E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Reduction of low density lipoprotein C (LDL-C) in Homozygous Familial Hypercholesterolemia (HoFH) |
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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 | 10057080 |
E.1.2 | Term | Homozygous familial 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 evaluate the incremental LDL-C lowering efficacy of ISIS 301012 at Week 28 in homozygous familial hypercholesterolemia (HoFH) subjects treated for 26 weeks with ISIS 301012 added on to stable lipid-lowering therapy |
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E.2.2 | Secondary objectives of the trial |
To evaluate in HoFH subjects treated for 26 weeks with ISIS 301012 added on to stable lipid-lowering therapy: 1) The incremental apo B lowering efficacy of ISIS 301012 2) The incremental total cholesterol lowering efficacy of ISIS 301012 3) The incremental non-HDL-C lowering efficacy of ISIS 301012 4) The incremental effects of ISIS 301012 on TG, VLDL-C, HDL-C, apo A-1, Lp(a), lipoprotein subclasses, and hsCRP |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects age ≥ 12 years, > Tanner Stage 2 2. Body weight ≥ 40 kg 3. Diagnosis of HoFH determined by at least one of the criteria below*: a. History of genetic testing confirming two mutated alleles at the LDL receptor gene locus, OR b, Documented history of untreated LDL-C greater than 500 mg/dL (13 mmol/L) AND at least one of the criteria below: i. Tendinous and/or cutaneous xanthoma prior to age 10 years ii. Documentation of elevated LDL-C > 190 mg/dL (4.9 mmol/L) prior to lipid-lowering therapy consistent with HeFH in both parents. In case a parent is not available, a history of coronary artery disease in a first degree male relative of the parent younger than 55 years or first degree female relative of the parent younger than 60 years is acceptable *Note: Inclusion of subjects who meet the clinical criteria for HoFH, but have a genetic diagnosis other than HoFH must be discussed with the Key Sponsor Contact prior to enrollment. 4. Satisfy one of the following: a. Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal, 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 b. Males: Surgically sterile, abstinent or subject or partner is utilizing an acceptable contraceptive method during and 6 months after the last study drug dose Please refer to Restriction on Lifestyle for acceptable contraceptive methods 5. For subjects on allowed lipid-lowering therapies (i.e., statins, cholesterol absorption inhibitors, bile-acid sequestrants, and niacin), the dose and regimen of the therapies must be stable for at least 12 weeks prior to Screening and the subject must be expected to remain on the same dose and regimen throughout the study 6. On stable low-fat diet (e.g., NCEP-ATP III diet, Appendix 2) beginning at least 8 weeks prior to the first dose of study drug and willing to maintain the diet throughout the study 7. Stable weight (± 4 kg) for > 6 weeks prior to Screening for adult subjects (≥ 18 years) 8. Fasting LDL-C ≥ 130 mg/dL (3.4 mmol/L) and triglycerides (TG) < 350 mg/dL (4.0 mmol/L) at Screening 9. Given informed consent, or, in the case of minors, the subject’s parent/legal guardian must be capable and willing of giving informed consent, and, if appropriate for the subject’s age, the subject must be capable of giving assent/consent for study participation |
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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 antiviral or antimicrobial therapy 4. Positive test for HIV or hepatitis B or C at Screening 5. Uncontrolled hypothyroidism, other uncontrolled endocrine disease or any uncontrolled condition that may predispose to secondary hyperlipidemia 6. Diabetes mellitus that is inadequately controlled (HbA1c > 8.0%), or newly diagnosed (within 12 weeks), or a change in antidiabetic pharmacotherapy (i.e., change in dosage [with the exception of ± 10 units of insulin] or the addition of new medication) within 8 weeks of Screening 7. Disorders of the hematologic, digestive, or central nervous systems including degenerative disease that would limit study evaluation or participation 8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated 9. Serum creatine phosphokinase (CPK) ≥ 3 x upper limit of normal (ULN) 10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 1.5 x ULN, unless pre-approved by Key Sponsor Contact 11. History of significant hepatic disease including liver cirrhosis, or documented liver steatosis prior to Screening 12. History of significant renal disease, or abnormal creatinine or proteinuria at Screening, unless pre-approved by Key Sponsor Contact 13. Current use of the following medications: a. Anti-obesity medications (e.g., orlistat, sibutramine), or has discontinued treatment < 12 weeks prior to Screening b. Fibrates within 8 weeks of Screening c. 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 Key Sponsor Contact. 14. 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 for the duration of the study: a. cardiovascular medications (e.g., beta-blockers, calcium-channel blockers, ACE inhibitors, nitrates, α-adrenergic blockers, thiazide diuretics, or angiotensin II receptor antagonists) b. fish oils c. Cholestin™ (also known as red yeast rice, or monascus purpureus extract) d. over-the-counter therapies known to affect serum lipids (e.g., psyllium, other fiber-based laxatives, phytosterol margarines) 15. Current use of oral anticoagulants (e.g. warfarin), unless the dose has been stable for > 4 weeks prior to Screening and regular clinical laboratory monitoring is performed 16. Current use of cyclical hormones unless the dose has been stable for > 12 weeks prior to Screening and is expected to be stable for the duration of the study 17. Treatment with another investigational drug, biological agent, or device within 4 weeks of Screening or five half-lives of study agent, whichever is longer 18. Currently receiving apheresis treatments or last apheresis treatment was within 8 weeks of Screening 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 two drinks (20 g) per day, and 8 drinks (80 g) per week; female subjects to a maximum of one drink (10 g) per day, and four drinks (40 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) |
Efficacy: Percent reduction in LDL-C from baseline at Week 28 (or LOCF)
Safety: All AEs and SAEs Platelets, liver transaminases, renal function tests Other laboratory results 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 | 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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | 2 |
E.8.9.1 | In the Member State concerned days | |
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 | 7 |