| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SB-480848 is under developement as a potential anti-atherosclerosis agent for reduction of major cardiovascular events in high risk patient populations. |
|
| 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 assess the ability of SB-480848 to produce sustained inhibition of plasma Lp- PLA2 activity in subjects receiving concomitant atorvastatin therapy. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the dose-response of SB-480848 on inhibition of plasma Lp-PLA2 activity
in the presence of therapy with either atorvastatin 20 mg or 80 mg.
• To examine dose-related effects of SB-480848 on circulating biomarkers, and whether these effects differ between the atorvastatin 20 mg and 80 mg groups.
• To assess the safety and tolerability of SB-480848.
• To describe the PK of SB-480848 using a population PK approach. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
1. Signed written informed consent prior to beginning study-related procedures (subject must understand the aims, investigational procedures and possible consequences of the study).
2. Male or female aged 18 to 80 years of age at Screen. Female subjects must be of non-childbearing potential (post-menopausal females who have been amenorrheic > 2 year, or pre-menopausal females with a documented hysterectomy or bilateral oophorectomy), who must not be planning or receiving any in-vitro fertilization treatment and must not be breastfeeding.
3. Established, stable CHD or CHD-risk equivalent documented by at least 1 of the following:
• Prior coronary angiography with ≥50% stenosis in at least 1 epicardial coronary artery
• Prior coronary revascularization [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)] >6 months prior to screening
• Prior history of MI, confirmed by ECG changes (pathological Q waves in 2 contiguous leads) and/or documented transient cardiac enzyme elevation (troponin T, troponin I or CK-MB) consistent with myocardial necrosis >6 months prior to screening
• Previously diagnosed diabetes mellitus on stable regimen of oral hypoglycemic agents and/or stable regimen of insulin therapy
• Documented carotid disease (carotid ultrasound confirming stenosis >50% at any time prior to screening or prior carotid surgery or stenting >6 months prior to screening)
• Peripheral arterial disease manifested by 1 of the following:
• Ankle/Brachial Index <0.9, or prior revascularization procedure (peripheral stenting or surgery >6 months prior to screening)
• documented abdominal aneurysm (abdominal ultrasound confirming aortic abdominal aneurysm at any time prior to screening or prior surgery or stenting > 6 months prior to screening)
• Cluster of risk factors resulting in 10 year risk for coronary events >20% according to Framingham risk score at the time of screening (Appendix 5)
4. Must have been on a stable dose of a statin for ≥4 weeks prior to screening, with statin tolerability and LDL <130 mg/dL (3.4 mmol/L) or off statin therapy for ≥4 weeks with LDL <160 mg/dL (4.1 mmol/L) at the Prescreen Visit.
5. Must be on a stable dose of at least one oral antiplatelet agent (e.g., aspirin>75 mg, clopidogrel, or ticlopidine), which can be initiated at the Presecreen Visit, and will be continued throughout the course of study. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Recent (i.e., <6 months prior to screening) CV event and / or vascular procedure defined as:
• ST-elevation MI or non-ST-elevation MI confirmed by cardiac enzyme elevation
• coronary revascularization (PCI or CABG)
• peripheral vascular surgery (including carotid surgery), transcatheter revascularization or abdominal aneurysm repair
• stroke of any etiology
• resuscitated sudden death
2. Required continued use of fibric acid derivatives or niacin, or atorvastatin 80 mg daily or therapy with any other lipid regulating medications not specified as study treatment in the protocol, or a history of difficult to manage dyslipidemia in the past that, in the opinion of the investigator, would make the subject an inappropriate candidate for the study regimen.
3. Planned cardiac surgery (e.g., CABG, valve repair or replacement, or aneurysmectomy) or planned PCI or planned major non-cardiac surgery within the study period.
4. Current inadequately controlled hypertension (blood pressure >160 mmHg systolic and/or >100 mmHg diastolic) on a stable dose of antihypertensive medication.
5. Current poorly controlled diabetes mellitus, defined as hemoglobin subtype A1c (HbA1c) >10% at screening.
6. Serum triglycerides >400 mg/dL (4.52 mmol/L) at screening.
7. Recent (< 3 months prior to screening) or ongoing acute infection.
8. Prior history of chronic inflammatory disease (e.g., systemic lupus erythematosis, rheumatoid arthritis, inflammatory bowel disease such as ulcerative colitis or Crohn’s disease).
9. Recently (<1 month prior to screening) or currently receiving topical, oral, inhaled or injectable corticosteroids.
10. Currently receiving oral or injectable strong CYP3A4 inhibitor(s) (refer to Section 9.2, Prohibited Medications). Subjects will be instructed to refrain from consumption of >8 oz (240 mL) daily of grapefruit-juice (Refer to Section 7, Lifestyle and/or Dietary Restrictions).
11. History of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody), or other chronic hepatic disorders; or ALT or AST >1.5 x ULN, or alkaline phosphatase or total bilirubin >1.5 x ULN of laboratory reference range at screening.
12. Renal impairment with serum creatinine >2.5 mg/dl (>221 µmol/L) at screening, or history of kidney transplant.
13. History of myopathy or inflammatory muscle disease, or elevated total serum CK (3 x ULN) at screening.
14. History of severe heart failure defined as NYHA class III or IV (Appendix 6), or those with known severe left ventricular dysfunction (ejection fraction <30%) regardless of symptomatic status.
15. History of adult asthma manifested by bronchospasm in the past 6 months, or currently taking inhaled bronchodilator on regular basis.
16. History of anaphylaxis, anaphylactoid reactions or severe allergic responses within the past 6 months.
17. History of malignancy within the past 2 years, other than non-melanoma skin cancer.
18. 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.
19. QTc interval >440 msec (males) or >450 msec (females) at screening.
20. Alcohol or drug abuse within the past 6 months.
21. Previous exposure to SB-480848.
22. Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication (blinded atorvastatin).
23. Any other subject the investigator deems unsuitable for the study (e.g., due to either medical reasons, laboratory abnormalities, expected study medication noncompliance, or subject’s unwillingness to comply with all study-related procedures).
24. Current untreated or uncontrolled thyroid disease (i.e., hypothyroidism or hyperthyrodism) at screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| On treatment sustained inhibition of plasma Lp-PLA2 activity at trough levels of SB- 480848 assessed by the difference in plasma Lp-PLA2 activity from the end of week 4 to the end of week 12 in subjects on stable atorvastatin background 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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