An Phase 1b Study of the Safety, Pharmacokinetics and Antiretroviral Activity of the Combination of 3BNC117 and 10-1074 in HIV-infected Individuals
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 2
- 主要终点
- Time to meeting ART re-initiation criteria (plasma HIV-1 RNA level ≥ 200 copies/ml, CD4+ T cell count < 350 cells/l in 2 consecutive measurements) following ART interruption in group 2.
研究概览
简要总结
This is a phase 1b clinical trial to evaluate the safety, pharmacokinetics and the antiretroviral effects of the combination of two anti-human immunodeficiency virus (HIV) broadly neutralizing antibodies, 3BNC117 and 10-1074, administered intravenously in HIV-infected individuals. This study is intended to support the development of the combination of 3BNC117 and 10-1074 mAbs for use in the treatment of HIV-1 infection.
详细描述
The proposed study is a Phase 1b clinical trial to evaluate the safety, pharmacokinetics and the antiretroviral effects of the combination of two anti-HIV broadly neutralizing antibodies, 3BNC117 and 10-1074, administered intravenously in HIV-infected individuals.
The study includes 5 study groups. Study participants will be administered one or three intravenous infusions of 3BNC117 and 10-1074, each mAb dosed at 10 or 30 mg/kg:
Single dose groups:
Group 1A (n=6) - HIV-infected individuals, on antiretroviral therapy (ART) with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one infusion of 10-1074, each dosed at 10 mg/kg (n=4), OR placebo (sterile saline; n=2), on day 0.
Group 1B (n=6) - HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg (n=4), OR placebo (sterile saline; n=2), on day 0.
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
- Triple (Participant, Care Provider, Investigator)
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
- •All groups:
- •Age 18 to
- •HIV-1 infection confirmed by two independent laboratory assays.
- •If sexually active male or female, and participating in sexual activity that could lead to pregnancy, agrees to use two effective methods of contraception (i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting intrauterine device (IUD), hormone-based contraceptive with condom) for the study duration.
- •Groups 1A and 1B:
- •HIV-infected volunteers on ART with HIV-1 plasma RNA levels < 20 copies/ml.
- •Current CD4 cell count > 300 cells/μl.
- •Groups 1C and 3:
- •HIV-infected volunteers off ART with detectable HIV-1 plasma RNA levels < 100,000 copies/ml by standard assays.
- •Current CD4 cell count > 300 cells/μl.
- •On antiretroviral therapy for a minimum of 24 months, with plasma HIV-1 RNA levels of < 50 copies/ml for at least 18 months, and < 20 copies/ml at screening. Note: a single viral load measurement > 50 but < 500 copies/ml during this time period is allowed.
- •Current CD4+ T cell counts > 500 cells/μl. CD4 cell count nadir > 200 cells/μl.
- •If on an NNRTI-based regimen willing to switch to a dolutegravir-based regimen for 4 weeks prior to discontinuing ART.
排除标准
- •Have a history of AIDS-defining illness within 3 year prior to enrollment.
- •History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months.
- •Any clinically significant acute or chronic medical condition (such as autoimmune diseases or coronary artery disease), other than HIV infection, that in the opinion of the investigator would preclude participation.
- •Hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood.
- •History of resistance to 2 or more classes of antiretroviral medication or known resistance to dolutegravir in participants on non-nucleoside reverse-transcriptase inhibitors (NNRTI), who would switch regimen prior to ATI (Group 2).
- •Laboratory abnormalities in the parameters listed below:
- •Absolute neutrophil count ≤ 1,000 cells/l
- •Hemoglobin ≤ 10 gm/dL
- •Platelet count ≤ 100,000 cells/l
- •Alanine Aminotransferase (AST) ≥ 1.5 x ULN
- •Aspartate Aminotransferase (AST) ≥ 1.5 x ULN
- •Alkaline phosphatase ≥ 1.5 x ULN
- •Total bilirubin > 1.0 ULN
- •eGFR < 60 mL/min/1.73m2
- •Pregnancy or lactation;
- •Any vaccination within 14 days prior to 3BNC117 and 10-1074 administration;
- •Subjects with known hypersensitivity to any constituent of the investigational products;
- •Receipt of any therapeutic HIV vaccine or monoclonal antibody therapy of any kind in the past;
- •Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
研究组 & 干预措施
Group 1A
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion of 10-1074), each dosed at 10 mg/kg OR placebo (sterile saline), on day 0.
