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

• ClinicalTrials.gov Identifier: NCT03208231
• Recruitment Status: Completed
• First Posted: July 5, 2017
• Results First Posted: May 24, 2023
• Last Update Posted: May 24, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
HIV Infections	Biological: VRC01; Drug: Combination Antiretroviral Therapy (cART)	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 6, 2018
• Actual Primary Completion Date: June 16, 2020
• Actual Study Completion Date: February 11, 2021

Arms and Interventions

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 Name: 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).

Outcome Measures

Primary Outcome Measures :

1. Percentage of Infants Experiencing at Least One Grade 3 or Higher Adverse Event (AE) [ Time Frame: From Week 0 to Week 14 ]
   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.
2. Change in HIV-1 DNA Concentration in Peripheral Blood Mononuclear Cells (PBMCs) From Week 0 to Week 14 [ Time Frame: Week 0 and 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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 0 Weeks to 12 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Botswana

Molepolole CRS

Molepolole, Kweneng District, Botswana

Gaborone CRS

Gaborone, South-East District, Botswana

Brazil

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio De Janeiro, Brazil

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, Brazil

Malawi

Malawi CRS

Lilongwe, Central, Malawi

Blantyre CRS

Blantyre, Malawi

Zimbabwe

Harare Family Care CRS

Harare, Zimbabwe

Sponsors and Collaborators

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

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol: Protocol Version 2.0  [PDF] May 29, 2017

Study Protocol: Letter of Amendment 1.0  [PDF] June 14, 2018

Study Protocol: Letter of Amendment 2.0  [PDF] April 22, 2020

Study Protocol: Protocol Clarification Memo 1.0  [PDF] April 26, 2018

Study Protocol: Protocol Clarification Memo 2.0  [PDF] April 1, 2020

Statistical Analysis Plan  [PDF] May 13, 2020

Informed Consent Form  [PDF] May 29, 2017

More Information

Additional Information:

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 

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03208231
• Other Study ID Numbers: IMPAACT 2008; 20735 ( Registry Identifier: DAIDS-ES Registry Number )
• First Posted: July 5, 2017
• Results First Posted: May 24, 2023
• Last Update Posted: May 24, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• 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.

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."

• URL: https://www.impaactnetwork.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents