Dual bNAb Treatment in Children

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the impact of two broadly neutralizing antibodies, VRC01LS and 10-1074, on the maintenance of HIV suppression in a cohort of early-treated children in Botswana.

Detailed Description
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This study will evaluate the impact of two broadly neutralizing antibodies, VRC01LS and 10-1074, on the maintenance of HIV suppression in a cohort of early-treated children in Botswana. The primary objectives are as follows: To conduct an interventional clinical trial to determine the safety, pharmacokinetics, dosing and antiviral efficacy of up to 24 weeks of maintenance VRC01LS and 10-1074 immunotherapy in early-treated HIV-1 infected children in Botswana. To evaluate effects of treatment with VRC01LS and 10-1074 on the size and cellular composition of residual viral reservoirs. To investigate the influence of VRC01LS and 10-1074 treatment on the magnitude and quality of antiviral innate and adaptive immune responses. The study includes 4 steps: the pharmacokinetics (PK) Step, Step 1, Step 2, and Step 3. In the PK Step, antiretroviral treatment (ART) is continued and 12 study participants will undergo safety and PK testing, 6 for each bNAb used in the study (10-1074 and VRC01LS). In Step 1, ART is continued and dual bNAb treatment occurs, with PK confirmation of dual bNAb dosing for the first 6 participants in Step 1. In Step 2, ART is withdrawn and dual bNAb maintenance treatment occurs. In Step 3, dual bNAbs will be discontinued and participants will be re-started on ART. Participants will be in the study for a minimum of 56 weeks, and a maximum of 98 weeks for those who start in the PK step and continue through the study.

Official Title
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A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in Botswana (Dual bNAb Treatment in Children)

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: ART
* Biological: VRC01LS
* Biological: 10-1074


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for PK Step*: On ART for at least 96 weeks Greater than or equal to 96 weeks and less than 5 years of age at enrollment HIV RNA less than 40 copies/mL for at least 24 weeks prior to entry Ability to remain in close study follow-up for at least 12 weeks Willingness to receive IV infusions of bNAbs Willingness to provide signed informed consent (by the parent/guardian) *It is anticipated that all children in PK Step will be from Early Infant Treatment (EIT) Study (NCT02369406); however, up to 4 HIV+ children outside the PK Study (age range 2-5 years) may participate in the PK Step if otherwise eligible and if EIT children are unavailable. Inclusion Criteria for Entry into Step 1 (followed by participation in Steps 2-3): EIT Study participant (NCT02369406) On ART for at least 96 weeks Greater than or equal to 96 weeks and less than 7 years of age at enrollment HIV RNA less than 40 copies/mL for at least 24 weeks prior to entry Ability to remain in close study follow-up for at least 56 weeks Willingness to receive IV infusions of bNAbs Willingness to provide signed informed consent (by the parent/guardian) Exclusion Criteria: Medical condition making survival for at least 32 weeks unlikely Active tuberculosis or malignancy Actively breastfeeding Previous receipt of VRC01/VRC01LS or 10-1074 (except during the PK Step)

Ages Eligible for Study
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Minimum Age: 96 Weeks
Maximum Age: 7 Years

