Evaluating the Safety and Pharmacokinetics of VRC01, VRC01LS, and VRC07-523LS, Potent Anti-HIV Neutralizing Monoclonal Antibodies, in HIV-1-Exposed Infants

Study Overview
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Brief Summary
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The purpose of this study was to assess the safety and pharmacokinetics (PK) of three monoclonal antibodies, VRC01, VRC01LS, and VRC07-523LS, in HIV-exposed infants who are at increased risk of mother-to-child HIV transmission.

Detailed Description
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VRC01, VRC01LS, and VRC07-523LS are anti-HIV neutralizing monoclonal antibodies that may help prevent mother-to-child transmission of HIV. This study enrolled HIV-infected mothers who were at increased risk of passing HIV on to their children. The purpose of this study was to assess the safety and PK of VRC01, VRC01LS, and VRC07-523LS in HIV-exposed infants. This study enrolled mother-infant pairs into five dose groups. Infants enrolled in Dose Group 1 and Dose Group 2 received a single VRC01 injection less than 72 hours after birth. Infants in Dose Group 3 received a VRC01 injection less than 5 days after birth, followed by VRC01 injections monthly for at least 6 months and no more than 18 months, while breastfeeding. Dose Groups 4 and 5 each enrolled infants into two cohorts: Cohort 1 (non-breastfeeding) or Cohort 2 (breastfeeding). Infants in Dose Group 4, Cohort 1 received a single VRC01LS injection less than 72 hours after birth. Infants in Dose Group 4, Cohort 2 received an initial VRC01LS injection no longer than 5 days after birth, and a second VRC01LS injection at Week 12 if they were still breastfeeding. Infants in Dose Group 5, Cohort 1 received a single VRC07-523LS injection less than 72 hours after birth. Infants in Dose Group 5, Cohort 2 received an initial VRC07-523LS injection no longer than 5 days after birth, and a second VRC07-523LS injection at Week 12 if they were still breastfeeding. The mothers did not receive any VRC01, VRC01LS, or VRC07-523LS injections. At study entry, all mothers underwent a medical history review and a blood collection, and then the study ended for the mothers. Infants in Dose Groups 1 and 2 attended study visits at days 0, 1, 3, 7, 14, 28 and at weeks 8, 16, 24, and 48. Infants in Dose Group 3 attended study visits at days 0, 1, 14, 28 and at weeks 8, 12, 16, 20, 24, and every 4 weeks until cessation of breastfeeding or week 72, then at weeks 84 and 96. Infants in Dose Group 4 attended study visits at days 0, 1, 14, 28 and at weeks 8, 12, 24, 36, 48, 60, 72, 84 and 96, with additional visits at weeks 14 and 16 for Cohort 2 participants. Infants in Dose Group 5 attended study visits at days 0, 1, 3, 7, 14, 28 and at weeks 8, 12, 24, 36, 48, 60, 72, 84 and 96, with additional visits at weeks 14 and 16 for Cohort 2 participants. Visits included a medical history review, physical examination, blood collection, and oral fluid collection.

Official Title
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Open-Label, Dose-Escalating, Phase I Study to Determine Safety and Pharmacokinetic Parameters of Subcutaneous (SC) VRC01, VRC01LS, and VRC07-523LS, Potent Anti-HIV Neutralizing Monoclonal Antibodies, in HIV-1-Exposed Infants

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: VRC01
* Biological: VRC01LS
* Biological: VRC07-523LS


