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A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

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ClinicalTrials.gov Identifier: NCT02651675
Recruitment Status : Recruiting
First Posted : January 11, 2016
Last Update Posted : September 23, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Regenxbio Inc.

Brief Summary:
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH).

Condition or disease Intervention/treatment Phase
Homozygous Familial Hypercholesterolemia (HoFH) Biological: AAV directed hLDLR gene therapy Phase 1 Phase 2

Detailed Description:
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder characterized by absent or severely reduced capacity to catabolize circulating LDL particles by the hepatic LDL receptor. As a consequence, HoFH subjects present abnormal total plasma cholesterol (LDL-C) levels, resulting in severe atherosclerosis often leading to early onset of cardiovascular disease. Early initiation of aggressive treatment for these patients is therefore essential. Unfortunately, despite existing therapies, treated LDL-C levels could remain well above acceptable levels. Thus, the functional replacement of the defective LDLR via AAV-based liver-directed gene therapy may be a viable approach to treat this disease and improve response to current lipid-lowering treatments. This first-in-human study is intended to evaluate the safety of this gene therapy investigational product and assess preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker for human LDLR transgene expression. Subjects may be asked to participate in an optional kinetics study to assess the metabolic mechanism by which LDL-C is reduced.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
Actual Study Start Date : March 2016
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : September 2023


Arm Intervention/treatment
Experimental: AAV directed hLDLR gene therapy
Single intravenous (IV) dose of human Low Density Lipoprotein Receptor (LDLR) Gene Therapy
Biological: AAV directed hLDLR gene therapy
A novel adeno-associated viral (AAV) vector with human low-density lipoprotein receptor (hLDLR) gene




Primary Outcome Measures :
  1. Number of participants experiencing investigational product-related adverse events [ Time Frame: Up to 24 weeks ]
    Physical examinations; Clinical laboratory parameters; and adverse event reporting


Secondary Outcome Measures :
  1. Percent change in in LDL-C [ Time Frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline. ]
    Percent change in LDL-C compared to baseline

  2. Percent change in lipid parameters compared to baseline values [ Time Frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline. ]
    total cholesterol (TC); non-high density lipoprotein cholesterol (non-HDL-C); HDL-C; fasting triglycerides (TG); overflow density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); apolipoprotein B (apoB) and apolipoprotein A-I (apo A-I)

  3. Number of participants experiencing investigational product-related adverse events [ Time Frame: up to 104 weeks ]
    Physical examinations; Clinical laboratory parameters; and adverse event reporting

  4. Amount of vector shedding [ Time Frame: up to 104 weeks ]
    Amount of virus secreted in urine and plasma



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female ≥ 18 years of age.
  • Untreated and/or treated LDL-C levels and clinical presentation consistent with the diagnosis of homozygous FH
  • Molecularly defined LDLR mutations at both LDLR alleles.
  • A baseline serum AAV8 NAb titer ≤ 1:10.

Exclusion Criteria

  • Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period:

    1. niacin > 250 mg/day: within 6 weeks of baseline
    2. fibrates: within 4 weeks of baseline
    3. lomitapide: within 8 weeks of baseline
    4. mipomersen: within 24 weeks of baseline
  • History of cirrhosis or chronic liver disease based on documented histological evaluation or non-invasive imaging or testing.
  • Abnormal liver function tests (LFTs) at screening (AST or ALT > 2 × upper limit of normal (ULN) and/or Total Bilirubin of > 1.5 × ULN

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02651675


Contacts
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Contact: Patient Advocacy 1-800-446-3401 HoFH@Regenxbio.com

Locations
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United States, Florida
Boca Raton location Recruiting
Boca Raton, Florida, United States, 33434
United States, Kansas
Kansas City Location Recruiting
Kansas City, Kansas, United States, 66160
United States, Oregon
Portland location Recruiting
Portland, Oregon, United States, 97239
United States, Pennsylvania
Philadelphia Location Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Nashville location Recruiting
Nashville, Tennessee, United States, 37232
Canada, Quebec
Chicoutimi location Active, not recruiting
Chicoutimi, Quebec, Canada, G7H7K9
Montreal location Recruiting
Montreal, Quebec, Canada, H1T1C8
Montreal location Recruiting
Montreal, Quebec, Canada, H3A1A1
Quebec City Location Withdrawn
Quebec City, Quebec, Canada, G1V 4W2
Italy
Palermo location Recruiting
Palermo, PA, Italy, 90127
Rome location Recruiting
Roma, RM, Italy, 00161
Netherlands
Rotterdam location Recruiting
Rotterdam, Netherlands, 3015 CE
Sponsors and Collaborators
Regenxbio Inc.
National Heart, Lung, and Blood Institute (NHLBI)

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Responsible Party: Regenxbio Inc.
ClinicalTrials.gov Identifier: NCT02651675     History of Changes
Other Study ID Numbers: FHGT002
P01HL059407 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2016    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Regenxbio Inc.:
LDL Receptors
Gene therapy
Metabolic Diseases
Rare diseases
Genetic Diseases
Atherosclerosis
cardiovascular disease
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type II
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias