An Open Label, Randomized Study of the Safety and Antiretroviral Activity of 3BNC117 and 10-1074 in HIV-infected Individuals on Combination Antiretroviral Therapy and During Analytical Treatment Interruption.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 2
- 主要终点
- The change in the size of the functional, latent HIV-1 reservoir between baseline and after seven infusions of 3BNC117 and 10-1074
研究概览
简要总结
The proposed study is a phase 1, open label, randomized study to evaluate the safety and antiretroviral activity of seven infusions of 3BNC117 and 10-1074, administered intravenously at 30 mg/kg dose level, in human immunodeficiency virus (HIV)-infected individuals on combination antiretroviral therapy (ART) and during an analytical interruption of ART.
详细描述
The proposed study is an open label study of the safety and antiretroviral activity of 3BNC117 and 10-1074 in HIV-infected individuals with well-controlled HIV infection on combination antiretroviral therapy (ART). 3BNC117 and 10-1074 are two broadly neutralizing antibodies (bNAbs) that target different sites on HIV-1 gp120. Our hypothesis is that the administration of repeated infusions of 3BNC117 and 10-1074 in the absence of ART will be safe and well tolerated, will maintain viral suppression in HIV-infected individuals during analytical treatment interruption (ATI) and will interfere with the maintenance of the HIV-1 reservoir.
Forty eligible participants will be randomized to either Group 1 or Group 2 in a 3:1 ratio:
Group 1 (n=30): participants will discontinue ART 2 days after the first infusion of 3BNC117 and 10-1074, and will receive 6 additional infusions of both antibodies at weeks 2, 4, 8, 12, 16 and 20 (Part A). Participants will remain off ART until week 38, if viral suppression is maintained (Part B).
Group 2 (n=10): participants will remain on ART and will be administered seven infusions of 3BNC117 and 10-1074 at weeks 0, 2, 4, 8, 12, 16 and 20 (Part A). ART will be discontinued at week 26 until week 38, if viral suppression is maintained (Part B).
After screening, participants will remain on ART and undergo leukapheresis, and will have the option to undergo LN biopsies 2-4 weeks prior to first 3BNC117 and 10-1074 infusions.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and females, age 18 to
- •Confirmed HIV-1 infection.
- •On antiretroviral therapy with plasma HIV-1 RNA levels of < 50 copies/ml for at least 12 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 and CD4+ T cell count nadir of > 200 cells/μl.
- •If on an NNRTI-based regimen, willing to switch to an integrase inhibitor-based regimen for at least 4 weeks prior to discontinuing ART
- •If sexually active male or female, participating in sexual activity that could lead to pregnancy and of reproductive potential, agrees to follow the contraception requirements outlined Section 6.12.12 Family Planning Counseling. Participants should also agree to use a male or female condom while off ART to prevent infecting sexual partners.
排除标准
- •Have a history of AIDS-defining illness within 3 years prior to enrollment.
- •History of systemic corticosteroids (long term use), immunosuppressive anti-cancer, interleukins, systemic interferons, systemic chemotherapy 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), 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.
- •Laboratory abnormalities in the parameters listed below:
- •Absolute neutrophil count ≤ 1,000 cells/μl
- •Hemoglobin ≤ 10 gm/dL
- •Platelet count ≤ 100,000 cells/μl
- •Alanine aminotransferase (ALT) ≥ 1.5 x ULN
- •Aspartate aminotransferase (AST) ≥ 1.5 x ULN
- •Alkaline phosphatase ≥ 1.5 x ULN
- •Total bilirubin ≥ 1.5 x ULN
- •eGFR < 60 mL/min/1.73m2
- •Prothrombin time (PT) > 1.2 x upper limit of normal (ULN). (only if LN biopsies are performed)
- •Partial Thromboplastin Time (PTT) > 1.2 x upper limit of normal (ULN) (only if LN biopsies are performed)
- •Pregnancy or lactation
- •Receipt of any therapeutic HIV vaccine or anti-HIV monoclonal antibody therapy in the past.
- •Participants with known hypersensitivity to any constituent of the investigational products.