Participation Criteria
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Eligibility Criteria
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Maternal Inclusion Criteria: HIV infection Greater than or equal to 18 years of age Able and willing to provide signed informed consent for herself and her infant Maternal Exclusion Criteria: Prior participation in any HIV-1 vaccine trial Receipt of any other active or passive HIV immunotherapy or investigational product during this pregnancy. (Note that administration of Food and Drug Administration [FDA]-approved antiretroviral (ARV) drugs when used to treat disease or prevent mother-to-child transmission were not considered investigational.) Documented or suspected serious medical illness or immediate life-threatening condition (other than HIV infection) in the mother that may have interfered with the ability to complete study requirements, as judged by the examining clinician Infant Inclusion Criteria: Born to an HIV-1-infected woman who met all maternal inclusion/exclusion criteria listed above Gestational age, by best obstetrical, ultrasound, or infant exam, greater than or equal to 36 weeks Birth weight greater than or equal to 2.0 kg Allowable infant age at the time of enrollment was dependent on the Dose Group and Cohort: Dose Groups 1, 2, 4 and 5 (Cohort 1): Less than 72 hours of age, and anticipated availability to receive VRC immunization at less than 72 hours after birth. Dose Groups 3, 4 and 5 (Cohort 2): Less than or equal to 5 days of age, and anticipated availability to receive VRC immunization no more than 5 days after birth. At increased risk of HIV acquisition defined as documentation of one or more of the following risk factors: Dose Groups 1, 2, 4 and 5 (Cohort 1), only: Mother received no antiretroviral therapy (ART) during pregnancy or mother began or reinitiated ART (after an interruption of greater than 14 days), during the third trimester of pregnancy; or Mother with any detectable viral replication (HIV RNA above the limit of detection) at last measurement prior to delivery determined within 30 days of delivery; or Prolonged rupture of membranes (greater than 12 hours); or Mother with documented 2-class resistant HIV infection, which may have included historical documentation of lack of response Women who had a documented history of virologic failure while on non-nucleoside reverse transcriptase inhibitors (NNRTIs) but who had no resistance testing at the time of viral failure were considered to have NNRTI-documented resistance. Dose Groups 3, 4 and 5 (Cohort 2), only (African sites): Mother intended to breastfeed Infant Exclusion Criteria: Receipt of any other active or passive HIV immunotherapy or investigational product other than the study vaccine (Note: Infant prophylaxis with any licensed ARV drugs clinically prescribed to prevent mother-to-child HIV transmission were not considered investigational.) Receipt of or anticipated need for blood products, immunoglobulin, or immunosuppressive therapy. This included infants who required hepatitis B immunoglobulin (HBIG) but did not require exclusion of infants who received hepatitis B vaccine in the newborn period. Documented or suspected serious medical illness, serious congenital anomaly, or immediate life-threatening condition in the infant that may have interfered with the ability to complete study requirements, as judged by the examining clinician Any requirement for supplemental oxygen beyond 24 hours of life or requiring supplemental oxygen at the time of the VRC01, VRC01LS, or VRC07-523LS dose Baseline laboratory results: Hemoglobin less than 12.0 g/dL Platelet count less than 100,000 cells/mm^3 Absolute neutrophil count: for infants less than or equal to 24 hours old, less than 4,000 cells/mm^3; for infants greater than 24 hours old, less than 1,250 cells/mm^3 Serum glutamic pyruvic transaminase (SGPT) greater than or equal to 1.25 times upper limit of age adjusted normal Dose Groups 1, 2, 4 and 5 (Cohort 1), only: Infant was breastfeeding at time of enrollment or mother had indicated an intention to initiate breastfeeding. Note: if a child was breastfed prior to known maternal diagnosis (in the case of a woman diagnosed in the intrapartum period), the child was still eligible as long as breastfeeding was stopped by the time the child was enrolled and there was no plan to resume breast milk feeding.

