Evaluation of Pharmacokinetics, Pharmacodynamics, and Safety of JL18008 Injection in Healthy Adult Subjects / HIV Immunological Non-Responders: A Randomized, Double-Blind, Placebo-Controlled Phase I/II Clinical Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Number of Participants with Treatment-Emergent Adverse Events (TEAEs) as Assessed by DAIDS v2.1
研究概览
简要总结
The Phase Ib clinical trial is an add-on study based on combination antiretroviral therapy (cART). It adopts a multicenter, randomized, double-blind, placebo-controlled, multiple-dose design to evaluate the safety and efficacy of multiple intramuscular injections of JL18008 added to cART in HIV immunological non-responders (INRs).
Based on the Phase Ia clinical data, three dose groups are planned for the Phase Ib trial: 20, 40, and 70 μg/kg of JL18008. Each group is planned to enroll 10 subjects (8 receiving active drug and 2 receiving placebo). All subjects must maintain their original cART regimen unchanged. Subjects in the active treatment groups will receive JL18008 injection in addition to cART, while those in the control group will receive placebo (JL18008 injection buffer) in addition to cART. The dosing regimen is tentatively once weekly (QW) for 4 consecutive weeks, which constitutes one treatment cycle, followed by an observation/follow-up period. The study drug will be administered by intramuscular injection.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 to 65 years (inclusive), male or female.
- •Body mass index (BMI) 18.0 to 32.0 kg/m² (inclusive); body weight ≥50.0 kg for males and ≥45.0 kg for females.
- •Receiving combination antiretroviral therapy (cART) for at least 48 months, with a stable antiretroviral regimen for at least 3 months prior to enrollment.
- •Maintained HIV-1 RNA below 50 copies/mL for at least 36 months (the earliest test date more than 36 months before enrollment), including transient viral blips (single HIV-1 RNA measurement between 50 and 200 copies/mL after excluding laboratory error). At least two HIV-1 RNA results <50 copies/mL must be available (one may be from screening).
- •Immunological non-responder criteria: CD4⁺ T cell count ≤350 cells/μL within 1 year before screening. At least three CD4⁺ T cell counts ≤350 cells/μL within 4 years before enrollment, with intervals of ≥3 months between tests (the third may be from screening).
- •Willing to use effective non-pharmacological contraception with partner from screening until 3 months after study completion, and no plan for sperm/egg donation during this period.
- •Able to understand and provide written informed consent, and willing to comply with all protocol-specified visits and procedures.
排除标准
- •Known allergy to the study drug or any of its excipients.
- •Receipt of immunosuppressants, immunomodulators, or systemic cytotoxic therapy within 3 months before screening.
- •Receipt of hormone therapy within 1 month before screening, except for daily doses ≤10 mg prednisone or equivalent.
- •History of severe autoimmune disease requiring systemic treatment or hospitalization, or any active autoimmune disease requiring treatment (including multiple sclerosis).
- •History of systemic infection (viral, bacterial, parasitic, or fungal) requiring systemic treatment and/or hospitalization, or other opportunistic infection, within 30 days before screening.
- •Active tuberculosis lesion within 30 days before screening.
- •Blood disorders associated with hypersplenism (e.g., thalassemia, hereditary spherocytosis, Gaucher's disease, autoimmune hemolytic anemia) or history of splenectomy.
- •Chronic diarrhea.
- •Severe cardiovascular disease within 6 months before screening, including myocardial infarction, unstable angina, congestive heart failure (NYHA class ≥II), or arrhythmia requiring medication.
- •Uncontrolled hypertension, defined as resting systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg on at least two repeated measurements on different days despite antihypertensive treatment.
- •Positive hepatitis B surface antigen (HBsAg), or positive hepatitis C virus antibody (HCV-Ab) with detectable HCV-RNA, or active syphilis.
