A 12-week, Randomised, Double-blind, Placebo-controlled Study to Assess the Anti-inflammatory Activity, Efficacy and Safety of GW856553 in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Subjects eligible for enrolment in the study must meet all of the following criteria:
- Male adults or female adults of non-childbearing potential who are between 40 and 75
years of age (inclusive). Note: a female is eligible to enter and participate in the
study if she is of non-childbearing potential (i.e. physiologically incapable of
becoming pregnant). This includes any female who is post-menopausal. For the purposes
of this study, post menopausal is defined as being amenorrhoeic for greater than 1
year with an appropriate clinical profile, e.g. age appropriate, history of vasomotor
symptoms. Postmenopausal status may be confirmed by serum FSH and oestradiol
concentrations at screening if deemed necessary by the PI. Surgical sterility will be
defined as females who have had a hysterectomy and/or bilateral oophorectomy or tubal
- Chronic obstructive pulmonary disease diagnosis: an established clinical history of
COPD in accordance with the following description by the American Thoracic
Society/European Respiratory Society [American Thoracic Society / European
Respiratory Society, 2004] Chronic obstructive pulmonary disease 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
- Subjects with a cigarette smoking history of ≥10 pack years (1 pack year = 20
cigarettes smoked per day for 1 year or the equivalent). Both current and former
smokers are eligible to be enrolled. A former smoker is defined as a subject who has
not smoked for ≥6 months at Visit 1.
- Subjects with a post-bronchodilator FEV1 to FVC ratio (FEV1:FVC) < 0.7 at Visit 1.
Subjects will be assessed 30 (± 5) minutes after receiving salbutamol 400 μg.
- Subjects with a post-bronchodilator FEV1 ≥ 50% and < 80% of predicted normal for
height, age and sex at Visit 1. Subjects will be assessed 30 (± 5) minutes after
receiving salbutamol 400 μg.
- Subjects capable of providing signed written informed consent to participate.
- Subjects must have a QTc <450 msec on baseline ECG or triplicate ECG averaged over a
brief recording interval. For subjects with baseline bundle branch block the QTc will
be <480msec on baseline ECG or triplicate ECG averaged over a brief recording
- A subject will be eligible for randomisation at the end of the run-in period only if
the following additional criterion applies: Subjects with no evidence of an ongoing
acute infection or sinus symptoms Specific information regarding warnings,
precautions, contraindications, AEs, and other pertinent information on the
investigational product that may impact subject eligibility is provided in the
Investigator Brochure/Investigator Brochure supplement(s), product label, and other
A subject will not be eligible for inclusion in this study if any of the following
- Women who are pre-menopausal and of child-bearing potential, or pregnant.
- Subjects with a primary diagnosis of asthma or α-1 antitrypsin deficiency.
- Subjects who have required hospitalisation or treatment with oral corticosteroids
and/or antibiotic therapy for acute worsening of COPD or lower respiratory tract
infection in the 6 weeks prior to Visit 1
- Subjects with active tuberculosis or being treated for active tuberculosis,
sarcoidosis or clinically overt bronchiectasis.
- Subjects with a history of any type of malignancy with the exception of successfully
treated squamous cell cancer of the skin.
- Subjects with rheumatoid arthritis, connective tissue disorders and other conditions
known to be associated with chronic inflammation (e.g. inflammatory bowel disease).
- Subjects with chronic infections such as gingivitis, periodontitis, prostatitis,
gastritis, and urinary tract infections.
- Subjects with any acute infection, sinus symptoms, or significant trauma (burns,
- Subjects with clinically significant renal disease, diabetes mellitus/metabolic
syndrome, hypertension or any other clinically significant cardiovascular,
neurological, endocrine, or haematological abnormalities that are uncontrolled on
permitted therapy (see Section 6.6.1).
- Subjects with clinically significant gastrointestinal or hepatic abnormalities.
- Subjects with hypoxaemia. (All subjects must have an O2 saturation of ≥ 88% on room
- History of Gilbert's syndrome. Subjects with a total bilirubin concentration above
the upper limit of normal at Visit 1 will be excluded.
- Liver function tests (bilirubin, ALT, or AST) above upper limit of normal at Visit 1.
The subject has a positive Hepatitis B surface antigen or Hepatitis C antibody
result within 3 months of the start of the study.The subject has a history of HIV or
other immunosuppressive disease.
- Subjects who have undergone recent surgery including lung volume reduction surgery or
have conditions that prevent them from performing spirometry.
- Subjects with a history (or suspected history) of alcohol misuse or any other
- The subject has a three month prior history of regular alcohol consumption exceeding
an average weekly intake of > 21 units (or an average daily intake of greater than 3
units) for males, or an average weekly intake of > 14 units (or an average daily
intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint
(284mL) of beer/lager; 25mL measure of spirits or 125mL of wine; or a positive
alcohol breath test at the screening visit
- Subjects who will commence or who are likely to commence statin therapy
(3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) or treatment with
intranasal or topical corticosteroids, acetylsalicyclic acid, non-steroidal
anti-inflammatory drugs, gemfibrozil, clopidogrel, abciximab, peroxidase
proliferator-activated receptor γ agonists (e.g, rosiglitazone), fibrates, or niacin
from Visit 1 until study completion. (Subjects who are receiving these medications at
a stable dose at Visit 1 may be entered in the study.)
- Subjects who require treatment with any of the following from the Visit 1 until study
- Inhaled corticosteroids
- Inhaled cromolyn sodium or nedocromil
- Xanthines (theophylline preparations)
- Leukotriene modifiers
- Long-acting inhaled β2-agonists (salmeterol, formoterol)
- Oral β2-agonists
- Macrolide antibiotics for more than five days
- Subjects who have received treatment with oral, intravenous or intra-articular
corticosteroids within 6 weeks of Visit 1 or thereafter.
- Subjects with any known hypersensitivity to salbutamol or ipratropium bromide.
- Subjects who are participating or plan to participate in the active phase of a
pulmonary rehabilitation programme during the study. Maintenance rehabilitation is
- Subjects who have received an investigational drug within 30 days or within five drug
half-lives of the investigational drug (whichever is longer).
- Subjects with any clinically relevant abnormality detected by the assessments at
- An unwillingness of male subjects to abstain from sexual intercourse with pregnant or
lactating women; or unwillingness of the male subject to use a condom/spermicide in
addition to having their female partner use another form of contraception such as an
intra-uterine devices, diaphragm with spermicide, oral contraceptives, injectable
progesterone, subdermal implants or a tubal ligation if the woman could become
pregnant from the time of the first dose of investigational product for the duration
of the study (i.e., through the follow-up phase).
- Subjects who have had a close household contact treated for active tuberculosis
within the past 12 months, or who in the judgement of the investigator are at high
risk for developing active tuberculosis, shall be excluded from the study.
- A subject will not be eligible for randomisation at the end of the run-in period if
either of the following criteria applies:
- Subjects who have experienced an exacerbation during the run-in period requiring
treatment with oral corticosteroids and/or antibiotics and/or hospitalisation.
- Subjects who are unable to produce an induced sputum sample.