E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects With Hypercholesterolemia |
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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 | PT |
E.1.2 | Classification code | 10058108 |
E.1.2 | Term | Dyslipidaemia |
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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 evaluate the reduction in plasma low-density lipoprotein cholesterol (LDL-C) in subjects with hypercholesterolemia when treated with lapaquistat acetate 50 mg once daily (QD) or placebo QD for 12 weeks. |
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E.2.2 | Secondary objectives of the trial |
To evaluate safety and tolerability (adverse events [AE]), safety laboratory tests, physical examination (PE), vital signs and electrocardiogram (ECG)). To evaluate changes in lipid variables non high-density lipoprotein cholesterol (non-HDL-C), (total cholesterol (TC), apolipoprotein B (Apo B), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), very-low-density lipoprotein cholesterol (VLDL-C). To evaluate changes in derived ratios LDL-C/HDL-C, TC/HDL-C, ApoB/ApoA1. To evaluate changes in high-sensitivity C-reactive protein (hs-CRP)
Secondary Objectives (Open-label Extension Period): To evaluate long-term safety and lipid variables of lapaquistat acetate 50 mg QD after 48 weeks of open-label treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The subject is a male or female and at least 18 years of age. 2. A female subject of childbearing potential who is sexually active agrees to use adequate contraception from screening throughout the duration of the study and for 30 days following the last dose. Women NOT of child bearing potential are defined as those who have been surgically sterilized (hysterectomy, oophorectomy, tubal ligation) or who are postmenopausal (defined as at least 2 years since last regular menses). Acceptable methods of contraception are defined in Section 9.1.10 Contraception and Pregnancy Avoidance Procedure. 3. The subject is capable of understanding and complying with protocol requirements. 4. The subject or the subject’s legally acceptable representative signs a written informed consent form prior to the initiation of any study procedures. 5. Prior to Randomization, the subject has a mean LDL-C ≥130 mg/dL (3.37 mmol/L) and ≤190 mg/dL (4.92 mmol/L) for 2 consecutive samples (at least 1 week apart). The difference between the 2 individual LDL-C values must not exceed 15% of the higher value. 6. Prior to Randomization, the subject has mean TG ≤400 mg/dL (4.52 mmol/L) for 2 consecutive samples (at least 1 week apart). The upper value for either sample must be ≤450 mg/dL (5.08 mmol/L). 7. The subject is willing and able to comply with a standardized diet (TLC or equivalent). |
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E.4 | Principal exclusion criteria |
1. The subject has an ALT or AST level >1.5 times the upper limit of normal (ULN), identified during screening (e.g., from the V1 blood sample). 2. The subject has a serum creatinine >133 mmol/L (>1.5mg/dL), identified during screening (e.g., from the V1 blood sample). 3. The subject has a CK >3 times the upper limit of normal (ULN), identified during screening (e.g., from the V1 blood sample). 4. The subject has active liver disease or jaundice. 5. The subject has taken any fibrates within 42 days of Visit 1 or any lipid-lowering therapy for at least 30 days prior to Screening (Visit 1). (See Excluded Medications 7.3). 6. The subject has a previous history of cancer that has been in remission for less than 5 years prior to the first dose of study medication. This criterion does not include those subjects with basal cell or stage 1 squamous cell carcinoma of the skin. 7. The subject has an endocrine disorder, such as Cushing’s syndrome, hyperthyroidism, or inappropriately treated hypothyroidism affecting lipid metabolism. Subjects with hypothyroidism on appropriate replacement therapy (defined as stable thyroid hormone replacement at least 3 months prior to Screening and TSH levels ≤1.5 times ULN) will be eligible for enrollment. 8. The subject has a history of myocardial infarction, angina pectoris, unstable angina, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft surgery), or multiple risk factors that confer a 10-year risk for cardiovascular heart disease (CHD) >20% based on Framingham risk scoring. 9. The subject has a positive hepatitis B surface antigen or hepatitis C virus antibody test, as determined by medical history and/or subject’s verbal report. 10. The subject has a positive human immunodeficiency virus (HIV) status or is taking antiretroviral medications, as determined by medical history and/or subject’s verbal report. 11. The subject is unable or unwilling to discontinue excluded medications or to continue stable doses of “stable dose” medications. (See Excluded Medications and Concomitant Medications.) 12. The subject has received any investigational medication 30 days prior to screening, (for drugs with a long half-life, within a period of less than 5 times the drug’s half-life) or has participated in an investigational study. 13. The subject has received lapaquistat acetate in a previous clinical study or as a therapeutic agent. 14. The subject has a history or presence of clinically significant food allergy that would prevent adherence to the specialized diet. 15. The subject has a known heterozygous or homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia (familial dysbetalipoproteinemia). 16. The subject has fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain. 17. The subject has uncontrolled hypertension (defined as resting diastolic blood pressure >100 mmHg and/or a resting systolic blood pressure >160 mmHg) at Screening. 18. The subject has had inflammatory bowel disease or any other malabsorption syndrome, or has had gastric bypass or any other surgical procedure for weight loss. 19. The subject is unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments. 20. The subject is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available. 21. The subject has a history of drug abuse (defined as illicit drug use) or a history of high alcohol intake (defined as regular or daily consumption of more than 3 alcoholic drinks per day by men and 2 by women) within the previous 2 years. 22. The subject has type 1 or 2 diabetes mellitus. 23. The subject is a study site employee, or is an immediate family member (i.e., spouse, parent, child, sibling) of a study site employee who is involved in conduct of this study. 24. If female, the subject is pregnant or lactating. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Variable: The primary efficacy variable for this study is fasting plasma LDL-C.
Secondary Efficacy Variables: The secondary efficacy variables for this study include: TC, Apo B, TG, HDL-C, Apo A1, VLDL-C and ratios LDL-C/HDL-C, TC/HDL-C, Apo B/Apo A1, and hs-CRP. The percentage of subjects reaching LDL-C levels of <160 mg/dL (4.1 mmol/L), <130 mg/dL (3.37 mmol/L) and <100 mg/dL (2.59 mmol/L) at Week 12 (or ET) during the double-blind will be evaluated.
Safety Assessments: The safety variables will include: AEs, safety laboratory tests, PE, vital signs and ECG |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
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 | Information not present in EudraCT |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
An optional 48 week open label extension period at the end |
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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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 |
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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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After a screening and dietary run-in period of 6 weeks, a treatment period of 12 weeks and an open label extension: 48 weeks. |
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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 | 6 |
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 | 6 |