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Gene Therapy for Homozygous Familial Hypercholesterolemia

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ClinicalTrials.gov Identifier: NCT06125847
Recruitment Status : Not yet recruiting
First Posted : November 9, 2023
Last Update Posted : November 9, 2023
Sponsor:
Information provided by (Responsible Party):
First Affiliated Hospital Xi'an Jiaotong University

Study Description
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Brief Summary:
This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of an intravenous infusion of NGGT006 in homozygous familial hypercholesterolemia (HoFH) patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) serotype 8 vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C).

Condition or disease Intervention/treatment Phase
Homozygous Familial Hypercholesterolemia Genetic: NGGT006 Early Phase 1

Detailed Description:
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism, characterized by extreme elevations in low-density lipoprotein cholesterol (LDL-C) and leading to early onset of severe coronary artery disease. This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of a single intravenous infusion of NGGT006 in HoFH patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) serotype 8 vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C). 3-12 subjects will be enrolled and divided into 3 groups according to the principle of dose escalation, respectively administered intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg). All subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Clinical Study for the Safety and Efficacy of Intravenous Infusion of NGGT006 in Treatment of Homozygous Familial Hypercholesterolemia With LDLR Mutations
Estimated Study Start Date : November 2023
Estimated Primary Completion Date : November 2024
Estimated Study Completion Date : November 2028

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: NGGT006
3 doses of NGGT006 will be administered according to the principle of dose escalation
 Genetic: NGGT006
Single intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg).


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of treatment-related adverse events (AE) and serious adverse events (SAE) [ Time Frame: 52 weeks ]
    Incidence of AE and SAE, as assessed by physical examinations, clinical laboratory parameters and adverse event reporting

  2. Absolute change and percent change in LDL-C [ Time Frame: 52 weeks ]
    Change in LDL-C concentration from baseline to week 52


Secondary Outcome Measures :
  1. Absolute change and percent change in lipid parameters [ Time Frame: 52 weeks ]
    Change in lipid concentrations from baseline to week 52. Lipid parameters include: non-high density lipoprotein cholesterol (non-HDL-C); apolipoprotein B (apoB); total cholesterol (TC); HDL-C; triglycerides (TG); very low-density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); and apolipoprotein A-I (apo A-I)


Eligibility Criteria
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Ages Eligible for Study:   12 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Voluntarily sign informed consent form;
  • Male or female, 12 ≤ age ≤ 35 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene;
  • Serum anti-AAV8 conjugate antibodies titer ≤ 1:80 and anti-AAV8 neutralizing antibodies titer ≤ 1:5;
  • Untreated LDL-C >10 mmol/L (180mg/ dL) or treated LDL-C ≥7 mmol/L (126 mg/ dL) together with cutaneous or tendon xanthoma before age 18 years;
  • Had been on stable medication for ≥30 days if receiving lipid-lowering therapy (or ≥60 days if receiving alirocumab or evolocumab) prior to screening and not scheduled for addition of new drugs or dose adjustments during the study;
  • Agreed to follow a low-fat diet and comply with all study procedures;
  • Agreed to maintain a similar exercise volume and intensity to baseline during the study period;
  • Agreed to maintain good lifestyle habits;
  • No history of alcohol abuse or alcohol dependence (diagnosed as F10 in ICD-10 code);
  • No sexual activity for 14 days prior to administration and negative serum pregnancy test in female participants;
  • Participants of childbearing potential agreed to use highly effective contraception for at least 365 days from administration of NGGT006;
  • No plan of stent implantation within 3 months.

Exclusion Criteria:

  • Positive for hepatitis B surface antigen, hepatitis C, human immunodeficiency virus (HIV) or syphilis test;
  • Clinically significant abnormalities in liver function test: alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) >2 × ULN;
  • Baseline blood pressure >160/100 mmHg (1 repeat measurement is allowed);
  • Uncontrolled myocardial infarction or heart failure, or had surgery plan within 1 year;
  • Diabetes diagnosed within 3 months or with poor control (HbA1c >9%);
  • Acute or chronic kidney failure;
  • Hemoglobin (Hb) < 120g/L (male), Hb < 110 (female);
  • Abnormal platelet counts or morphology;
  • History or laboratory tests suggestive of thrombosis;
  • Had contraindications to glucocorticoid (e.g., epilepsy, severe schizophrenia, active peptic ulcer);
  • Life expectancy less than 1 year;
  • With malignant tumors;
  • Liver fibrosis or liver cancer;
  • Previous gene therapy treatment;
  • Hypersensitivity to AAV or cortisone or immunosuppressants (sirolimus, rituximab, tacrolimus);
  • Participation in any other clinical trial within 3 months;
  • History of stent implantation within 1 month or myocardial infarction within 3 months;
  • Breastfeeding females;
  • Any other condition that may not be appropriate for the study in the opinion of the Investigator.
Contacts and Locations
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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): NCT06125847


Contacts
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Contact: Tao Zheng, M.D. 15229218127 ext 0086- zhengtao900305@163.com
Contact: Ge Gao, M.M. 18229068097 ext 0086- gaoge1030@163.com

Locations
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China, Shaanxi
First Affiliated Hospital of Xian Jiaotong University
Xi'an, Shaanxi, China, 710061
Contact: Tao Zheng, MD    15229218127 ext 0086-    zhengtao900305@163.com   
Contact: Yue Wu, MD    18092826334 ext 0086-    yue.wu@xjtu.edu.cn   
Sponsors and Collaborators
First Affiliated Hospital Xi'an Jiaotong University
Investigators
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Study Chair: Zuyi Yuan, M.D. First Affiliated Hospital of Xian Jiaotong University
More Information
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Responsible Party: First Affiliated Hospital Xi'an Jiaotong University
ClinicalTrials.gov Identifier: NCT06125847    
Other Study ID Numbers: XJYFY-IIT-CX2023001
First Posted: November 9, 2023    Key Record Dates
Last Update Posted: November 9, 2023
Last Verified: November 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by First Affiliated Hospital Xi'an Jiaotong University:
Homozygous familial hypercholesterolemia
Gene therapy
Low-density lipoprotein cholesterol
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type II
Homozygous Familial Hypercholesterolemia
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
 Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias