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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV
• Intervention / Treatment: Biological: VRC-HIVMAB0115-00-AB

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: VRC Clinic; Phone Number: (301) 451-8715; Email: vaccines@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

A subject must meet all of the following criteria:

1. Willing and able to complete the informed consent process.
2. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
3. Available for clinical follow-up through the last study visit.
4. 18 to 60 years of age.
5. In good general health without clinically significant medical history.
6. Physical examination without clinically significant findings within the 56 days prior to enrollment.
7. Adequate venous access if assigned to an IV group or adequate abdominal subcutaneous tissue if assigned to SC group.

8. Willing to have blood samples collected, stored indefinitely, and used for research purposes.

   Laboratory Criteria within 56 days prior to enrollment:

9. White blood cell count (WBC): 2,500-12,000/mm3.
10. WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval.
11. Platelets: 125,000 - 500,000/mm3.
12. Hemoglobin within institutional normal range or accompanied by PI or designee approval.
13. Creatinine: <= 1.1 x Upper Limit of Normal (ULN).
14. ALT: <= 1.25 x ULN.
15. AST: <= 1.25 x ULN.

16. Negative for HIV infection by an FDA approved method of detection.

    Female-Specific Criteria:

17. Agrees to use an effective means of birth control from 21 days prior to enrollment through the duration of study participation.
18. 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:

1. Woman who is breast-feeding or planning to become pregnant during study participation.
2. Weight > 115 kg.
3. 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.
4. Hypertension that is not well controlled.
5. Receipt of any investigational study product within 28 days prior to enrollment (Note: Emergency Use Authorization of a COVID-19 vaccine is not exclusionary).
6. Receipt of an investigational HIV vaccine or anti-HIV monoclonal antibody.
7. Receipt of any live attenuated vaccine within 28 days prior to enrollment.
8. Receipt of any vaccine within 2 weeks prior to enrollment.
9. 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.
10. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 5 mg/kg IV single administration	Biological: VRC-HIVMAB0115-00-AB; 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.
Experimental: Group 2; 5 mg/kg SC single administration	Biological: VRC-HIVMAB0115-00-AB; 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.
Experimental: Group 3; 20 mg/kg IV single administration	Biological: VRC-HIVMAB0115-00-AB; 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.
Experimental: Group 4; 40 mg/kg IV single administration	Biological: VRC-HIVMAB0115-00-AB; 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.
Experimental: Group 5; 5 mg/kg SC repeat dosing	Biological: VRC-HIVMAB0115-00-AB; 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.
Experimental: Group 6; 20 mg/kg IV repeat dosing	Biological: VRC-HIVMAB0115-00-AB; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Lesia K Dropulic, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Gaudinski MR, Coates EE, Houser KV, Chen GL, Yamshchikov G, Saunders JG, Holman LA, Gordon I, Plummer S, Hendel CS, Conan-Cibotti M, Lorenzo MG, Sitar S, Carlton K, Laurencot C, Bailer RT, Narpala S, McDermott AB, Namboodiri AM, Pandey JP, Schwartz RM, Hu Z, Koup RA, Capparelli E, Graham BS, Mascola JR, Ledgerwood JE; VRC 606 Study Team. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018 Jan 24;15(1):e1002493. doi: 10.1371/journal.pmed.1002493. eCollection 2018 Jan.
• Gaudinski MR, Houser KV, Doria-Rose NA, Chen GL, Rothwell RSS, Berkowitz N, Costner P, Holman LA, Gordon IJ, Hendel CS, Kaltovich F, Conan-Cibotti M, Gomez Lorenzo M, Carter C, Sitar S, Carlton K, Gall J, Laurencot C, Lin BC, Bailer RT, McDermott AB, Ko SY, Pegu A, Kwon YD, Kwong PD, Namboodiri AM, Pandey JP, Schwartz R, Arnold F, Hu Z, Zhang L, Huang Y, Koup RA, Capparelli EV, Graham BS, Mascola JR, Ledgerwood JE; VRC 605 study team. Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial. Lancet HIV. 2019 Oct;6(10):e667-e679. doi: 10.1016/S2352-3018(19)30181-X. Epub 2019 Aug 28.
• Kwon YD, Asokan M, Gorman J, Zhang B, Liu Q, Louder MK, Lin BC, McKee K, Pegu A, Verardi R, Yang ES, Program VP, Carlton K, Doria-Rose NA, Lusso P, Mascola JR, Kwong PD. A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention. MAbs. 2021 Jan-Dec;13(1):1946918. doi: 10.1080/19420862.2021.1946918.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2023
• Primary Completion (Estimated): October 15, 2024
• Study Completion (Estimated): October 15, 2025

Study Registration Dates

• First Submitted: November 23, 2022
• First Submitted That Met QC Criteria: November 23, 2022
• First Posted (Actual): November 25, 2022

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 6, 2024
• Last Verified: April 5, 2024

More Information

Terms related to this study

• Keywords: HIV; Immune Response; First in Human; Broadly Neutralizing
• Other Study ID Numbers: 10000889; 000889-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: .Please refer to protocol Section 9.3.4.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No