A Clinical Study for the Safety and Efficacy of Intravenous Infusion of NGGT006 in Treatment of Homozygous Familial Hypercholesterolemia With LDLR Mutations
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Incidence of treatment-related adverse events (AE) and serious adverse events (SAE)
研究概览
简要总结
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) 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).
详细描述
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) 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). 4-21 subjects will be enrolled and divided into 4 groups according to the principle of dose escalation, respectively administered intravenous infusion of NGGT006 at dose group 1 (7.5e12vg/kg), dose group 2 (1.5e13vg/kg) , dose group 3 (3e13vg/kg) and dose group 4 (4e13vg/kg). The researcher is allowed to extend 0-9 patients. All subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntarily sign informed consent form;
- •Male or female, 12 ≤ age ≤ 55 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene;
- •AAV8 neutralizing antibodies can be negative or reduced to negative levels through methods such as plasma exchange or IgG-degrading enzymes.
- •Untreated LDL-C ≥10 mmol/L (386mg/ dL) or treated LDL-C ≥7 mmol/L (270mg/ 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, including dietary requirements, study visits, fasting blood draws, and the study treatment regimen.;
- •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.
排除标准
- •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) >3 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) >3 × 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);
- •Platelet test results deemed clinically significantly abnormal by the investigator;
- •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 any excipient of the AAV product (including trehalose) 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.
研究组 & 干预措施
NGGT006
4 doses of NGGT006 will be administered according to the principle of dose escalation
干预措施: NGGT006 (Genetic)
结局指标
主要结局
Incidence of treatment-related adverse events (AE) and serious adverse events (SAE)
时间窗: 52 weeks
Incidence of AE and SAE, as assessed by physical examinations, clinical laboratory parameters and adverse event reporting
Absolute change and percent change in LDL-C
时间窗: 52 weeks
Change in LDL-C concentration from baseline to week 52
次要结局
- Absolute change and percent change in apoB(52 weeks)
- Absolute change and percent change in TC(52 weeks)
- Absolute change and percent change in HDL-C(52 weeks)
- Absolute change and percent change in TG(52 weeks)
- Absolute change and percent change in Lp(a)(52 weeks)