E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with hypercholesterolemia who are intolerant to statins |
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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 | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
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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 determine safety and efficacy of ISIS 301012 in the reduction of total cholesterol, LDL-C, and apoB in hypercholesterolemic subjects intolerant to statins |
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E.2.2 | Secondary objectives of the trial |
To determine percent change from baseline HDL-C, triglyceride, non-HDL-C, VLDL, Lp(a) and LDL-C particle size and concentration |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects, age ≥ 18 years 2. Statin intolerant 3. Satisfy one of the following: • Females: Non-pregnant and non-lactating; surgically sterile, postmenopausal, abstinent, or subject or partner compliant with an acceptable contraceptive regimen for 4 weeks prior to, during, and 6 months after the last study drug dose • Males: Surgically sterile, abstinent or subject or partner is utilizing an acceptable contraceptive method (defined per protocol) during and 6 months after the last study drug dose 4. Stable weight (± 4 kg) for > 6 weeks prior to Screening 5. Fasting LDL-C ≥ 130 mg/dL (3.4 mmol/L) and triglycerides (TG) < 200 mg/dL (2.3 mmol/L) at Screening 6. Given informed consent |
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E.4 | Principal exclusion criteria |
1. Myocardial infarction (MI), percutaneous transluminal coronary intervention, or coronary artery bypass graft surgery within 12 weeks prior to Screening, or cerebrovascular accident within 24 weeks prior to Screening. Subjects with adequately treated stable angina, per Investigator assessment, may be included 2. Congestive heart failure defined by New York Heart Association (NYHA) Classes III or IV 3. Active infection requiring systemic antiviral or antimicrobial therapy 4. Positive test for hepatitis B or C at Screening 5. Uncontrolled hypothyroidism, other uncontrolled endocrine disease or any uncontrolled condition that may predispose to secondary hyperlipidemia 6. Ezetemibe within 2 weeks of Screening 7. Current diagnosis of diabetes or fasting glucose > 125 mg/dL (> 6.9 mmol/L) at Screening 8. Disorders of the hematologic, digestive, or central nervous systems including degenerative disease that would limit study participation 9. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated 10. Serum creatine phosphokinase (CPK) ≥ 3 x upper limit of normal (ULN) 11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > ULN, unless pre-approved 12. History of significant hepatic disease 13. History of significant renal disease, or abnormal creatine or proteinuria (> 1+ on dipstick, confirmed on retest, further confirmed by quantitative total urine protein > 1.0 g/24hr) at Screening 14. Current use of the following medications: • Anti-obesity medications (e.g., orlistat, sibutramine) or has discontinued treatment within 6 weeks prior to Screening • Fibrates within 2 weeks of Screening • Systemic corticosteroids or anabolic agents within 6 weeks of Screening* *Note: Concomitant therapy of oral corticosteroids used as replacement therapy for pituitary/adrenal disease as well as inhaled steroid therapy (e.g., Pulmicort®), or intra-articular, or topical may be acceptable; however, the subject must be on a stable regimen for at least 4 weeks prior to Screening. All exceptions should be discussed with the study Investigator. 15. Current use of the following medications unless the dose has been stable for > 12 weeks prior to Screening and is expected to be stable and the subject agrees to continue this regimen during the treatment period: • cardiovascular medications (e.g., beta-blockers, calcium-channel blockers, ACE inhibitors, nitrates, α-adrenergic blockers, thiazide diuretics, angiotensin II receptor antagonists, GPIIb/IIIa receptor antagonists or other anti-platelet agents) • fish oils • Cholestin™ • over-the-counter therapies known to affect serum lipids (e.g., psyllium, other fiber-based laxatives, phytosterol margarines) 16. Current use of oral anticoagulants (e.g. warfarin), unless the dose has been stable for > 4 weeks prior to Screening and prothrombin time is measured at least once every 2 weeks during the treatment period 17. Current use of hormone replacement therapy unless the dose has been stable for > 12 weeks prior to Screening and is expected to be stable during the treatment period of the study 18. Treatment with another investigational drug, biological agent, or device within 4 weeks of Screening or 5 half-lives of study agent, whichever is longer 19. Recent history of, or current drug or alcohol abuse, or unwilling to limit alcohol consumption for the entire duration of the study, including follow-up: male subjects to a maximum of 3 drinks (30 g) per day, and 12 drinks (120 g) per week; female subjects to a maximum of 2 drinks (20 g) per day, and 8 drinks (80 g) per week 20. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 21. Have any other conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrollment, or could interfere with the subject participating in or completing the study
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E.5 End points |
E.5.1 | Primary end point(s) |
• Total cholesterol, LDL cholesterol, apolipoprotein B • Safety: chemistry including Glucose, BUN, electrolytes, AST, ALT, alkaline phosphatase, bilirubin, CK, creatinine, hematology, and urinalysis.
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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) | 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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | 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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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 | 2 |
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 | 2 |