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 5 Days

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Group 1<br>Infants in Dose Group 1 received a single VRC01 20 mg/kg injection less than 72 hours after birth. | Biological: VRC01<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC01 mAb;|
| Experimental: Dose Group 2<br>Infants in Dose Group 2 received a single VRC01 40 mg/kg injection less than 72 hours after birth. | Biological: VRC01<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC01 mAb;|
| Experimental: Dose Group 3<br>Infants in Dose Group 3 received a VRC01 40 mg/kg injection less than 5 days after birth. They then received a VRC01 20 mg/kg injection monthly for at least 6 months and no more than 18 months while breastfeeding. | Biological: VRC01<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC01 mAb;|
| Experimental: Dose Group 4, Cohort 1<br>Infants in Cohort 1 received a single VRC01LS injection less than 72 hours after birth. Dose was based on weight: 80 mg for infants weighing less than 4.5 kg and 100 mg for infants weighing 4.5 kg or greater. | Biological: VRC01LS<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC-HIVMAB080-00-AB;|
| Experimental: Dose Group 4, Cohort 2<br>Infants in Cohort 2 received an initial VRC01LS injection no longer than 5 days after birth. Dose was based on weight: 80 mg for infants weighing less than 4.5 kg and 100 mg for infants weighing 4.5 kg or greater. A second dose of 100 mg VRC01LS was administered at Week 12 if an infant was still breastfeeding. | Biological: VRC01LS<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC-HIVMAB080-00-AB;|
| Experimental: Dose Group 5, Cohort 1<br>Infants in Cohort 1 received a single VRC07-523LS injection less than 72 hours after birth. Dose was based on weight: 80 mg for infants weighing less than 4.5 kg and 100 mg for infants weighing 4.5 kg or greater. | Biological: VRC07-523LS<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC-HIVMAB075-00-AB;|
| Experimental: Dose Group 5, Cohort 2<br>Infants in Cohort 2 received an initial VRC07-523LS injection no longer than 5 days after birth. Dose was based on weight: 80 mg for infants weighing less than 4.5 kg and 100 mg for infants weighing 4.5 kg or greater. A second dose of 100 mg VRC07-523LS was administered at Week 12 if an infant was still breastfeeding. | Biological: VRC07-523LS<br>* Administered by subcutaneous injection in the thigh<br>* Other names: VRC-HIVMAB075-00-AB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died | The Overall Number of Participants Analyzed represents infants. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Deaths from day 0 to 4 weeks after the participants' last immunization were included. | From day 0 to 4 weeks after last immunization (at week 4 for Dose Groups 1, 2, 4-Cohort 1, 5-Cohort 1; at week 16-48 for Dose Group 3; at week 16 for Dose Group 4-Cohort 2, 5-Cohort 2.) | 
| Percentage of Participants With an Occurrence of at Least One Grade 3 or Higher Adverse Event (AE) | The Overall Number of Participants Analyzed represents infants. AE severity grading was based on the Division of AIDS (DAIDS) AE Grading table, Corrected Version 2.1. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Adverse events from day 0 to 4 weeks after the participants' last immunization were included. | From day 0 to 4 weeks after last immunization (at week 4 for Dose Groups 1, 2, 4-Cohort 1, 5-Cohort 1; at week 16-48 for Dose Group 3; at week 16 for Dose Group 4-Cohort 2, 5-Cohort 2.) | 
| Percentage of Participants With at Least One VRC01-, VRC01LS-, or VRC07-523LS-related Grade 3 or Higher Adverse Event (AE) | The Overall Number of Participants Analyzed represents infants. AE severity grading was based on the Division of AIDS (DAIDS) AE Grading table, Corrected Version 2.1. The study sites assessed and determined if AEs were related to study treatment. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Adverse events from day 0 to 4 weeks after the participants' last immunization were included. | From day 0 to 4 weeks after last immunization (at week 4 for Dose Groups 1, 2, 4-Cohort 1, 5-Cohort 1; at week 16-48 for Dose Group 3; at week 16 for Dose Group 4-Cohort 2, 5-Cohort 2.) | 
| Percentage of Participants Diagnosed With HIV Infection | The Overall Number of Participants Analyzed represents infants. Diagnosis testing was performed using a HIV-1 NAT (nucleic acid testing) by a method that detects DNA. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. HIV diagnoses from day 0 to 4 weeks after the participants' last immunization were included. | From day 0 to 4 weeks after last immunization (at week 4 for Dose Groups 1, 2, 4-Cohort 1, 5-Cohort 1; at week 16-48 for Dose Group 3; at week 16 for Dose Group 4-Cohort 2, 5-Cohort 2.) | 
| Pharmacokinetics (PK) Parameter: Area Under the Curve (AUC) for Dose Groups 1, 2, 3 and 4 | The Overall Number of Participants Analyzed represents infants. PK parameters were determined from plasma concentration-time profiles using noncompartmental methods (SAS 9.4, Cary, NC). AUC0-28 days (area-under-the-curve from 0 to 28 days) for Dose Groups 1, 2 and 3 and AUC0-84 days for Dose Group 4, were determined using the linear trapezoidal rule. Median and range were summarized. | Dose Groups (DG) 1, 2: at days 0, 1, 3, 7, 14, 28; DG 3: at days 0, 1, 14, 28, weeks 16, 20, 24; DG 4-Cohort 1: at days 0, 1, 14, 28; Cohort 2: at days 0, 1, 14, 28, 84. | 