干预措施: 3BNC117 (Drug)
Group 1A
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion of 10-1074), each dosed at 10 mg/kg OR placebo (sterile saline), on day 0.
干预措施: 10-1074 (Drug)
Group 1A
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion of 10-1074), each dosed at 10 mg/kg OR placebo (sterile saline), on day 0.
干预措施: Placebo (Drug)
Group 1B
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion 10-1074, each dosed at 30 mg/kg, OR placebo (sterile saline), on day 0.
干预措施: 3BNC117 (Drug)
Group 1B
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion 10-1074, each dosed at 30 mg/kg, OR placebo (sterile saline), on day 0.
干预措施: 10-1074 (Drug)
Group 1B
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be randomized in a 2:1 ratio to receive one intravenous infusion of 3BNC117 and one intravenous infusion 10-1074, each dosed at 30 mg/kg, OR placebo (sterile saline), on day 0.
干预措施: Placebo (Drug)
Group 1C
HIV-infected individuals, off ART will be administered one infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg, on day 0.
干预措施: 3BNC117 (Drug)
Group 1C
HIV-infected individuals, off ART will be administered one infusion of 3BNC117 and one infusion 10-1074, each dosed at 30 mg/kg, on day 0.
干预措施: 10-1074 (Drug)
Group 2
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg, on days 0, 21 and 42. Participants enrolled in Group 2 will undergo an analytical treatment interruption and they will discontinue their antiretroviral (ART) regimen on day 2.
干预措施: 3BNC117 (Drug)
Group 2
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg, on days 0, 21 and 42. Participants enrolled in Group 2 will undergo an analytical treatment interruption and they will discontinue their antiretroviral (ART) regimen on day 2.
干预措施: 10-1074 (Drug)
Group 2
HIV-infected individuals, on ART with HIV-1 RNA < 20 copies/ml will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg, on days 0, 21 and 42. Participants enrolled in Group 2 will undergo an analytical treatment interruption and they will discontinue their antiretroviral (ART) regimen on day 2.
干预措施: Analytical treatment interruption (Other)
Group 3
HIV-infected individuals, off ART who will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg on days 0, 14 and 28.
干预措施: 3BNC117 (Drug)
Group 3
HIV-infected individuals, off ART who will be administered three infusions of 3BNC117 and three infusions of 10-1074, each dosed at 30 mg/kg on days 0, 14 and 28.
干预措施: 10-1074 (Drug)
结局指标
主要结局
Time to meeting ART re-initiation criteria (plasma HIV-1 RNA level ≥ 200 copies/ml, CD4+ T cell count < 350 cells/l in 2 consecutive measurements) following ART interruption in group 2.
时间窗: 30 weeks
The number of participants with adverse events 1 week after 3BNC117 and 10-1074 infusions in all study groups.
时间窗: 1 week following each combination of 3BNC117 and 10-1074 infusion
Adverse events include: signs, symptoms and laboratory abnormalities, in addition to local and systemic reactogenicity
The decline in plasma HIV-1 RNA levels by a standard clinical assay in participants off ART enrolled in groups 1C and 3.
时间窗: 20-24 weeks
The percentage of participants who meet ART re-initiation criteria (plasma HIV-1 RNA ≥ 200 copies/ml and/or CD4 count < 350 cells/μl on two consecutive measurements) prior to 8 weeks after ART interruption in group 2.
时间窗: 30 weeks
次要结局
- Level of induced anti-3BNC117 and anti-10-1074 antibodies.(20-30 weeks)
- Change in number of CD4+ T cells/uL(20-30 weeks)
- The number of participants with adverse events that occur during study follow up after 3BNC117 and 10-1074 infusions in all study groups.(20-30 weeks)
- Number of participants with induced anti-3BNC117 and anti-10-1074 antibodies.(20-30 weeks)
- The serum level of 3BNC117 and 10-1074 at the time of viral rebound in all study groups.(20-30 weeks)