A Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRCHIVMAB0115-00-AB (VRC01.23LS), Administered Intravenously or Subcutaneously to Healthy Adults

Study Overview
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Brief Summary
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Background: HIV causes AIDS, a serious disease that can lead to fatal infections. HIV infection can be controlled but not cured, nor is there a vaccine to prevent it. Antibodies may offer a promising new way to prevent HIV infection. Antibodies are proteins that are naturally made by the body to fight germs. One antibody (VRC01.23LS) has been tested in the lab and was found to block HIV-like viruses. Researchers want to find out if it is safe to inject VRC01.23LS into people. Objective: To test the safety of VRC01.23LS in healthy adults. Eligibility: Healthy people aged 18 to 60 years. Design: Participants will be divided into 6 groups: Some will get 1 dose of VRC01.23LS. They will visit the clinic up to 14 times in 24 weeks. Some will get 3 doses, each 12 weeks apart. They will have 25 clinic visits over 48 weeks. For some participants, the drug will be given through a tube attached to a needle inserted into a vein in the arm. This will take about 30 minutes. Others will receive the drug as an injection under the skin in a fatty area of the belly, arm, or thigh; each dose may need up to 3 individual injections. Participants will stay in the clinic up to 8 hours on the days they receive VRC01.23LS. Participants will receive a thermometer and measuring tool. They will check their temperature daily for 7 days after they receive the study drug. They will measure any redness, swelling, or bruising at the injection site.

Detailed Description
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Study Design: This first-in-human, open-label study will evaluate VRC01.23LS (VRCHIVMAB0115- 00-AB) in a dose-escalation design to examine safety, tolerability, dose, and pharmacokinetics (PK) in healthy adults. The primary hypothesis is that subcutaneous (SC) and intravenous (IV) administrations of VRC01.23LS will be safe and well-tolerated in healthy adults. A secondary hypothesis is that VRC01.23LS will be detectable in human sera with a definable half-life. Study Products: The VRC01.23LS broadly neutralizing monoclonal antibody (bnAb) targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve the antibody half-life in vivo. VRC01.23LS was developed by the VRC/NIAID/NIH and manufactured under cGMP regulations at the VRC Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick. MD. Subjects: Healthy adults, 18-60 years of age Study Plan: This open-label study will include 6 groups to evaluate VRC01.23LS administered alone or by repeat dosing as shown below in the Study Schema. Enrollment will begin with the 5 mg/kg dose groups, and enrollment for subsequent dose groups will proceed after dose-escalation safety reviews. Assessment of safety will include solicited reactogenicity, clinical observation, and monitoring of hematological and chemical parameters at clinical visits throughout the study.

Official Title
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VRC 615: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB-0115-AB (VRC01.23LS), Administered Intravenously or Subcutaneously to Healthy Adults

Conditions
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HIV

Intervention / Treatment
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* Biological: VRC-HIVMAB0115-00-AB


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: A subject must meet all of the following criteria: Willing and able to complete the informed consent process. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. Available for clinical follow-up through the last study visit. 18 to 60 years of age. In good general health without clinically significant medical history. Physical examination without clinically significant findings within the 56 days prior to enrollment. Adequate venous access if assigned to an IV group or adequate abdominal subcutaneous tissue if assigned to SC group. Willing to have blood samples collected, stored indefinitely, and used for research purposes. Laboratory Criteria within 56 days prior to enrollment: White blood cell count (WBC): 2,500-12,000/mm3. WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval. Platelets: 125,000 - 500,000/mm3. Hemoglobin within institutional normal range or accompanied by PI or designee approval. Creatinine: <= 1.1 x Upper Limit of Normal (ULN). ALT: <= 1.25 x ULN. AST: <= 1.25 x ULN. Negative for HIV infection by an FDA approved method of detection. Female-Specific Criteria: Agrees to use an effective means of birth control from 21 days prior to enrollment through the duration of study participation. Negative Beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential. EXCLUSION CRITERIA: A subject will be excluded if one or more of the following conditions apply: Woman who is breast-feeding or planning to become pregnant during study participation. Weight > 115 kg. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study. Hypertension that is not well controlled. Receipt of any investigational study product within 28 days prior to enrollment (Note: Emergency Use Authorization of a COVID-19 vaccine is not exclusionary). Receipt of an investigational HIV vaccine or anti-HIV monoclonal antibody. Receipt of any live attenuated vaccine within 28 days prior to enrollment. Receipt of any vaccine within 2 weeks prior to enrollment. Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, infectious disease, autoimmune disease, psychiatric disorder, heart disease, or cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>5 mg/kg IV single administration | Biological: VRC-HIVMAB0115-00-AB<br>* VRC01.23LS is a broadly neutralizing monoclonal antibody that targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo.<br>|
| Experimental: Group 2<br>5 mg/kg SC single administration | Biological: VRC-HIVMAB0115-00-AB<br>* VRC01.23LS is a broadly neutralizing monoclonal antibody that targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo.<br>|
| Experimental: Group 3<br>20 mg/kg IV single administration | Biological: VRC-HIVMAB0115-00-AB<br>* VRC01.23LS is a broadly neutralizing monoclonal antibody that targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo.<br>|
| Experimental: Group 4<br>40 mg/kg IV single administration | Biological: VRC-HIVMAB0115-00-AB<br>* VRC01.23LS is a broadly neutralizing monoclonal antibody that targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo.<br>|
| Experimental: Group 5<br>5 mg/kg SC repeat dosing | Biological: VRC-HIVMAB0115-00-AB<br>* VRC01.23LS is a broadly neutralizing monoclonal antibody that targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo.<br>|
| Experimental: Group 6<br>20 mg/kg IV repeat dosing | Biological: VRC-HIVMAB0115-00-AB<br>* VRC01.23LS is a broadly neutralizing monoclonal antibody that targets the CD4 binding site in the HIV-1 envelope, is human in origin, and contains two amino acid modifications within the C-terminus of the heavy chain constant region designed to improve antibody half-life in vivo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of VRC01.23LS (5 mg/kg SC) administered to healthy adults | To evaluate the safety and tolerability of a single SC dose | Through 24 weeks after product administration | 
| Safety and tolerability of VRC01.23LS (20 mg/kg IV) administered to healthy adults | To evaluate the safety and tolerability of a single IV dose | Through 24 weeks after product administration | 
| Safety and tolerability of VRC01.23LS (20 mg/kg IV) administered for a total of 3 injections in 12 week intervals to healthy adults | To evaluate the safety and tolerability of repeat IV dosing | Through 24 weeks after last product administration | 
| Safety and tolerability of VRC01.23LS (40 mg/kg IV) administered to healthy adults | To evaluate the safety and tolerability of a single IV dose | Through 24 weeks after product administration | 
| Safety and tolerability of VRC01.23LS (5 mg/kg IV) administered to healthy adults | To evaluate the safety and tolerability of a single IV dose | Through 24 weeks after product administration | 
| Safety and tolerability of VRC01.23LS (5 mg/kg SC) administered for a total of 3 injections in 12 week intervals to healthy adults | To evaluate the safety and tolerability of repeat SC dosing | Through 24 weeks after the last product administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK will be evaluated at each dose level and route of administration. | To evaluate the pharmacokinetics (PK) of VRC01.23LS | Throughout the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune Response, HIV, First in Human, Broadly Neutralizing