| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003601 |
| E.1.2 | Term | Atherosclerosis |
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| 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 measure in-vivo macrophage activity, by FDG-PET/CT imaging, in carotid arteries and aorta following a 12 week treatment with GW856553 (7.5 mg once daily and 7.5mg twice daily), in the setting of chronic statin therapy, as compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of 12 weeks of dosing with GW856553 (7.5 mg once daily and 7.5mg twice daily)
• To evaluate the effect of 12 weeks of dosing with GW856553, on inflammatory biomarkers.
• To determine the effect of short–term p38 inhibition (once daily dosing of 7.5mg GW856553) versus the effect of a 24hr p38 inhibition (twice daily dosing of 7.5 mg GW856553), over a period of 12 weeks, on in-vivo macrophage activity, as assessed by FDG-PET/CT imaging, in the setting of chronic statin therapy. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Cardia MRI - ZM2007/00140/02, issued 27 June 2008. To assess the change in cardiac function following a 12 week treatment with GW856553 (7.5mg once daily and 7.5mg twice daily) in the setting of chronic statin therapy, as compared to placebo.
Pulse Wave Analysis (PWA), ZM2007/00140/02, issued 27 June 2008. To characterise vascular compliance modifications (by Pulse Wave Analysis and Pulse Wave Velocity) following a 12 week treatment with GW856553 (7.5mg once daily and 7.5mg twice daily) in the setting of chronic statin therapy, as compared to placebo.
Ankle - Brachial Pressure Index (ABPI), ZM2007/00140/02, issued 27 June 2008. To compare changes in ABPI following a 12 week treatment with GW856553 (7.5mg once daily and 7.5mg twice daily) in the setting of chronic statin therapy, as compared to placebo.
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| E.3 | Principal inclusion criteria |
1. Male and female subjects, between 50 and 80 years of age, inclusive, with a body weight > 50 kg and body mass index (BMI) between 19 and 35 kg/m2
2. Subjects who have either:
• experienced a CV event (i.e. acute coronary syndrome, unstable agina, CABG, PCI, stroke, MI, TIA, carotid endarterectomy), but have been clinically stable for at least 6 months since that event [note: if subject with carotid endarterectomy includedtarget vessel for TBR measurement can not be the carotid artery],
• or, have peripheral vascular disease (PVD), as indicated by;
symptoms of claudication a positive imaging/treadmill test or
reduced ankle branchial pressure index,
or, have a diagnosis of CAD corroborated by stress testing (exercise or pharmacological) or any other confirmed diagnosis of atherosclerotic arterial disease
• Individuals who have experienced a CV event or have PVD will be given preference for enrolment in the study, if they also have one of the following:
• metabolic syndrome, as defined by NCEP ATP III
• Framingham score > 20
• Current smokers (at least 1pack/day)
• Well-controlled diabetes, defined for the purposes of this study as HbA1c ≤ 8%, or fasting blood glucose ≤ 126mg/dL (7mmol/L)
3. Subjects must be on a stable dose of statin for at least 3 months prior to first dose of study medication. Subjects must be capable of continuing statin therapy from screening until the final follow up visit.
4. Either carotid or ascending aortic TBR≥1.6, as measured on FDG-PET/CT, signifying active inflammation.
5. AST and ALT <2x ULN at screening; alkaline phospatase and bilirubin≤ 1.5x ULN at screening (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
6. 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
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| E.4 | Principal exclusion criteria |
1. Any medical history or clinically relevant abnormality identified on the screening medical examination, vital sign measurement, 12-lead ECG recording and/or clinical laboratory examination that is deemed by the principal investigator and/or medical monitor to make the subject ineligible for inclusion because of a safety concern.
2. History of heart failure defined as NYHA class II - IV or those with known severe LV systolic dysfunction (EF<30%) regardless of symptomatic status
3. Subjects with atrial fibrillation (AF) at screening will be excluded
4. Type 1 or Type 2 diabetes requiring insulin therapy.
5. Diabetics with fasting glucose > 126mg/dL (7mmol/L) or HbAc1 levels > 8%, at screening [note: fasting glucose to be checked again at first FDG-PET scan, and if glucose > 11mmol/L at that visit, subject will be excluded from study]
6. A positive pre-study hepatitis B surface antigen or hepatitis C antibody results within 3 months of screening.
7. Current or chronic history of liver disease, or known hepatic or biliar abnormalities (with the exception of Glibert's syndrome or asymptomatic gallstones).
8.. Renal impairment with creatinine clearance of <40 ml/min at screening, or history of kidney transplant or history of contrast nephropathy.
9. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic inflammation (e.g. Inflammatory Bowel Disease).
10. Subjects with chronic infections such as HIV, gingivitis, periodonitis, prostatitis, gastritis, and urinary tract infections, or any active diseases, including active tuberculosis or a history of active tuberculosis.
11. Subjects with any acute infection, symptoms suggestive of sinusitis, or significant trauma (burns, fractures)
12. History of malignancy within the past 5 years, other than non-melanoma skin cancer.
13. History of skeletal muscle myopathy or rhabdomyolysis
14. Previous exposure to GW856553.
15. Current use of steroids (inhaled or oral).
16. Subjects who have donated more than 500 mL of blood within 56 days prior to the study medication administration.
17. Participation in a clinical study where the subject has received a drug or new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of the drug (whichever is longer) prior to the first dose of study medication
18. History of alcohol/drug abuse or dependence within 12 months of the study
19. 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 halfpint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine; or a positive alcohol breath test at the screening visit
20. A positive urine test for drugs of abuse (not related to known medications the subject is taking, e.g. codeine for pain management) or alcohol at screening or prior to study medication administration.
21. QTc interval > 450 msec (using average value of triplicate ECGs).
22. Subjects will be excluded if they have participated in clinical research studies involving radiation in the past three years
23. Women of childbearing potential are excluded from this study. Women must be of non-childbearing potential [i.e. either postmenopausal or documented hysterectomy – tubal ligation is not sufficient]. 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 or urine FSH and oestradiol concentrations at screening, if appropriate. Surgical sterility will be defined as females who have had a hysterectomy and/or bilateral oophorectomy.
24. 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, 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 follow up procedures. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in mean standard uptake values of FDG in aortic and carotid arteries, as assessed by PET/CT (TBR), following 12 weeks of treatment with GW856553 (7.5 mg once daily or 7.5mg twice daily), in the setting of chronic statin therapy, as compared to placebo. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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
| 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 | 4 |
| 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 | Yes |
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
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