- •Any of the following laboratory abnormalities at screening: hemoglobin <90 g/L; neutrophil count <1.5×10⁹/L; platelet count <100×10⁹/L; serum creatinine >1.5× upper limit of normal (ULN); alanine aminotransferase >2.5×ULN; aspartate aminotransferase >2.5×ULN; alkaline phosphatase >2.5×ULN; total bilirubin >1.5×ULN; international normalized ratio >1.5; activated partial thromboplastin time >1.5×ULN.
- •Diagnosis of cancer within the screening period.
- •Severe neurological or psychiatric disease, or history of seizures.
- •History of drug abuse within 3 months before screening, or positive urine drug screen (including morphine, methamphetamine, ketamine, MDMA, THC, cocaine), or history of alcohol abuse.
- •Participation in another clinical trial with receipt of investigational drug within 3 months before screening.
- •Vaccination within 6 weeks before screening, or plan to receive any vaccination within 1 year after enrollment.
- •Pregnancy, positive pregnancy test, or breastfeeding.
- •Any other condition that, in the opinion of the investigator, makes the subject unsuitable for participation in this clinical study.
研究组 & 干预措施
Placebo (for 70 μg/kg Group)
Participants receive placebo (JL18008 injection buffer) intramuscularly once weekly for 4 weeks, in addition to their stable cART regimen.
干预措施: Placebo (for 70 μg/kg Group) (Drug)
JL18008 20 μg/kg
Participants receive JL18008 20 μg/kg intramuscularly once weekly for 4 weeks, in addition to their stable cART regimen.
干预措施: JL18008 20 μg/kg (Drug)
Placebo (for 20 μg/kg Group)
Participants receive placebo (JL18008 injection buffer) intramuscularly once weekly for 4 weeks, in addition to their stable cART regimen.
干预措施: Placebo (for 20 μg/kg Group) (Drug)
JL18008 40 μg/kg
Participants receive JL18008 40 μg/kg intramuscularly once weekly for 4 weeks, in addition to their stable cART regimen.
干预措施: JL18008 40 μg/kg (Drug)
Placebo (for 40 μg/kg Group)
Participants receive placebo (JL18008 injection buffer) intramuscularly once weekly for 4 weeks, in addition to their stable cART regimen.
干预措施: Placebo (for 40 μg/kg Group) (Drug)
JL18008 70 μg/kg
Participants receive JL18008 70 μg/kg intramuscularly once weekly for 4 weeks, in addition to their stable cART regimen.
干预措施: JL18008 70 μg/kg (Drug)
结局指标
主要结局
Number of Participants with Treatment-Emergent Adverse Events (TEAEs) as Assessed by DAIDS v2.1
时间窗: Up to 24 weeks
The incidence and severity of adverse events (AEs) and serious adverse events (SAEs). Adverse events are graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1. Assessed from first dose up to Week 24.
Change from Baseline in Vital Signs: Pulse Rate (bpm)
时间窗: Up to 24 weeks
Change from baseline in pulse rate. Measured in beats per minute (bpm). Assessed at baseline and Weeks 1, 4, 8, 12, 16, 20, and 24.
Change from Baseline in Vital Signs: Systolic and Diastolic Blood Pressure (mmHg)
时间窗: Up to 24 weeks
Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Both measured in millimeters of mercury (mmHg). Assessed at baseline and Weeks 1, 4, 8, 12, 16, 20, and 24.
Change from Baseline in Hematology Parameters
时间窗: Up to 24 weeks
Change from baseline in hematology parameters including white blood cell count (10\^9/L), hemoglobin (g/L), platelet count (10\^9/L), neutrophil count (10\^9/L), lymphocyte count (10\^9/L), and red blood cell count (10\^12/L). Assessed at baseline and Weeks 1, 2, 4, 8, 12, 16, 20, and 24.
Change from Baseline in Serum Chemistry Parameters
时间窗: Up to 24 weeks
hange from baseline in serum chemistry parameters including alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), creatinine (μmol/L), triglycerides (mmol/L), total cholesterol (mmol/L), glucose (mmol/L), and electrolytes (Na⁺, K⁺, Cl-, Ca²⁺, Mg²⁺, Pi). Assessed at baseline and Weeks 1, 2, 4, 8, 12, 16, 20, and 24.
