A Multi-center, Open-label Extension Study to Evaluate the Long-term Safety and Efficacy of HRS-7249 in Patients With Hypertriglyceridemia
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 400
- 试验地点
- 2
- 主要终点
- Heart rate
研究概览
简要总结
This is a Phase II multi-center, open-label extension (OLE) clinical trial of HRS-7249, a GalNAc-conjugated APOC3-targeted siRNA injection, enrolling two cohorts of participants. Cohort 1 includes subjects who completed parent study HRS-7249-201 within 24 weeks; Cohort 2 newly recruited patients with fasting triglyceride (TG) ≥2.3 mmol/L aged 18-79 years. All participants receive subcutaneous HRS-7249 for a 48-week treatment period followed by a 24-week safety follow-up phase, with two dosing regimens. The primary objective is to assess long-term safety and tolerability of repeated HRS-7249 administration. Secondary objectives include evaluating sustained lipid-lowering effects on TG, APOC3 and other lipid profiles, impacts on glycometabolism, incidence of acute pancreatitis and major adverse cardiovascular events (MACE), long-term pharmacokinetic/pharmacodynamic (PK/PD) profiles, and anti-drug antibody (ADA) dynamics. All safety assessments including vital signs, physical examinations, laboratory tests, 12-lead ECG, injection site reactions and adverse events will be collected throughout the study. Lipid parameters, HbA1c, pancreatitis and cardiovascular events will be monitored to characterize the clinical benefit-risk profile of long-term HRS-7249 therapy in hypertriglyceridemia patients. A total of at least 400 subjects will be enrolled nationwide in China.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- Cohort 1 (Roll-over participants from HRS-7249-201)
- •Able to understand trial procedures, voluntarily participate and provide written informed consent;
- •Completed last visit of parent study HRS-7249-201 within 24 weeks prior to screening;
- •Male or female subjects aged ≥18 and <80 years at consent signature. Cohort 2 (Newly enrolled participants)
- •1. Able to understand trial procedures, voluntarily participate and provide written informed consent;
- •Fasting triglyceride ≥2.3 mmol/L at screening;
- •Male or female subjects aged ≥18 and <80 years at consent signature.
排除标准
- •- Cohort 1 Exclusion
- •Permanently discontinued parent study treatment due to treatment-related adverse events (TRAE);
- •Persistent clinically significant adverse events or lab abnormalities unresolved by parent study final visit, judged by investigator to increase risk of continued dosing;
- •Unstable or severe hepatic, renal, cardiovascular, neurological, endocrine, hematologic disorders that render participation unacceptable;
- •Plan to receive major surgery during study period;
- •Planned plasmapheresis during trial;
- •Intend to use weight-loss drugs or undergo weight-altering surgery during trial;
- •Refuse lifestyle intervention or limit daily alcohol intake below 30 g/day;
- •Pregnant or breastfeeding females;
- •Fertile women without contraception within 30 days pre-screening; fertile male/female subjects refusing contraception and gamete donation restrictions through follow-up;
- •Any other conditions judged unsuitable by investigator. Cohort 2 Exclusion
- •1. History of acute pancreatitis within 3 months pre-randomization;
- •Plasmapheresis received or planned within 4 weeks pre-randomization;
- •Malignancy diagnosed within past 5 years (except cured non-melanoma skin cancer/cervical carcinoma in situ);
- •NYHA Class III/IV heart failure at screening/randomization;
- •Acute coronary syndrome, stroke, TIA, major cardiovascular revascularization within past 3 months;
- •Severe symptomatic arrhythmia within 3 months pre-randomization;
- •Severe trauma/major surgery within 6 months or planned major operation during trial;
- •Severe infection within past 3 months;
- •Nephrotic syndrome, severe liver disease, Cushing syndrome interfering with lipid metabolism;
- •Unstable severe multi-organ systemic diseases;
- •Uncontrolled hypertension (SBP≥160 mmHg or DBP≥100 mmHg);
- •Plan to take weight-loss agents or bariatric surgery within 2 months pre-screening;
- •Type 1 DM, newly diagnosed DM within 12 weeks, or HbA1c ≥8.5%;
- •Current/history hyper/hypothyroidism;
- •History of substance/alcohol abuse (daily ethanol >80 g);
- •Major lifestyle modification within past 4 weeks or refusal of alcohol/lifestyle limits;
- •eGFR <60 mL/min/1.73m² by MDRD formula;
- •ALT/AST ≥2×ULN;
- •Total/direct bilirubin ≥1.5×ULN;
- •CK >1.5×ULN;
- •Platelet count <100×10⁹/L or thrombocytopenia history;
- •Positive HIV/HCV-Ab, or HBsAg positive with HBV-DNA ≥1000 copies/mL;
- •Participated in other interventional drug trials within 3 months pre-screening;
- •Pregnant or lactating women;
- •Fertile subjects without compliant contraception;
- •Any other conditions deemed inappropriate by investigator.
研究组 & 干预措施
Arm 1
HRS-7249 Injection; Low dose, subcutaneous administration
干预措施: HRS-7249 Injection (Drug)
Arm 2
HRS-7249 Injection; High dose, subcutaneous administration
干预措施: HRS-7249 Injection (Drug)
结局指标
主要结局
Heart rate
时间窗: 72 weeks；
PR interval
时间窗: 72 weeks
QRS duration
时间窗: 72 weeks
QT interval
时间窗: 72 weeks
Injection site reactions
时间窗: 48 weeks
All adverse events (AEs)
时间窗: 72 weeks
Respiratory rate
时间窗: 72 weeks
Pulse rate
时间窗: 72 weeks
Systolic and diastolic blood pressure
时间窗: 72 weeks
Body temperature
时间窗: 72 weeks
Complete Blood Count
时间窗: 72 weeks
Blood chemistry
时间窗: 72 weeks
High-sensitivity C-reactive protein (hs-CRP)
时间窗: 72 weeks；
QTc interval
时间窗: 72 weeks
Urinalysis
时间窗: 72 weeks
次要结局
- Proportion of patients with TG<1.7 mmol/L(48 weeks)
- Proportion of patients with TG<2.3 mmol/L(48 weeks)
- Proportion of patients with baseline TG≥5.7 mmol/L achieving TG<5.7 mmol/L(48 weeks)
- Percentage change and absolute value change from baseline in TG(72 weeks)
- Percentage change and absolute value change from baseline in APOC3(72 weeks)
- Percentage change and absolute value change from baseline in HDL-C(72 weeks)
- Percentage change and absolute value change from baseline in TC(72 weeks)
- Percentage change and absolute value change from baseline in LDL-C(72 weeks)
- Percentage change and absolute value change from baseline in sdLDL-C(72 weeks)
- Percentage change and absolute value change from baseline in non-HDL-C(72 weeks)
- Percentage change and absolute value change from baseline in ApoB(72 weeks)
- Percentage change and absolute value change from baseline in ApoA1(72 weeks)
- Percentage change and absolute value change from baseline in Lp(a)(72 weeks)
- Percentage change and absolute value change from baseline in VLDL-C(72 weeks)
- Percentage change and absolute value change from baseline in RC(72 weeks)
- Percentage change and absolute value change from baseline in HbA1c(72 weeks)
- Incidence rate of acute pancreatitis(72 weeks)
- Incidence rate of major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization)(72 weeks)
- Plasma Concentration of long-term HRS-7249 treatment(72 weeks)
- Dynamics of anti-drug antibody (ADA) following long-term HRS-7249 treatment(72 weeks)