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).

• Conditions: Chronic obstructive pulmonary disease; MedDRA version: 9.1Level: LLTClassification code 10009033Term: Chronic obstructive pulmonary disease

• Registration Number: EUCTR2007-004033-42-DE
• Lead Sponsor: GlaxoSmithKline Research and Development Ltd

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2007-10-24
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 740

Inclusion Criteria

1.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 ligation.
2.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 systemic consequences.
3.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.
4.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 micrograms.
5.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 micrograms.
6.Subjects capable of providing signed written informed consent to participate.
7.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 interval.

A subject will be eligible for randomisation at the end of the run-in period only if the following additional criterion applies:
1.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 pertinent documents.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Women who are pre-menopausal and of child-bearing potential, or pregnant.
2. Subjects with a primary diagnosis of asthma or alpha-1 antitrypsin deficiency.
3. 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
4. Subjects with active tuberculosis or being treated for active tuberculosis, sarcoidosis or clinically overt bronchiectasis.
5. Subjects with a history of any type of malignancy with the exception of successfully treated squamous cell cancer of the skin.
6. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with chronic inflammation
7. Subjects with chronic infections such as gingivitis, periodontitis, prostatitis, gastritis, and urinary tract infections.
8. Subjects with any acute infection, sinus symptoms, or significant trauma
9. 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.
10. Subjects with clinically significant gastrointestinal or hepatic abnormalities.
11. Subjects with hypoxaemia.
12. History of Gilbert's syndrome. Subjects with a total bilirubin concentration above the upper limit of normal at Visit 1 will be excluded.
13. Liver function tests 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.
14. Subjects who have undergone recent surgery including lung volume reduction surgery or have conditions that prevent them from performing spirometry.
15. Subjects with a history of alcohol misuse or any other substance abuse.
16. The subject has a three month prior history of regular alcohol consumption exceeding an average weekly intake of > 21 units for males, or an average weekly intake of > 14 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
17. 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 ? 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.)
18. Subjects who require treatment with any of the following from the Visit 1 until study completion:
•Inhaled corticosteroids
•Inhaled cromolyn sodium or nedocromil
•Xanthines (theophylline preparations)
•Leukotriene modifiers
•Tiotropium
•Long-acting inhaled beta2-agonists (salmeterol, formoterol)
•Oral beta2-agonists
•Macrolide antibiotics for more than five days
19. Subjects who have received treatment with oral, intravenous or intra-articular corticosteroids within 6 weeks of Visit 1 or thereafter.
20. Subjects with any known hypersensitivity to salbutamol or ipratropium bromide.
21. Subjects who are part

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the effects of 12 weeks of treatment with GW856553 7.5 mg BID compared with placebo on the percentage of sputum neutrophils at 12 weeks.;Secondary Objective: To evaluate the effects of 12 weeks of treatment with GW856553 7.5 mg BID compared with placebo on:<br>- Pulmonary function assessed by body plethysmography<br>- Pulmonary function assessed by spirometry<br>- Pulmonary function assessed by impulse oscillometry<br>- Parameters measured in induced sputum <br>- Serum fibrinogen and additional systemic inflammation biomarkers <br>- Levels of ex vivo lipopolysaccharide (LPS) induced tumour necrosis factor (TNF)-alpha in whole blood pre-dose and 2 h post-dose at selected centres. <br>- Levels of ex vivo sorbitol induced phosphorylation of heat shock protein 27 (pHSP27) in whole blood pre-dose and 2 h post-dose at selected centres.<br><br>Refer to the protocol for full details.<br>;Primary end point(s): Percentage of neutrophils in induced sputum at week 12.