Evaluating the Safety and Antiviral Activity of Monoclonal Antibody VRC01 in Infants With HIV Receiving Combination Antiretroviral Therapy

Phase I/II Multisite, Randomized, Controlled Study of Monoclonal Antibody VRC01 With Combination Antiretroviral Therapy to Promote Clearance of HIV-1-Infected Cells in Infants

The purpose of this study was to evaluate the safety and antiviral activity to promote clearance of HIV-1 infected cells of VRC01 in infants with HIV beginning combination antiretroviral therapy (cART).

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Biological: VRC01; Drug: Combination Antiretroviral Therapy (cART)

Detailed Description

VRC01 is an experimental human immunoglobulin G1 (IgG1) monoclonal antibody. The purpose of this study was to evaluate the safety and antiviral activity to promote clearance of HIV-1 infected cells of VRC01 received within 12 weeks of birth in infants with HIV initiating cART.

All infants were required to have initiated cART within 14 days before or at study entry. Infants were randomly assigned to either receive VRC01 (VRC01, Arm 1) or not receive VRC01 (No-VRC01, Arm 2). Randomization was stratified by whether the initial cART regimen included an integrase inhibitor.

Infants in the VRC01 arm received VRC01 injections at study entry (Week 0) and Weeks 2, 6, and 10. Infants in the No-VRC01 arm received no study product.

Infants attended study visits at Weeks 1, 2, 3, 6, 7, 10, 11, 14, 16, 20, 24, 36, and 48. Visits included physical examinations, blood and urine collection.

Infants' mothers could optionally be enrolled in the study for one-time specimen collection for exploratory evaluations. Maternal study participation was not required for infant study participation.

The study was closed to enrollment prematurely on March 19, 2020 due to the outbreak of coronavirus disease 2019 (COVID-19) and after enrolling 61 of the targeted 68 infants.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Botswana
  • Kweneng District
    • Molepolole, Kweneng District, Botswana
      • Molepolole CRS
  • South-East District
    • Gaborone, South-East District, Botswana
      • Gaborone CRS
• Brazil
  • Rio De Janeiro, Brazil
    • Hosp. Geral De Nova Igaucu Brazil NICHD CRS
  • Rio de Janeiro, Brazil
    • Hospital Federal dos Servidores do Estado NICHD CRS
• Malawi
  • Blantyre, Malawi
    • Blantyre CRS
  • Central
    • Lilongwe, Central, Malawi
      • Malawi CRS
• Zimbabwe
  • Harare, Zimbabwe
    • Harare Family Care CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 3 years (Child)
• Accepts Healthy Volunteers: No

Description

Infant Inclusion Criteria:

• Weigh at least 2500 grams
• Confirmed HIV-1 infection

• The following laboratory values at screening:

  • Cluster of differentiation 4 (CD4) lymphocyte percentage greater than 15
  • Severity grade 1 or lower hemoglobin, platelet count, and absolute neutrophil count
  • Severity grade 1 or lower alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase
• First dose of initial combination antiretroviral therapy (cART) regimen taken on the day of randomization or within 14 days prior to the day of randomization
• Expected to be available for 48 weeks of follow-up at study entry
• Parent or legal guardian willing and able to provide written informed consent for infant participation in the study
• Parent or legal guardian willing and able to complete reactogenicity memory aids for study purposes, based on parent/guardian report.

Infant Exclusion Criteria:

• Infant or infant's mother received exclusionary active or passive HIV-specific immunotherapy
• Initiated a combination of three or more antiretrovirals, all at or above recommended treatment doses, within 48 hours of birth

• Received within 30 days prior to study entry, or was identified as requiring, any of the following:

  • Chronic (more than 14 days) systemic steroid treatment
  • Immunoglobulin treatment
  • Immunomodulators (interleukins, interferons, cyclosporin)
  • Cytotoxic chemotherapy
  • Treatment for active tuberculosis (TB) disease
  • Any investigational agent
  • Note: Treatment for latent TB infection was permitted
• Any documented or suspected clinically significant medical illness, clinically significant congenital anomaly, or immediately life-threatening condition that, in the opinion of the site investigator or designee, would interfere with the infant's ability to comply with study requirements
• Any other condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