- •Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
- •History of intolerance, sensitivity, allergy or anaphylaxis to benzodiazepines or other narcotics to be used during LN biopsy. (only if LN biopsies are performed)
- •Previous adverse reaction or allergy to lidocaine or other amide anesthetics, as well as benzocaine or other ester type anesthetics. (only if LN biopsies are performed)
- •History of underlying medical condition for which antibiotic prophylaxis for invasive procedures is required (only if LN biopsies are performed)
- •Currently taking anticoagulants including but not limited to: heparin (Hep-Lock, Hep-Pak, Hep-Pak CVC, Heparin Lock Flush), warfarin (Coumadin), tinzaparin (Innohep), enoxaparin (Lovenox), danaparoid (Orgaran), dalteparin (Fragmin), clopidogrel (Plavix), dipyridamole (Persantine), fondaparinux (Arixtra), argatroban (Agratroban), and bivalrudin (Angiomax). Prophylactic aspirin and regular NSAID use permitted. (only if LN biopsies are performed)
研究组 & 干预措施
Group 1
HIV infected participants on ART will undergo analytical treatment interruption 2 days after the first infusion of 3BNC117 and 10-1074, and will receive 6 additional infusions of both antibodies at weeks 2, 4, 8, 12, 16 and 20 (Part A). Participants will remain off ART until week 38, if viral suppression is maintained (Part B).
干预措施: 3BNC117 (Drug)
Group 1
HIV infected participants on ART will undergo analytical treatment interruption 2 days after the first infusion of 3BNC117 and 10-1074, and will receive 6 additional infusions of both antibodies at weeks 2, 4, 8, 12, 16 and 20 (Part A). Participants will remain off ART until week 38, if viral suppression is maintained (Part B).
干预措施: 10-1074 (Drug)
Group 1
HIV infected participants on ART will undergo analytical treatment interruption 2 days after the first infusion of 3BNC117 and 10-1074, and will receive 6 additional infusions of both antibodies at weeks 2, 4, 8, 12, 16 and 20 (Part A). Participants will remain off ART until week 38, if viral suppression is maintained (Part B).
干预措施: Analytical treatment interruption (Other)
Group 2
HIV infected participants on ART will remain on ART and will be administered seven infusions of 3BNC117 and 10-1074 at weeks 0, 2, 4, 8, 12, 16 and 20 (Part A). Analytical treatment interruption will begin at week 26 until week 38, if viral suppression is maintained (Part B).
干预措施: 3BNC117 (Drug)
Group 2
HIV infected participants on ART will remain on ART and will be administered seven infusions of 3BNC117 and 10-1074 at weeks 0, 2, 4, 8, 12, 16 and 20 (Part A). Analytical treatment interruption will begin at week 26 until week 38, if viral suppression is maintained (Part B).
干预措施: 10-1074 (Drug)
Group 2
HIV infected participants on ART will remain on ART and will be administered seven infusions of 3BNC117 and 10-1074 at weeks 0, 2, 4, 8, 12, 16 and 20 (Part A). Analytical treatment interruption will begin at week 26 until week 38, if viral suppression is maintained (Part B).
干预措施: Analytical treatment interruption (Other)
结局指标
主要结局
The change in the size of the functional, latent HIV-1 reservoir between baseline and after seven infusions of 3BNC117 and 10-1074
时间窗: Day 0 and week 26
The size of the functional, latent HIV-1 reservoir is determined by the number of infectious units per 106 resting memory CD4+ T cells (IUPM) using a viral outgrowth assay at baseline and after seven infusions of 3BNC117 and 10-1074
Time to return of HIV-1 viremia
时间窗: 48 weeks
Time to return of HIV-1 viremia (plasma HIV-1 RNA level \> 200 copies/ml in 2 consecutive measurements) after ART interruption.
The rate of viral rebound
时间窗: Week 12 (group 1) and week 38 (group 2)
Rate of viral rebound (plasma HIV-1 RNA level \> 200 copies/ml in 2 consecutive measurements) or indication to reinitiate ART at 12 weeks after ART interruption (study week 12 in group 1, study week 38 in group 2).
The size of the proviral HIV-1 reservoir
时间窗: 48 weeks
Size of the proviral HIV-1 reservoir as determined by total HIV-1 DNA and integrated HIV-1 DNA in circulating total CD4+ T cells before and after seven infusions of 3BNC117 and 10-1074.
The rate of adverse events (AE) and serious adverse events (SAE).
时间窗: 48 weeks
The rate of adverse events (AE) and serious adverse events (SAE).
The severity of adverse events (AE) and serious adverse events (SAE).
时间窗: 48 weeks
The severity of adverse events (AE) and serious adverse events (SAE).
次要结局
- Serum levels of 3BNC117 and 10-1074 at the time of viral rebound(48 weeks)
- The rate of viral rebound at 26 weeks after ART interruption in group 1.(26 weeks)