E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atherosclerotic Carotid Disease |
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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 establish whether inflammatory activity of the atherosclerotic plaque, as measured by USPIO-enhanced MRI, can be modified after the administration of high- or low- dose of atorvastatin. |
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E.2.2 | Secondary objectives of the trial |
• To investigate MRI-derived tensile stress in carotid plaques following the administration of high or low dose atorvastatin. • To quantify changes in cerebral micro-embolization occurring in patients with carotid plaques treated with high and low dose atorvastatin • To investigate the effects of high and low dose of atorvastatin on selected soluble plasma biomarkers • To compare macrophage content as determined by USPIO-enhanced MRI with histology of carotid plaques following the administration of high or low dose atorvastatin. • To assess appearance of new lesions on brain MR and correlate these with USPIO uptake in the carotid plaque and micro-embolic burden. • To assess the pharmacokinetic parameters of atorvastatin.
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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 are met: 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 >1 year, or pre-menopausal females with a documented hysterectomy or bilateral oophorectomy). 3. Positive USPIO-enhanced MRI of carotid plaque confirmed by a consultant neuroradiologist. This is defined as a signal decrease of ≥10% in 2 or more quadrants between pre-Sinerem and post-Sinerem MRI scans. 4. Must either be statin naïve or have been on a stable dose of a statin1 for ≥4 weeks prior to screening, with no evidence of statin intolerability.
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E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. Required continued use of non-statin lipid modifying therapies (e.g. fibric acid derivatives, niacin, resins, ezetimibe, fish oil supplements, etc.) or therapy with any other lipid regulating medications not specified as study treatment in the protocol.2 2. History of statin intolerance. 3. 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. 4. Renal impairment with creatinine clearance <50 ml/min (defined by Cockcroft-Gault formula). 5. History of myocardial infarction or cerebrovascular accident within the past 2 weeks. 6.History of myopathy or inflammatory muscle disease, or elevated total serum CK (3 x ULN) at screening visit. 7. Doppler assessment of less than 40% stenosis during screening assessment. 8. History of clinically significant atopy (e.g. anaphylaxis, skin rash to medication or topical therapies, hypersensitivity to iodinated contrasts, allergies to food (e.g. shellfish), bronchial asthma, etc.) or allergy to dextran and iron salts. 9. Contraindication to MRI scanning including but not limited to: • Intracranial aneurysm clips (except Sugita) with an appropriate operative conformation, • History of intra- orbital metal fragments that have not been removed by an MD, • Pacemakers and non-MR compatible heart valves, • Inner ear implants, • History of claustrophobia in MR. 10. Planned carotid surgery or endovascular intervention earlier than 10 weeks within the study period. 11. Serum triglycerides >400 mg/dl (4.52 mmol/L) at screening. 12. Untreated or uncontrolled hypothyroidism or thyrotoxicosis. 13. Patients with poorly controlled diabetes mellitus with HbA1c ≥8.5%. 14. Patients with poorly controlled hypertension (SBP≥160 mmHg and/or DBP≥100 mmHg). 15. History of malignancy within the past 2 years, other than non-melanoma skin cancer. 16. Evidence of recent (<4 weeks) severe infection (e.g. pneumonia, cellulites, etc.). 17. Current life-threatening condition other than vascular disease (e.g., severe chronic airways disease, HIV positive, life-threatening arrhythmias) that may prevent a subject from completing the study. 18. Alcohol or drug abuse within the past 6 months. 19. Concomitant use of potent CYP450 3A4 inhibitors (e.g. clarithromycin, grapefruit juice [> 8 oz (240 ml) daily], itraconazole, ketoconazole, etc.). 20. Chronic use of NSAIDS and oral steroids therapy.3 21. Chronic use of immunosuppressants (cyclosporine, methotrexate, etc.). 22. Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication. 23. Any other subject the investigator and GSK medical monitor 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 procedures). 24. Inability to give informed consent.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Changes from baseline in USPIO-enhanced MRI signal in carotid plaques at 6 weeks |
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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 | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Information not present in EudraCT |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
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 | 3 |