Maternal Inclusion Criteria (maternal study participation was not required for infant study participation):

The mothers of enrolled infants were asked to consent to blood collection and storage for this study. The following criteria must have been met in order for mothers to undergo blood collection for this purpose:

• Mother was willing and able to provide independent written informed consent for blood collection and storage for virology and immunology investigations
• Mother had no documented or suspected condition that, in the opinion of the site investigator or designee, would make blood collection unsafe

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VRC01 (Arm 1); Infants received VRC01 subcutaneous injections (40 mg/kg) at Weeks 0, 2, 6, and 10.	Biological: VRC01; 40 mg/kg of VRC01 administered by subcutaneous injection.; Other Names: VRC-HIVMAB060-00-AB; Drug: Combination Antiretroviral Therapy (cART); All infants received non-study provided cART selected by their primary care provider and supplied through non-study sources (i.e., cART not provided through the study).
Active Comparator: No-VRC01 (Arm 2); Infants did not receive VRC01.	Drug: Combination Antiretroviral Therapy (cART); All infants received non-study provided cART selected by their primary care provider and supplied through non-study sources (i.e., cART not provided through the study).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Infants Experiencing at Least One Grade 3 or Higher Adverse Event (AE)	Includes reactogenicity outcomes, abnormal laboratory test results, signs, symptoms, and diagnoses. Adverse event severity grading was based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Two-sided exact 95% Clopper-Pearson confidence intervals were calculated.	From Week 0 to Week 14
Change in HIV-1 DNA Concentration in Peripheral Blood Mononuclear Cells (PBMCs) From Week 0 to Week 14	Mean changes (Week 14 - Week 0) were calculated on log10-transformed HIV-1 DNA concentration. Values below the assay detection limit were set to half the lower assay limit of 4.09 copies/million PBMCs. Values above the detection limit were set to the upper limit of 10,000 copies/million PBMCs.	Week 0 and Week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only)	Median (mcg/ml) pre-dose VRC01 concentrations in the plasma (VRC01 Arm only)	Weeks 2, 6, 10, 14, and 16
Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only)	Geometric mean (mcg/ml) of pre-dose VRC01 concentrations with 90% confidence intervals	Weeks 2, 6, 10, 14, and 16
Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only)	Percentage of infants with pre-dose VRC01 concentrations >= 20 mcg/ml in the plasma (VRC01 Arm only)	Weeks 2, 6, 10, 14, 16
Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only)	Percentage of infants with pre-dose VRC01 concentrations >= 50 mcg/ml in the plasma (VRC01 Arm only)	Weeks 2, 6, 10, 14, 16

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Elizabeth (Betsy) McFarland, MD, University of Colorado School of Medicine; Study Chair: Alka Khaitan, MD, Indiana University School of Medicine

Publications and helpful links

General Publications

• Khaitan A, Lindsey J, Capparelli E, Tierney C, Coletti A, Perlowski C, Cotton MF, Yin DE, Majji S, Moye J, Spiegel H, Harding P, Costello D, Krotje C, Gama L, Persaud D, McFarland EJ, on behalf of the IMPAACT 2008 Protocol Team. Phase I/II Study of monoclonal antibody VRC01 with early antiretroviral therapy to promote clearance of HIV-1 infected cells in infants (IMPAACT 2008). Oral presentation at 24th International AIDS Conference, July 2022.

Helpful Links

• Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (AE) Grading Table, Corrected Version 2.1, dated July 2017.
• Manual for Expedited Reporting of Adverse Events (EAE) to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2018
• Primary Completion (Actual): June 16, 2020
• Study Completion (Actual): February 11, 2021

Study Registration Dates

• First Submitted: June 30, 2017
• First Submitted That Met QC Criteria: June 30, 2017
• First Posted (Actual): July 5, 2017

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: April 27, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Anti-Infective Agents; Antiviral Agents; Anti-Retroviral Agents
• Other Study ID Numbers: IMPAACT 2008; 20735 (Registry Identifier: DAIDS-ES Registry Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
• IPD Sharing Access Criteria: With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.; For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network.; By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/studies/submit-research-proposal. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data."
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No