This is a study to investigate if gene therapy is safe in people with homozygous familial hypercholesterolemia (also called HoFH).

Phase 1

• Conditions: Adults with homozygous familial hypercholesterolemia; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2016-001446-25-IT
• Lead Sponsor: REGENXBIO Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-05-06
• Last Update Posted: 10 May 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

1. Male or female = 18 years of age.
2. Untreated and/or treated LDL-C levels and clinical presentation consistent with the diagnosis of homozygous FH
3. Molecularly defined LDLR mutations at both LDLR alleles.
4. Concurrent allowed lipid lowering medication must be stable for = 4 weeks before the baseline visit and must remain stable until 18 weeks after vector administration. (or 4 weeks post steroid termination). These include but are not limited to: statins, ezetimibe, bile acid sequestrants, PCSK9 inhibitors, and LDL and/or plasma apheresis. Subjects on other lipid- lowering medications are eligible for the study but must wash out of these medications for the pre-specified time period.
5. Females of childbearing potential must have a negative pregnancy test at screening and baseline visits and be willing to have additional pregnancy tests during the study.
6. Sexually active subjects (both female and male) must be willing to use a medically accepted method of contraception from screening visit until 6 months after vector administration
7. A baseline serum AAV8 NAb titer = 1:10.
8. Subjects must be able to comprehend and be willing to provide a signed institutional review board/ethics committee (IRB/EC) approved Informed Consent Form. (ICF).
9. Subjects must be willing to comply with all study-related procedures and be available for the duration of the study.

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

1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period:
niacin > 250 mg/day: within 6 weeks of baseline
fibrates: within 4 weeks of baseline
lomitapide: within 8 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. Uncontrolled diabetes defined as HbA1c > 8.5% or an average fasting glucose = 160 mg/dl..
6. Known hypersensitivity to prednisone.
7. History of cirrhosis or chronic liver disease based on documented histological evaluation or non- invasive imaging or testing.
8. 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
9. Abnormal liver function tests (LFTs) at screening (AST or ALT > 2 x upper limit of normal (ULN) and/or Total Bilirubin of >1.5x ULN unless patient has unconjugated hyperbilirubinemia due to Gilbert’s syndrome).
10. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA
11. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA.
12. History of chronic alcohol abuse within 52 weeks of the screening visit.
13. Certain prohibited medications known to be potentially hepatotoxic, especially those that can induce microvesicular or macrovesicular steatosis. These include but are not limited to: Accutane (isotretinoin), amiodarone, HAART medications, heavy acetaminophen use (2 g/day more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen, valproate.
14. Active tuberculosis, systemic fungal disease, or other chronic infection.
15. History of immunodeficiency diseases, including a positive HIV test result.
16. Chronic renal insufficiency defined as estimated GFR < 30 mL/min/1.73m2.
17. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer.
18. Previous organ transplantation.
19. Administration of an investigational drug within 12 weeks or 5 half-lives of the drug (whichever is longer) prior to the screening visit and until 52 weeks after receiving AAV8.TBG.hLDLR. Subjects are not prohibited from receiving investigational drugs after 52 weeks.
20. Any major surgical procedure occurring less than 3 months prior to the screening visit, or any planned future surgical procedure within 3 months of baseline.
21. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject’s safety or successful participation in the study.
22. Any other medical condition or finding that would make it not in the subject’s best interest to participate in the stu

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective will be to determine the safety of AAV8.TBG.hLDLR administration in this patient population.;Secondary Objective: The key secondary objective is to assess the efficacy of LDL-C reduction achieved with AAV8.TBG.hLDLR administration.;Primary end point(s): Safety assessments up to 24 weeks post vector administration;Timepoint(s) of evaluation of this end point: Safety assessments up to the primary endpoint: <br>Days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84<br>Week 14, 16, 18, 20, 22, 24

Secondary Outcome Measures

Name	Time	Method
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 Week 12 (Cohort 1 only) or Week 18.<br>- To assess changes in other lipid parameters at Week 12 (Cohort 1 only) or Week 18 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).<br>- To assess safety up to 104 weeks.<br>- To assess vector shedding in plasma and urine.;Timepoint(s) of evaluation of this end point: Safety endpoints after primary endpoint:<br>Week 30, 36, 52, 78, 104<br><br>Efficacy timepoints: <br>Day 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84<br>Week 14, 16, 18, 20, 22, 24, 30, 36, 52, 78, 104