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group PK-A: ART + VRC01LS<br>In the PK Step, participants will continue ART and receive VRC01LS at Weeks 0, 4, and 8 as a single intravenous (IV) dose (30 mg/kg load then 10 mg/kg maintenance). | Drug: ART<br>* ART will not be provided by the study. Participants will continue to receive their ART regimen they were receiving prior to enrolling in the study.<br>Biological: VRC01LS<br>* Administered by intravenous (IV) infusion<br>|
| Experimental: Group PK-B: ART + 10-1074<br>In the PK Step, participants will continue ART and receive 10-1074 at Weeks 0, 4, and 8 as a single IV dose (30 mg/kg). | Drug: ART<br>* ART will not be provided by the study. Participants will continue to receive their ART regimen they were receiving prior to enrolling in the study.<br>Biological: 10-1074<br>* Administered by intravenous (IV) infusion<br>|
| Experimental: Steps 1-3 Participants (ART + 10-1074 + VRC01LS)<br>In Step 1, eligible participants will continue to receive ART and will receive both 10-1074 and VRC01LS at Weeks 0, 4, and 8. Following a recommendation from the study team and Safety Monitoring Committee (SMC) to increase the maintenance dosing based on the PK Step, a VRC01LS loading dose of 30 mg/kg will be given at the start of Step 1, followed by 15 mg/kg dosing at each 4-weekly visit, and 10-1074 dosing will be at 30 mg/kg at each 4-weekly visit. In Step 2, participants with ongoing viral suppression throughout Step 1 will undergo withdrawal of ART and will continue maintenance 10-1074 (30 mg/kg) and VRC01LS (15 mg/kg) treatment for up to 24 weeks. In Step 3, both 10-1074 and VRC01LS will be discontinued and ART will be re-started. | Drug: ART<br>* ART will not be provided by the study. Participants will continue to receive their ART regimen they were receiving prior to enrolling in the study.<br>Biological: VRC01LS<br>* Administered by intravenous (IV) infusion<br>Biological: 10-1074<br>* Administered by intravenous (IV) infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Treatment-associated Adverse Events (AEs) [Number of Participants With Treatment-associated Adverse Event(s) of Any Grade] |  | Measured until 30 days after study completion for each participant | 
| Severity of Treatment-associated AEs (Number of Participants With Grade 3 or Higher Related AEs) | Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table). The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with Grade 1 indicating a mild event, Grade 2 indicating a moderate event, Grade 3 indicating a severe event, Grade 4 indicating a potentially life-threatening event, and Grade 5 indicating death. | Measured until 30 days after study completion for each participant | 
| Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 400 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART | Based on laboratory evaluations | Measured through Week 24 of Step 2 | 
| Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 40 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART | Based on laboratory evaluations | Measured through Week 24 of Step 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VRC01LS or 10-1074 Concentrations in Plasma | Median pre-dose trough (28 days post previous dose) based on laboratory evaluations | Measured through Week 12 (PK Step) | 
| Median Trough Concentration of VRC01LS or 10-1074 in Plasma 28 Days After the Third Dose | Based on laboratory evaluations | Measured through Week 12 (PK Step) | 
| VRC01LS and 10-1074 Concentrations in Plasma for Each Time Point | Based on laboratory evaluations | Measured through Week 32 following Step 1 entry | 
| Proportion of Children With Trough VRC01LS and 10-1074 Concentrations Below Defined Trough Ranges | Based on laboratory evaluations | Measured through Week 32 following Step 1 entry | 
| Height Z-scores of Virally Suppressed Children Receiving bNAbs | World Health Organization (WHO) standardized Z-scores will be evaluated for changes over time: WHO Length/height-for-age z-score (0-19 yrs), Change from Step 1, Day 0 to Step 3, Week 24. A z-score of 0 corresponds to the population mean. Scores above 0 indicate a participant's height is above the mean, while a score below 0 indicates a participant's height is below the mean. A positive change in z-score corresponds to a higher z-score at the second timepoint compared to the first. | Measured through Week 24 (Step 3) | 
| Weight Z-scores of Virally Suppressed Children Receiving bNAbs | WHO standardized Z-scores will be evaluated for changes over time: WHO Weight-for-age z-score (0-10 yrs), Change from Step 1, Day 0 to Step 3, Week 24. A z-score of 0 corresponds to the population mean. Scores above 0 indicate a participant's weight is above the mean, while a score below 0 indicates a participant's weight is below the mean. A positive change in z-score corresponds to a higher z-score at the second timepoint compared to the first. | Measured through Week 24 (Step 3) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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broadly neutralizing antibodies, HIV suppression