3BNC117 and 10-1074 in HIV Uninfected Adults

Study Overview
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Brief Summary
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This is a phase 1 clinical trial to evaluate the safety and pharmacokinetics of the highly neutralizing anti-human immunodeficiency virus-1 monoclonal antibodies 3BNC117 and 10-1074, when given in combination, in human immunodeficiency virus (HIV)-uninfected individuals. This study is intended to support the development of the combination of 3BNC117 and 10-1074 mAbs for use as prophylaxis against HIV infection in healthy HIV-uninfected individuals at risk for HIV infection.

Detailed Description
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The study will be conducted under a placebo-controlled, double blind, randomized allocation of the study products. Study participants in each study group will be randomized to receive intravenous infusions of 3BNC117 and 10-1074 or placebo. 3BNC117 and 10-1074 will be administered at 2 dose levels (3 mg/kg and 10 mg/kg). These doses were selected based on the planned development of subcutaneous formulations for the prophylactic use of these products. The study will consist of 3 groups. Enrollment in Group 1 will begin first and participants will be enrolled at least one day apart. Eight participants will be enrolled in each group; 6 will be randomized receive the study drugs and 2 will be randomized to receive placebo. Participants in Group 1 will receive a single infusion of each antibody at 10mg/kg at Week 0. Enrollment in Group 2 will begin only after Day 28 safety data from all participants in Group 1, including ophthalmologic exams, are available. Enrollment in Group 3 will begin only after the Day 28 safety data from all participants in Group 2 is available. If > 1 grade 3 or higher adverse events deemed probably or definitely related to the study drugs occurs in a single group, the next group will not be enrolled pending safety monitoring committee (SMC) review. Participants in Groups 2 and 3 will receive 3 infusions of each antibody at Weeks 0, 8, and 16, at a dose of either 3mg/kg or 10mg/kg. The antibodies will be administered sequentially via intravenous infusion. Each antibody will be administered over 60 minutes. Following product infusions, study participants will return for safety assessments at multiple time points. Blood samples will be collected for safety testing at weeks 1, 2, and 4 following each infusion, then at multiple time points until the end of study follow up. Baseline pharmacokinetic (PK) assessments will be performed before the start of the first infusion. Peak PK sampling for 3BNC117 will occur following the completion of the 3BNC117 infusion prior to the start of the 10-1074 infusion. Peak PK sampling for 10-1074 will occur following the completion of the 10-1074 infusion. Additional PK assessments will occur at multiple time points during study follow up. Study participants will be followed for a total of 24 weeks following the final antibody infusion.

Official Title
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A Phase 1 Study of the Safety and Pharmacokinetics of the Combination of 3BNC117 and 10-1074 in HIV-uninfected Adults

Conditions
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Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: 3BNC117
* Drug: 10-1074
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, age 18 to 65. Amenable to HIV risk reduction counseling and agrees to maintain behavior consistent with low risk of HIV exposure. 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 IUD, hormone-based contraceptive with condom) for the duration of the study. Exclusion Criteria: Confirmed HIV-1 or HIV-2 infection. History of immunodeficiency or autoimmune disease; use 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) that in the opinion of the investigator would preclude participation. Within the 12 months prior to enrollment, the participant has a history of sexually transmitted infection. Chronic Hepatitis B or Hepatitis C infection. Laboratory abnormalities in the parameters listed: Absolute neutrophil count ≤ 2,000; Hemoglobin ≤ 12 gm/dL if female; ≤ 13.5 gm/dL if male; Platelet count ≤ 125,000; Alanine Aminotransferase (ALT) ≥ 1.25 x ULN; Aspartate Aminotransferase (AST) ≥ 1.25 x ULN; Alkaline phosphatase ≥ 1.5 x ULN Total bilirubin > 1.0 x ULN; Creatinine ≥1.1 x ULN; Pregnancy or lactation. Any vaccination within 14 days prior to infusion Receipt of any experimental HIV vaccine in the past. History of severe reaction to a vaccine or drug infusion or history of severe allergic reactions. Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Participants will be randomized in a 3:1 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. | Drug: 3BNC117<br>* Intravenous Infusion of 3BNC117<br>* Other names: Monoclonal Antibody 3BNC117;Drug: 10-1074<br>* Intravenous Infusion of 10-1074<br>* Other names: Monoclonal Antibody 10-1074;Drug: Placebo<br>* Intravenous Infusion of Sterile Saline (NaCl 0.9%)<br>* Other names: Sterile Saline (NaCl 0.9%);|
| Experimental: Group 2<br>Participants will be randomized in a 3:1 ratio to receive three intravenous infusions of 3BNC117 and three intravenous infusions of 10-1074, each dosed at 3 mg/kg OR placebo (sterile saline), on day 0, week 8, and week 16. | Drug: 3BNC117<br>* Intravenous Infusion of 3BNC117<br>* Other names: Monoclonal Antibody 3BNC117;Drug: 10-1074<br>* Intravenous Infusion of 10-1074<br>* Other names: Monoclonal Antibody 10-1074;Drug: Placebo<br>* Intravenous Infusion of Sterile Saline (NaCl 0.9%)<br>* Other names: Sterile Saline (NaCl 0.9%);|
| Experimental: Group 3<br>Participants will be randomized in a 3:1 ratio to receive three intravenous infusions of 3BNC117 and three intravenous infusions of 10-1074, each dosed at 10 mg/kg OR placebo (sterile saline), on day 0, week 8, and week 16. | Drug: 3BNC117<br>* Intravenous Infusion of 3BNC117<br>* Other names: Monoclonal Antibody 3BNC117;Drug: 10-1074<br>* Intravenous Infusion of 10-1074<br>* Other names: Monoclonal Antibody 10-1074;Drug: Placebo<br>* Intravenous Infusion of Sterile Saline (NaCl 0.9%)<br>* Other names: Sterile Saline (NaCl 0.9%);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants who experience adverse events within 1 week after the combination of 3BNC117 and 10-1074 infusion in all study groups. | Adverse events include signs, symptoms and laboratory abnormalities, in addition to local and systemic reactogenicity adverse events. | 1 week following each combination of 3BNC117 and 10-1074 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with induced anti-3BNC117 and anti-10-1074 antibodies |  | 8 weeks following each combination of 3BNC117 and 10-1074 infusion | 
| Level of induced anti-3BNC117 and anti-10-1074 antibodies |  | 8 weeks following each combination of 3BNC117 and 10-1074 infusion | 
| The number of participants who experience adverse events that occur during study follow up after 3BNC117 and 10-1074 infusions in all study groups. | Adverse events include signs, symptoms and laboratory abnormalities. | 24-40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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3BNC117, 10-1074, Broadly neutralizing antibody, HIV Prevention