E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
GW-856553 is under development as a potential anti-atherosclerosis agent for reduction of major cardiovascular events in high risk patient populations |
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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 |
To determine the effect of GW-856553 on endothelium function as compared to placebo in subjects with dyslipidaemia |
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E.2.2 | Secondary objectives of the trial |
• To determine the effect of GW856553 on endothelium-independent vasodilation as compared to placebo in subjects with dyslipidaemia • To determine the effect of GW856553 on basal NO activity in endothelium as compared to placebo • To characterize vascular compliance modifications in response to GW856553 administration in subjects with dyslipidaemia • To assess the pharmacodynamic effect of daily doses over four weeks of GW856553 (7.5mg BD) as measured by the level of phosphorylated heat shock protein-27 (pHSP-27) in sorbitol induced whole blood cells of patients with dyslipidaemia. • Examine safety and tolerability of GW856553
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Healthy adult male and females between 18 and 75 years of age, inclusive. 2. To be eligible, female subjects must have a negative pregnancy test (i.e. Urine or serum B-hCG (for females) and be of: a. 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 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. Postmenopausal status will be confirmed by serum FSH and oestradiol concentrations at screening. Surgical sterility will be defined as females who have had a hysterectomy and/or bilateral oophorectomy or tubal ligation. OR b. childbearing potential and agree to commit to one of the protocol-approved methods of contraception as detailed in Section 7.3. 3. Body weight > 50 kg and body mass index (BMI) between 19 and 32kg/m2 4. Subjects with high LDLc levels, as per NCEP ATPIII criteria:fasting LDLc level > 4.1 mmol/L (160 mg/dL), inclusive. Fasting TG level should be < 4.5mmol/L (400 mg/dL) 5. A signed and dated written informed consent prior to admission to the study 6. The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
Note: Standard inclusion criteria apply to the healthy control subjects to be used as lipid control group. |
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E.4 | Principal exclusion criteria |
1. History of symptomatic coronary artery disease, stroke, or other known atherosclerotic disease. 2. Subjects who are current smokers and require a cigarette within 30 minutes after they wake in the morning, or cannot abstain from smoking for approximately 5 hours. 3. History of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody), or other chronic hepatic disorders. 4. History of increased liver function tests (ALT, AST) due to acute or chronic liver conditions, above the upper limit of normal in the past 6 months and/or liver function tests (bilirubin, ALT, AST) above the upper limit of normal at Screening. 5. Renal impairment with creatinine clearance of <50 ml/min at screening, or history of kidney transplant or history of contrast nephropathy. 6. Current inadequately controlled hypertension (blood pressure >180 mmHg systolic and/or >100mmHg diastolic) or any subject who has experienced a modified regimen of antihypertensive medication within 6 weeks prior to first dose of study medication, or any subject who is likely to commence treatment of a hypertensive medication 7. Current poorly controlled diabetes mellitus, defined as HbA1c >10% at Screen. 8. History of heart failure defined as NYHA class II - IV or those with known severe LV dysfunction (EF<30%) regardless of symptomatic status 9. History of malignancy within the past 5 years, other than non-melanoma skin cancer. 10. Current life-threatening condition other than vascular disease (e.g., very severe chronic airways disease, HIV positive, life-threatening arrhythmias) that may prevent a subject from completing the study. 11. Alcohol or drug abuse within the past 6 months. 12. Previous exposure to GW856553. 13. Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication. 14. Subjects who will commence or who are likely to commence treatment with oral intranasal or topical corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) (other than aspirin), PPARγ agonists (e.g. rosiglitazone), sulfonylureas, insulin, fibrates, niacin, ACEI, ARBs, nitrates, HRT, etc from screening until study completion. 15. Any non-stable dosing of ongoing medication regimens (as noted above (#14)) throughout the study trial. 16. Any subject that is likely to commence statin treatment from screening until the final follow up visit. Any subjects currently receiving treatment with statins must be able to washout from the statin for 28 days prior to first dose of study medication. 17. The subject has a three month prior history of regular alcohol consumption exceeding an average weekly intake of > 28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of > 21 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 18. A positive urine test for drugs of abuse (not related to known medications the subject is taking, ie, codeine for pain management) or alcohol at screening or prior to study medication administration. 19. Any other subject whom the Investigator deems unsuitable for the study (e.g., due to either medical reasons, laboratory abnormalities, expected study medication non-compliance, or subject’s unwillingness to comply with all study-related study procedures). 20. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with chronic inflammation (e.g. Inflammatory Bowel Disease). 21. Subjects with chronic infections such as gingivitis, periodonitis, prostatitis, gastritis, and urinary tract infections, or any active diseases, including active tuberculous or a history of active tuberculosis. 22. Subjects with any acute infection, symptoms suggestive of sinusitis, or significant trauma (burns, fractures). 23. Subjects who have donated more than 500 mL of blood within 56 days prior to the study medication administration. 24. History of myopathy or rhabdomyolysis. 25. QTc interval >450 msec 26. An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject 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, sub dermal implants or a tubal ligation if the women could become pregnant from the time of the first dose of the study medication until completion of the follow-up procedures. 27. Pregnant or nursing women.
Note: These exclusion criteria do not apply to the healthy control subjects. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Forearm blood flow ratio, as measured by venous occlusion plethysmography, in response to maximum dose of intra-arterial acetylcholine infusion. |
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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 | 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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 3 |
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 | Information not present in EudraCT |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |