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Dual bNAb Treatment in Children

Primary Purpose

HIV Infection

Status
Completed
Phase
Phase 1
Locations
Botswana
Study Type
Interventional
Intervention
ART
VRC01LS
10-1074
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infection focused on measuring broadly neutralizing antibodies, HIV suppression

Eligibility Criteria

96 Weeks - 7 Years (Child)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Francistown Non-Network CRS
  • Botswana Harvard AIDS Institute Partnership CRS Non-Network

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Group PK-A: ART + VRC01LS

Group PK-B: ART + 10-1074

Steps 1-3 Participants (ART + 10-1074 + VRC01LS)

Arm Description

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).

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).

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.

Outcomes

Primary Outcome Measures

Frequency of Treatment-associated Adverse Events (AEs) [Number of Participants With Treatment-associated Adverse Event(s) of Any Grade]
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.
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
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

Secondary Outcome Measures

VRC01LS or 10-1074 Concentrations in Plasma
Median pre-dose trough (28 days post previous dose) based on laboratory evaluations
Median Trough Concentration of VRC01LS or 10-1074 in Plasma 28 Days After the Third Dose
Based on laboratory evaluations
VRC01LS and 10-1074 Concentrations in Plasma for Each Time Point
Based on laboratory evaluations
Proportion of Children With Trough VRC01LS and 10-1074 Concentrations Below Defined Trough Ranges
Based on laboratory evaluations
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.
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.

Full Information

First Posted
October 12, 2018
Last Updated
January 18, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT03707977
Brief Title
Dual bNAb Treatment in Children
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
June 17, 2019 (Actual)
Primary Completion Date
December 3, 2021 (Actual)
Study Completion Date
December 3, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infection
Keywords
broadly neutralizing antibodies, HIV suppression

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group PK-A: ART + VRC01LS
Arm Type
Experimental
Arm Description
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).
Arm Title
Group PK-B: ART + 10-1074
Arm Type
Experimental
Arm Description
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).
Arm Title
Steps 1-3 Participants (ART + 10-1074 + VRC01LS)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ART
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
VRC01LS
Intervention Description
Administered by intravenous (IV) infusion
Intervention Type
Biological
Intervention Name(s)
10-1074
Intervention Description
Administered by intravenous (IV) infusion
Primary Outcome Measure Information:
Title
Frequency of Treatment-associated Adverse Events (AEs) [Number of Participants With Treatment-associated Adverse Event(s) of Any Grade]
Time Frame
Measured until 30 days after study completion for each participant
Title
Severity of Treatment-associated AEs (Number of Participants With Grade 3 or Higher Related AEs)
Description
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.
Time Frame
Measured until 30 days after study completion for each participant
Title
Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 400 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART
Description
Based on laboratory evaluations
Time Frame
Measured through Week 24 of Step 2
Title
Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 40 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART
Description
Based on laboratory evaluations
Time Frame
Measured through Week 24 of Step 2
Secondary Outcome Measure Information:
Title
VRC01LS or 10-1074 Concentrations in Plasma
Description
Median pre-dose trough (28 days post previous dose) based on laboratory evaluations
Time Frame
Measured through Week 12 (PK Step)
Title
Median Trough Concentration of VRC01LS or 10-1074 in Plasma 28 Days After the Third Dose
Description
Based on laboratory evaluations
Time Frame
Measured through Week 12 (PK Step)
Title
VRC01LS and 10-1074 Concentrations in Plasma for Each Time Point
Description
Based on laboratory evaluations
Time Frame
Measured through Week 32 following Step 1 entry
Title
Proportion of Children With Trough VRC01LS and 10-1074 Concentrations Below Defined Trough Ranges
Description
Based on laboratory evaluations
Time Frame
Measured through Week 32 following Step 1 entry
Title
Height Z-scores of Virally Suppressed Children Receiving bNAbs
Description
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.
Time Frame
Measured through Week 24 (Step 3)
Title
Weight Z-scores of Virally Suppressed Children Receiving bNAbs
Description
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.
Time Frame
Measured through Week 24 (Step 3)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
96 Weeks
Maximum Age & Unit of Time
7 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roger Shapiro, MD, MPH
Organizational Affiliation
Harvard School of Public Health (HSPH)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Daniel Kuritzkes, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mathias Lichterfeld, MD, PhD
Organizational Affiliation
Brigham and Women's Hospital/Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Francistown Non-Network CRS
City
Francistown
Country
Botswana
Facility Name
Botswana Harvard AIDS Institute Partnership CRS Non-Network
City
Gaborone
Country
Botswana

12. IPD Sharing Statement

Citations:
PubMed Identifier
36094485
Citation
Capparelli EV, Ajibola G, Maswabi K, Holme MP, Bennett K, Powis KM, Moyo S, Mohammed T, Maphorisa C, Hughes MD, Seaton KE, Tomaras GD, Mosher S, Taylor A, O'Connell S, Narpala S, Mcdermott A, Caskey M, Gama L, Lockman S, Jean-Philippe P, Makhema J, Kuritzkes DR, Lichterfeld M, Shapiro RL; Tatelo Study Team. Safety and Pharmacokinetics of Intravenous 10-1074 and VRC01LS in Young Children. J Acquir Immune Defic Syndr. 2022 Oct 1;91(2):182-188. doi: 10.1097/QAI.0000000000003033.
Results Reference
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Dual bNAb Treatment in Children

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