| Pharmacokinetics (PK) Parameter: Area Under the Curve (AUC) for Dose Group 5 | The Overall Number of Participants Analyzed represents infants. PK parameters were determined from plasma concentration-time profiles using noncompartmental methods (SAS 9.4, Cary, NC). AUC0-84 days (area-under-the-curve from 0 to 84 days) were determined using the linear trapezoidal rule. Median and range were summarized. | Dose Group 5 - Cohort 1: at days 0, 1, 3, 7, 14, 28; Cohort 2: at days 0, 1, 3, 7, 14, 28, 84. | 
| Pharmacokinetics (PK) Parameter: Concentration for Dose Groups 1, 2, 3 and 4 | The Overall Number of Participants Analyzed represents infants. PK parameters were determined from plasma concentration-time profiles using noncompartmental methods (SAS 9.4, Cary, NC). Median and range were summarized for C28 days (concentration at 28 days) for Dose Groups 1, 2 and 3 and C84 days for Dose Group 4. | Dose Groups (DG) 1, 2: at days 0, 1, 3, 7, 14, 28; DG 3: at days 0, 1, 14, 28, weeks 16, 20, 24; DG 4-Cohort 1: at days 0, 1, 14, 28; Cohort 2: at days 0, 1, 14, 28, 84. | 
| Pharmacokinetics (PK) Parameter: Concentration for Dose Group 5 | The Overall Number of Participants Analyzed represents infants. PK parameters were determined from plasma concentration-time profiles using noncompartmental methods (SAS 9.4, Cary, NC). Median and range were summarized for C84 days (concentration at 84 days). | Dose Group 5 - Cohort 1: at days 0, 1, 3, 7, 14, 28; Cohort 2: at days 0, 1, 3, 7, 14, 28, 84. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died After Last Immunization for Dose Groups 1, 2, 3 and 4 | The Overall Number of Participants Analyzed represents infants. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Data for Dose Groups 1, 2, 3 and 4 are presented here. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 48 for Dose Groups 1 and 2 and at week 96 for Dose Group 3 and 4). | 
| Percentage of Participants Who Died After Last Immunization for Dose Group 5 | The Overall Number of Participants Analyzed represents infants. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 96 for Dose Group 5). | 
| Percentage of Participants With an Occurrence of at Least One Grade 3 or Higher Adverse Event (AE) After Last Immunization for Dose Groups 1, 2, 3 and 4 | The Overall Number of Participants Analyzed represents infants. AE severity grading was based on the Division of AIDS (DAIDS) AE Grading table, Corrected Version 2.1. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Data for Dose Groups 1, 2, 3 and 4 are presented here. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 48 for Dose Groups 1 and 2 and at week 96 for Dose Groups 3 and 4). | 
| Percentage of Participants With an Occurrence of at Least One Grade 3 or Higher Adverse Event (AE) After Last Immunization For Dose Group 5 | The Overall Number of Participants Analyzed represents infants. AE severity grading was based on the Division of AIDS (DAIDS) AE Grading table, Corrected Version 2.1. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 96 for Dose Group 5). | 
| Percentage of Participants With at Least One VRC01-, VRC01LS-, or VRC07-523LS-related Grade 3 or Higher Adverse Event (AE) After Last Immunization For Dose Groups 1, 2, 3, and 4 | The Overall Number of Participants Analyzed represents infants. AE severity grading was based on the Division of AIDS (DAIDS) AE Grading table, Corrected Version 2.1. The study sites assessed if AEs were related to study treatment. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Data for Dose Groups 1, 2, 3 and 4 are presented here. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 48 for Dose Groups 1 and 2 and at week 96 for Dose Groups 3 and 4). | 
| Percentage of Participants With at Least One VRC01-, VRC01LS-, or VRC07-523LS-related Grade 3 or Higher Adverse Event (AE) After Last Immunization for Dose Group 5 | The Overall Number of Participants Analyzed represents infants. AE severity grading was based on the Division of AIDS (DAIDS) AE Grading table, Corrected Version 2.1. The study sites assessed if AEs were related to study treatment. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 96 for Dose Group 5). | 
| Percentage of Participants Diagnosed With HIV Infection After Last Immunization for Dose Groups 1, 2, 3, and 4 | The Overall Number of Participants Analyzed represents infants. Diagnosis testing was performed using a HIV-1 NAT (nucleic acid testing) by a method that detects DNA. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. Data for Dose Groups 1, 2, 3 and 4 are presented here. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 48 for Dose Groups 1 and 2 and at week 96 for Dose Groups 3 and 4). | 
| Percentage of Participants Diagnosed With HIV Infection After Last Immunization for Dose Group 5 | The Overall Number of Participants Analyzed represents infants. Diagnosis testing was performed using a HIV-1 NAT (nucleic acid testing) by a method that detects DNA. Two-sided 90% exact Clopper-Pearson confidence intervals (CI) were calculated. | From four weeks after the participants' last immunization to the end of the study follow-up (at week 96 for Dose Group 5). | 
| Number of Participants Who Developed Anti-VRC Antibodies | The Overall Number of Participants Analyzed represents infants with samples collected and tested. The number of infants who developed anti antibodies to the study products are summarized. For Dose Groups 1, 2, and 3, these are anti-VRC01 antibodies. For Dose Group 4, these are anti-VCR07 antibodies and for Dose Group 5, these are anti-VRC07-523LS antibodies. | At weeks 24 and 48. |