Adults with homozygous familial hypercholesterolemia
Conditions
Interventions
Product Name: AAV8.TBG.hLDLR
Product Code: AAV8.TBG.hLDLR
Pharmaceutical Form: Infusion
Sponsors
University of Pennsylvania
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age: 18 years or older; 2. Molecularly defined LDLR mutations in both LDLR alleles and clinical presentation consistent with HoFH; 3. No cardiovascular event or cardiovascular intervention within 12 weeks of enrollment; 4. A baseline serum AAV8 neutralizing antibody titer = 1:10. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 12 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period: niacin > 250 mg/day: within 4 weeks of baseline fibrates: within 4 weeks of baseline Lomitapide: within 6 weeks of baseline Mipomersen: within 24 weeks of baseline 2. Heart failure defined by the NYHA classification as functional Class III with history of hospitalization(s) within 12 weeks of the baseline visit or functional Class IV. 3. History within 12 weeks of the baseline visit of a myocardial infarction (MI), unstable angina leading to hospitalization, coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI), uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention. 4. Uncontrolled hypertension defined as: systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg. 5. History of cirrhosis or chronic liver disease based on documented histological evaluation or non- invasive imaging or testing. 6. Documented diagnosis of any of the following liver diseases: Nonalcoholic steatohepatitis (biopsy-proven) Alcoholic liver disease Autoimmune hepatitis Liver cancer Primary biliary cirrhosis Primary sclerosing cholangitis Wilson’s disease Hemochromatosis a1 anti-trypsin deficiency 7. Abnormal LFTs at screening (AST or ALT >2x upper limit of normal (ULN) and/or Total Bilirubin of >1.5x ULN unless patient has unconjugated hyperbilirubinemia due to Gilbert’s syndrome). 8. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA 9. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA. 10. History of alcohol abuse within 52 weeks. 11. Certain prohibited medications known to be potentially hepatotoxic, especially those that can induce microvesicular or macrovesicular steatosis. These include but are not limited to: acutane, amiodarone, HAART medications, heavy acetaminophen use (2g/day more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen, valproate. 12. Current use of systemic corticosteroids or active tuberculosis, systemic fungal disease, or other chronic infection. 13. History of immunodeficiency diseases, including a positive HIV test result. 14. Chronic renal insufficiency defined as estimated GFR 1:10. 21. Any other medical condition or finding that would make it not in the subject’s best interest to participate in the study 22. Study staff member or any direct family member.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective will be to determine the safety of AAV8.TBG.hLDLR administration in this patient population.;Secondary Objective: The secondary objective is to assess the efficacy of LDL-C reduction achieved with AAV8.TBG.hLDLR administration.;Primary end point(s): Safety assessments;Timepoint(s) of evaluation of this end point: Safety visits take place at 24, 48 and 72 hours. Additional full safety visits will occur on days 7, 14, 28, and 56. Day 21, 35, 42,49,63,70,77 (± 3 days). Week 12 (±1 week). Weeks 24 and 36 (± 2 weeks) Week 52 (±2 weeks) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - To assess the LDL-C reduction achieved with AAV8.TBG.hLDLR administration as defined by percent change in LDL-C at 12 weeks compared to baseline. - To assess changes in other lipid parameters at 12 weeks compared to baseline values, specifically percent change in total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), HDL-C, fasting triglycerides (TG), very low density lipoprotein cholesterol (VLDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). - To assess long term (up to 260 weeks) safety and efficacy after vector administration;Timepoint(s) of evaluation of this end point: Safety Timepoints : Weeks 72, 96, 120, 144, 168, 192, 216, 260 (±4 weeks) Efficacy Timepoints: Day 1, 2 3,4,7,14,28,56 (± 3 days) Day 21, 35, 42,49,63,70,77 (± 3 days) Week 12 (±1 week) Weeks 24 and 36 (± 2 weeks) Week 52 (±2 weeks) Weeks 96, 144, 192, 260 (±4 weeks) | — |
Countries
Canada, Italy, Netherlands, United States
Contacts
Public ContactMaria Caturla, Regulatory Affairs
University of Pennsylvania
Outcome results
None listed