E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
primary hypercholesterolemia |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
|
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 |
Evaluate the efficacy and dose response of once daily oral dosing of GW501516 (2.5 mg, 5 mg and 10 mg) versus placebo in percentage change from baseline in LDL-c levels after 12 Weeks of dosing in subjects with primary hypercholesterolemia on background statin therapy.
|
|
E.2.2 | Secondary objectives of the trial |
• Evaluate the effect of once daily oral dosing of GW501516 (2.5 mg, 5 mg and 10 mg) versus placebo on fasting levels of TC, HDL-c, TG, apolipoproteins, ApoB and ApoAI, non-HDL-c, VLDL-c, FFA and an inflammatory marker hs-CRP during 12 weeks of dosing in subjects with primary hypercholesterolemia on background statin therapy. • Evaluate the safety and tolerability of once daily oral dosing of GW501516 (2.5 mg, 5 mg and 10 mg) versus placebo in subjects with primary hypercholesterolemia on background statin therapy.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects aged 18-70 years (inclusive at the time of Pre- Screening Visit 1) 2. Subjects who are on stable, approved dose of Simvastatin (20, 40 or 80 mg) or Atorvastatin (10, 20, 40 or 80 mg) for a minimum of 8 Weeks prior to the prescreening visit 1. 3. Subjects with stable LDL-C ≥100 mg/dl (2.59 mmol/L) and ≤160 mg/dL (4.14 mmol/L) at Visits 1 and 2 4. Females, to be eligible to enter and participate in this study must be: • of non –child bearing potential ( i.e. physiologically incapable of becoming pregnant (tubal ligation, documented hysterectomy), including any female who is post-menopausal [> 1 year without menstrual period and FSH/estradiol concentrations are consistent with postmenopausal state]. Other reasons for amenorrhoea should also be excluded by the Investigator 5. Subject has given full written informed consent prior to any study-related procedures being performed.
|
|
E.4 | Principal exclusion criteria |
1. Metabolic Disease including: • Diagnosis of Type 1 or Type 2 diabetes mellitus, or FPG >126mg/dL(>7.0mmol/L) • Uncorrected thyroid dysfunction • Significant weight gain or loss within the past 3 months prior to Screening Visit 2. 2. History of recent clinically significant cardiovascular disease at Visit 2 including: • CHD, CHF (NYHA Class II-IV), stroke, peripheral vascular disease. • History or ECG evidence of prior myocardial infarction in the past 6 months. • Current unstable angina or history of unstable angina in the past 6 months. • Coronary revascularization including percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery • Clinically significant arrhythmia or valve heart disease. • Blood pressure > 160/100 mmHg or resting heart rate > 100 bpm. • Has a QTc interval > 450 msec in males or females, QTcb or QTcf, machine or manual overreads at Screening Visit 2. • Clinically significant ECG abnormalities 3. History of significant co-morbid diseases [e.g., severe Chronic Obstructive Pulmonary disease (COPD), chronic gastrointestinal disease, etc.] 4. TGs in excess of 400mg/dL (4.52 mmol/L) at Visits 1 or 2 (for permitted re-test details see Section 3.1.3) 5. Subjects with cTnI > 0.35ng/ml 6. Serum creatinine at Visit 2 > 1.4 mg/dL (124μmol/L) for females, or > 1.5mg/dL (133μmol/L) for males at Visit 2. 7. Clinically significant anaemia defined by haemoglobin concentration (<12.0g/dL or 120.0 g/L) for males or (<11.0g/dL or <110.0g/L) for females at Visit 2 8. Documented history of hepato-biliary disease including a history of, or positive laboratory results for hepatitis at Screening Visit 2, and/or clinically significant hepatic enzyme elevation, including any one of the following enzymes greater than 2.5 times the upper limit of normal (ULN) value at Screening:ALT, AST, ALP, total or direct bilirubin > 1.5 x ULN at Screening, unless consistent with presumed or diagnosed Gilbert’s disease. 9. History of metabolic acidosis or rhabdomyolysis, or a history of myalgia, myositis or myopathy after taking statins and/or fibrates. 10. Signs or symptoms of myositis and/or CPK ≥3xULN at Visit 2 11. Any subject who has been withdrawn from therapy due to AEs after taking a PPARγ or a PPARα/γ dual agonist 12. Any subject who is taking medications that are contraindicated for use in the atorvastatin and simvastatin label. 13. Any subject currently taking or who has taken any of the following medications as assessed at Screening Visit 2. • Lipid-lowering agents (with exception of simvastatin 20, 40 or 80 mg and atorvastatin 10, 20, 40, or 80 mg) and drugs known to have substantial effect on lipid metabolism including but not limited to fish oil and vitamins within 8 Weeks prior to pre-screening Visit 1 • All oral glucose-lowering agents and insulin • Anti-obesity agents • Warfarin and digoxin • Oral or injectable corticosteroids • Oral anti-coagulant (other than aspirin, clopidogrel and non-steroidal anti-inflammatory drugs [NSAIDs]) within 30 days prior to the pre-screening Visit 1 • Antiretroviral drugs • St. John’s Wort • Use of Thiazolidinedione ( TZDs ) • Any major change in diet, exercise habits or smoking status • Methotrexate, cyclosporine or monoclonal antibodies for rheumatoid arthritis or psoriasis • Atypical antipsychotics medications • Monoamine oxidase inhibitors • Any OTC or herbal medications, including but not limited to vitamins supplements, unless prepared to cease self-medication at the start of the pre-screening Visit 1. except: aspirin, paracetamol, laxatives and antihistamines. Other OTC medications may be used as needed as long as deemed acceptable by the GSK medical monitor 14. History of cancer except for basal cell carcinoma, superficial squamous cell carcinoma treated by local excision, or cervical cancer in situ treated more than 6 months prior to Screening Visit 2 15. Women who are lactating, pregnant, or planning to become pregnant or a positive pregnancy test at screening. Only women of non-child bearing potential will be included as per inclusion criterion 4. 16. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to any drug chemically related to the study drug. 17. Known allergy to any of the capsule excipients, or history of drug or other allergy, which, in the opinion of the responsible study physician, contradicts participation. 18. Has a history of substance abuse within the past year as determined by the Investigator at (Visit 2) or during treatment • 19. Received treatment with any investigational product during the previous 4 months or any other trial during the previous 3 months, or has participated in a previous study with GW501516. An investigational product is defined as any compound not in Phase 3. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary and Secondary Endpoints: • Lipids: • LDL-C, HDL-C, TC, TG, non-HDL-C (calculated), VLDL-C and FFA • Apolipoproteins: • ApoB and ApoAI • Inflammatory markers • hs-CRP • Safety Analysis • ECGs • Physical Examination • Vital signs • Clinical Laboratory tests • Body weight • AE’s • Exploratory endpoints: • Lipid sub-fractions: (detailed in Section 5.2.3.1) • Inflammatory and metabolic biomarker endpoints including but not limited to novel biomarkers |
|
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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
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
|
please refer to the protocol |
|
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 | 12 |
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 | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |