| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heterozygous Familial Hypercholesterolemia |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057079 |
|
| 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 |
| The primary objective of this study is to demonstrate the efficacy of fixed combination torcetrapib/atorvastatin in lowering LDL-C, raising levels of HDL-C and favorably altering the levels of other lipid parameters and biomarkers, when compared to atorvastatin alone, in subjects with heFH. |
|
| E.2.2 | Secondary objectives of the trial |
| Additional objectives include assessing the safety and tolerability of torcetrapib/atorvastatin in subjects with heFH. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Men and women at least 18 years of age.
2. Signed informed consent prior to the initiation of any study procedures.
3. Subjects who have heFH. The diagnosis of heterozygous familial hypercholesterolemia will be defined by two alternative methods: (a) clinical criteria (patient and family history, physical examination, and plasma lipid levels) or (b) LDL receptor genotyping. Secondary causes for hypercholesterolemia should be absent (eg, nephrotic syndrome, steroid treatment and obstructive jaundice).
4.1.1. Genotyping Diagnostic Criteria
LDL receptor genotype performed prior to this protocol.
4.1.2. Clinical Diagnostic Criteria At the time of diagnosis, with a fasting triglyceride level of <400 mg/dL (4.52 mmol/L), the subject must meet one of criteria (a) to (e). (Please see Table 1 in the protocol).
a. The subject meets the first degree relative LDL C criteria (see Table 1) in the absence of lipid lowering treatment and the subject has tendinous xanthomas, or
b. The subject is an adult relative of previously diagnosed FH subject (homozygous FH or heFH by genotyping or heFH by the clinical criteria as outlined here) and the subject meets the appropriate first, second or third degree relative LDL C criteria for first, second or third degree relatives, or
c. The subject meets the first degree relative LDL C criteria and the subject has 2 or more first degree relatives who meet the general population LDL C criteria for general population in the absence of lipid lowering treatment, or
d. The subject meets the 100% probability criteria in the absence of lipid lowering treatment and the subject has a relative who meets the appropriate first, second or third degree criteria for LDL C or the subject has a pediatric relative (<18 years of age) who meets the appropriate first, second or third degree relative LDL C or TC criteria, or
e. The subject meets the general population criteria for LDL C and the subject has a first degree relative <20 years old who meets first-degree relative LDL C or TC criteria.
NOTE: Diagnostic criteria for each subject must be noted in source documents. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating, or planning to become pregnant, or women of child bearing potential who have not successfully been using acceptable contraceptive methods over the previous three months. 2. Subjects who are unable to tolerate 20 mg atorvastatin during the run in period or who have been intolerant of atorvastatin prior to screening. 3. Subjects with active cardiac disease such as unstable angina, myocardial infarction, coronary angioplasty, coronary artery bypass graft, moderate or severe congestive heart failure (NYHA Class III or IV) within the last 1 month prior to the screening visit and through to randomization. 4. Subjects with uncontrolled hypertension, defined as an average systolic blood pressure >140 mmHg or an average diastolic blood pressure >90 mmHg from the last visit before randomization (at run-in Visit 3, 4 or 5) and the randomization visit (Visit 6). 5. Subjects with a clinically indicated need for statin (HMG CoA reductase inhibitor) therapy other than atorvastatin (including Cholestin™) or other concomitant therapy with known lipid altering effects on LDL C and HDL C, including, but not limited to lipid lowering combination therapies (eg, amlodipine/atorvastatin or simvastatin/ezetimibe), fibrates, bile acid sequestrants if administered with study medication, and nicotinic acid (>500 mg/day). Bile acid sequestrants and cholesterol absorption inhibitors such as ezetimibe are allowed if already being taken at Visit 1 and the dose remains the same throughout the study. Bile acid sequestrants should be administered at least 2 hours before or 4 hours after study medication.
6. Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG CoA reductase inhibitors, including but not limited to erythromycin, clarithromycin, telithromycin, any chronic systemic antifungal use, nefazodone, fluvoxamine, any immunosuppressive drugs including cyclosporine, any protease inhibitors and other potent inhibitors of cytochrome P450 3A4 (CYP3A4). Should these medications be necessary during the course of the trial, consideration should be given to temporarily withholding study drug and restarting it only after time has elapsed to allow for sufficient clearance of the medication.
7. Subjects with any other medical condition or laboratory abnormality prior to randomization, which in the opinion of the principal investigator could affect subject safety, preclude evaluation of response, or render unlikely that the subject would complete the study, including but not limited to: a. Subjects with fasting triglycerides >500 mg/dL (5.65 mmol/L) at Visit 1; b. Subjects with uncontrolled diabetes mellitus, as determined by the PI; c. Subjects with renal disease including 1. any history of nephrotic syndrome; 2. chronic renal failure; 3. serum creatinine >1.7 times the upper limit of the reference range (ULRR); d. Subjects with uncontrolled hypothyroidism defined as a TSH >2 times ULRR at Visit 1; e. Subjects with any active hepatobiliary disease, serologic evidence of past or active hepatitis B or hepatitis C infection, or an AST(SGOT) or ALT(SGPT) >2 times the ULRR, alkaline phosphatase >1.5 times ULRR (with elevated liver isoform of alkaline phosphatase), or total bilirubin >1.5 times ULRR at Visit 1. f. Subjects with unexplained serum CK >3 times ULRR at Visit 1 (eg, recent trauma, intramuscular injections, heavy exercise). A repeat CK >3 times ULRR in the absence of conditions explaining CK elevation is exclusionary. g. Subjects with any prior history of malignancy who have been cancer-free for less than ten years. Subjects with prior history of squamous cell carcinoma who have been cancer-free for less than five years. Subjects with prior history of basal cell skin carcinoma may be included. h. Subjects with gastrointestinal disease limiting drug absorption or partial ileal bypass or gastric stapling or gastric banding;
i. Subjects with alcohol and/or any other drug abuse or dependence. 8. Subjects who have received an investigational drug or device within 30 days of Visit 1, or who expect to participate in any other investigational drug or device study during the conduct of this trial. 9. Subjects previously hypersensitive to or currently receiving CETP Inhibitor therapy, have received a CETP vaccine, or have previously participated in any clinical trial using torcetrapib (CP 529,414). 10. Subjects, who during the run-in period (Visits 2 to 5) demonstrate poor compliance of, on average, <80% as assessed by tablet count. 11. Donation of blood or blood products or participation in another study of an investigational or marketed drug during this study is prohibited. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change in LDL-C and HDL-C from baseline [defined as the arithmetic mean of values from the last run-in period visit, the randomization visit (Week 0, Visit 6)] as measured at the end of the study (EOS) (Week 24, Visit 9) or early termination (ET). |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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) | 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 | 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) | Yes |
| 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 | 4 |
| 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 | 4 |
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