E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who are Not on Apheresis |
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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 | LLT |
E.1.2 | Classification code | 10020603 |
E.1.2 | Term | Hypercholesterolaemia |
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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 compare the safety and efficacy of 26 weekly, subcutaneous injections of mipomersen (200 mg) against placebo in treating severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years 2. Fasting TG < 350 mg/dL (4.0 mmol/L) at Screening 3. Fasting LDL-C ≥ 200 mg/dL (5.1 mmol/L) at Screening and the presence of at least 1 of the following criteria: a) Myocardial infarction (MI) b) Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) c) CAD documented by angiography or any other accepted imaging technique d) Positive exercise test (≥ 1 mm ST-depression at maximal exercise or test terminated because of angina) or a perfusion defect, e.g., thallium or single photon emission computed tomography (SPECT) e) Other clinical atherosclerotic diseases: PAD, symptomatic carotid artery disease, AAA f) Or, if a) through e) are not met, fasting LDL-C ≥ 300 mg/dL (7.8 mmol/L) 4. On a stable, maximally tolerated lipid-lowering regimen and expected to remain on it through Week 28 (must satisfy all criteria): a) A statin at a maximally tolerated dose per Investigator judgment, for at least 8 weeks prior to Screening b) A stable low-fat diet (e.g., NCEP-ATP III therapeutic lowering cholesterol [TLC] or equivalent) beginning at least 12 weeks prior to the first dose of study drug c) A medication from an additional class of hypolipidemic agents, per Investigator’s judgment (e.g., bile acid sequestrants, niacin/nicotinic acid, fibrates) for at least 8 weeks prior to Screening 5. Body mass index (BMI) ≤ 40 kg/m2 with weight stable (± 4 kg) for > 6 weeks prior to Screening per patient report. 6. Satisfy 1 of the following (see Section 9.2.6.8): a) Females: Non-pregnant and non-lactating; surgically sterile, postmenopausal, or patient or partner compliant with an acceptable and highly effective contraceptive regimen for 4 weeks prior to Screening, during the treatment phase, and 6 months after the last study drug dose b) Males: Surgically sterile or patient or partner is utilizing an acceptable and highly effective contraceptive method during the treatment phase and 6 months after the last study drug dose 7. Given informed consent |
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E.4 | Principal exclusion criteria |
1. Any of the following diagnoses, conditions, or prior treatments: a) MI, PCI, CABG, cerebrovascular accident (CVA), unstable angina or acute coronary syndrome within 24 weeks of Screening b) Presence of a clinically significant arrhythmia deemed to be uncontrolled at any time < 12 months from screening or if medication for an arrhythmia has been started or dose has changed < 12 months from screening. Patients with implantable pacemakers or automatic implantable cardioverter defibrillators (AICDs) may be considered if deemed to be stable for the previous 12 months by the Investigator c) Type 1 diabetes mellitus d) New York Heart Association (NYHA) functional classification III or IV heart failure e) Hypertension, systolic blood pressure (BP) ≥ 160 mmHg, or diastolic BP ≥ 95 mmHg at Screening (despite antihypertensive medication/therapy) f) Active infection requiring systemic antimicrobial therapy unless treatment is expected to be completed prior to Day 1 g) Positive test for human immunodeficiency virus (HIV) or hepatitis B or C at Screening h) Any uncontrolled condition that may predispose the patient to secondary hyperlipidemia such as uncontrolled hypothyroidism. i) Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated j) Clinically significant hepatic or renal disease or Gilbert’s syndrome k) Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase 2. The following laboratory values at Screening: a) Serum creatine phosphokinase (CPK) ≥ 3 x upper limit of normal (ULN) b) Alanine aminotransferase (ALT) levels > 1.5 x ULN c) Serum creatinine > 0.1 mg/dL (> 8.8 µmol/L) above ULN for women, or > 0.2 mg/dL (> 17.7 µmol/L) above ULN for men d) Proteinuria (> 1+ on dipstick, confirmed on retest, with further confirmation by quantitative total urine protein > 1.0 g/24 hr) e) Total Bilirubin > 1.0 x ULN f) Glycosylated hemoglobin A (HbA1C) > 8.0% 3. Use of the following medications within 12 weeks of Screening: a) Medications that may affect lipids except those allowed per the protocol, including but not limited to Cholestin™ (also known as red yeast rice, or monascus purpureus extract) b) Chronic systemic corticosteroids or anabolic agents except for replacement therapy c) Oral contraceptives or contraceptive patch 4. Use of the following medications unless a stable dose regimen was used for at least 12 weeks prior to Screening and the dose and regimen are expected to remain stable until Week 28: a) Oral anticoagulants (e.g., warfarin) b) Hormone replacement therapy c) Diabetes medications including but not limited to sulfonylureas, metformin and glitazones, with the exception of changes of ± 10 units of insulin. d) Antiviral therapy for herpes simplex virus (HSV) e) Anti-obesity medications 5. Treatment with another investigational drug, biological agent, or device within 4 weeks of Screening or 5 half-lives of study agent, whichever is longer 6. Recent history of, or current, drug or alcohol abuse, or unwillingness to limit alcohol consumption for the entire duration of the study, including follow-up 7. Any disorders that would limit study participation or unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 8. Have any other medical conditions that, in the opinion of the Investigator, would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change in LDL-C from Baseline to Week 28/Early Termination (ET represents the observation closest to 2 weeks after last dose among patients who terminate study medication dosing early). |
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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 | 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 | No |
E.6.10 | Pharmacogenetic | No |
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) | 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) | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 | 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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |