Reduction of low density lipoprotein C (LDL-C) in Homozygous Familial Hypercholesterolemia (HoFH) MedDRA version: 9.1 Level: LLT Classification code 10057080 Term: Homozygous familial hypercholesterolemia
Conditions
Interventions
Product Name: ISIS 301012
Product Code: ISIS 301012
Pharmaceutical Form: Solution for injection
Current Sponsor code: ISIS 301012
Other
Sponsors
Genzyme Europe B.V.
Eligibility
Sex/Gender
All
Inclusion criteria
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) =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 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, a-adrenergic blockers, thiazide diuretics, or angiotensin II receptor antagonists) b. fish oils c. Cholestin™ (also known as red yeast rice, or mo
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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; Secondary Objective: 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 ; 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 | — |
Countries
United Kingdom
Contacts
Public ContactGenzyme Europe B.V.
Genzyme Europe B.V.
Outcome results
None listed