Change from Baseline in Coagulation Parameters
时间窗: Up to 24 weeks
Change from baseline in coagulation parameters including international normalized ratio (INR), activated partial thromboplastin time (APTT, seconds), prothrombin time (PT, seconds), and fibrinogen (g/L). Assessed at baseline and Weeks 1, 2, 4, 8, 12, 16, 20, and 24.
Change from Baseline in ECG Parameter: QTcF Interval
时间窗: Up to 24 weeks
Change from baseline in the QT interval corrected for heart rate using Fridericia's formula (QTcF). Measured in milliseconds (ms). Assessed at baseline and Weeks 1, 4, 8, 12, 16, 20, and 24.
次要结局
- Proportion of Participants with CD4⁺ T Cell Count Increase ≥100 cells/μL from Baseline(Up to 24 weeks)
- Proportion of Participants Achieving CD4⁺ T Cell Count ≥500 cells/μL(Up to 24 weeks)
- Proportion of Participants with Average CD4⁺ T Cell Count Increase ≥100 cells/μL over 12 Weeks(Baseline through Week 12)
- Proportion of Participants with Average CD4⁺ T Cell Count ≥500 cells/μL over 12 Weeks(Baseline through Week 12)
- Proportion of Participants with Average CD4⁺ T Cell Count Increase ≥100 cells/μL over 24 Weeks(Baseline through Week 24)
- Proportion of Participants with Average CD4⁺ T Cell Count ≥500 cells/μL over 24 Weeks(Baseline through Week 24)
- Change from Baseline in CD4/CD8 T Cell Ratio(Up to 24 weeks)
- Proportion of Participants with HIV-1 RNA <50 copies/mL(Up to 24 weeks)
- Number of Participants with Clinical Events(Up to 24 weeks)
- Change from Baseline in Serum Cytokine Levels (IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ)(Up to 24 weeks)
- Change from Baseline in Lymphocyte Subset Counts (cells/μL)(Up to 24 weeks)
- Peak Plasma Concentration (Cmax) - Single Dose(Up to 168 hours after first dose)
- Time to Reach Peak Plasma Concentration (Tmax) - Single Dose(Up to 168 hours after first dose)
- Elimination Half-Life (t½) - Single Dose(Up to 168 hours after first dose)
- Area Under the Curve from Time 0 to Last Measurable Concentration (AUC0-last) - Single Dose(Up to 168 hours after first dose)
- Area Under the Curve from Time 0 to Infinity (AUC0-inf) - Single Dose(Up to 168 hours after first dose)
- Area Under the Curve from Time 0 to 168 Hours (AUC0-168h) - Single Dose(Up to 168 hours after first dose)
- Apparent Clearance (CL/F) - Single Dose(Up to 168 hours after first dose)
- Apparent Volume of Distribution (Vz/F) - Single Dose(Up to 168 hours after first dose)
- Steady-State Peak Plasma Concentration (Cmax, ss)(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Time to Reach Peak Plasma Concentration (Tmax, ss)(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Minimum Plasma Concentration (Cmin, ss)(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Average Plasma Concentration (Cavg, ss)(Up to 168 hours after the fourth dose (Week 4))
- Area Under the Curve Over Dosing Interval (AUC0-tau) - Steady State(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Area Under the Curve from Time 0 to Infinity (AUC0-inf, ss)(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Apparent Clearance (CLss/F)(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Apparent Volume of Distribution (Vss/F)(Up to 168 hours after the fourth dose (Week 4))
- Steady-State Elimination Half-Life (t½, ss)(Up to 168 hours after the fourth dose (Week 4))
- Degree of Fluctuation (DF) - Steady State(Up to 168 hours after the fourth dose (Week 4))
- Accumulation Ratio for Cmax (RacCmax)(From first dose to steady state (Week 4))
- Accumulation Ratio for AUC (RacAUC0-tau)(From first dose to steady state (Week 4))
- Number of Participants with Anti-Drug Antibodies (ADA)(Up to 24 weeks)