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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: VRC01
* Drug: Combination Antiretroviral Therapy (cART)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Weeks
Maximum Age: 12 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VRC01 (Arm 1)<br>Infants received VRC01 subcutaneous injections (40 mg/kg) at Weeks 0, 2, 6, and 10. | Biological: VRC01<br>* 40 mg/kg of VRC01 administered by subcutaneous injection.<br>* Other names: VRC-HIVMAB060-00-AB;Drug: Combination Antiretroviral Therapy (cART)<br>* 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).<br>|
| Active Comparator: No-VRC01 (Arm 2)<br>Infants did not receive VRC01. | Drug: Combination Antiretroviral Therapy (cART)<br>* 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).<br>|

What is the study measuring?
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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 |