethanol. The detection of alcohol
would not be an exclusion at any of the screening visits but the subject would need to
provide a negative test result pre-dose and during the study.
19. A suspected history of alcohol abuse within the 6 months prior to Screening Visit 2.
20. The subject has tested positive for hepatitis C antibody, hepatitis B surface antigen or
HIV (if tested according to site standard operating procedures) at Screening Visit 2.
(Applicable only if subject has the relevant risk factors which would necessitate
testing, at the discretion of the investigator)
21. Subject has received an investigational drug within 30 days of Screening Visit 2.
22. The subject has donated a unit of blood within 30 days of Screening Visit 2, or,
intends to donate during the study.
23. Subject has claustrophobia that may be aggravated by entering the plethysmography
cabinet.
24. The subject has a known allergy or hypersensitivity to ipratropium bromide,
tiotropium bromide, atropine and any of its derivatives or lactose.
25. Subject is unable to use the DISKUS/ACCUHALER/HandiHaler devices correctly.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Morning (trough) forced expiratory volume in 1 second (FEV1) on Day 8, following 7 days of twice daily treatment. |
|
| 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 | No |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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