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

NCT02256631 | Completed Phase 1 Results DMC

• 2 other identifiers: IMPAACT P111211903
• Study Type: interventional
• Target: 83
• Locations: 4 countries
• Sites: 14

Brief Summary

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (9)

• Percentage of Participants Who Died After Last Immunization for Dose Groups 1, 2, 3 and 4

  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

  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

  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

  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

  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).

Study Arms (7)

Dose Group 1

EXPERIMENTAL

Infants in Dose Group 1 received a single VRC01 20 mg/kg injection less than 72 hours after birth.

Biological: VRC01

Dose Group 2

EXPERIMENTAL

Infants in Dose Group 2 received a single VRC01 40 mg/kg injection less than 72 hours after birth.

Biological: VRC01

Dose Group 3

EXPERIMENTAL

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

Dose Group 4, Cohort 1

EXPERIMENTAL

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

Dose Group 4, Cohort 2

EXPERIMENTAL

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

Dose Group 5, Cohort 1

EXPERIMENTAL

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

Dose Group 5, Cohort 2

EXPERIMENTAL

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

Interventions

VRC01 BIOLOGICAL

Administered by subcutaneous injection in the thigh

Also known as: VRC-HIVMAB-060-00-AB, VRC01 mAb

Dose Group 1; Dose Group 2; Dose Group 3

VRC01LS BIOLOGICAL

Administered by subcutaneous injection in the thigh

Also known as: VRC-HIVMAB080-00-AB

Dose Group 4, Cohort 1; Dose Group 4, Cohort 2

VRC07-523LS BIOLOGICAL

Administered by subcutaneous injection in the thigh

Also known as: VRC-HIVMAB075-00-AB

Dose Group 5, Cohort 1; Dose Group 5, Cohort 2

Eligibility Criteria

• Age: 0 Days - 5 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• HIV infection
• Greater than or equal to 18 years of age
• Able and willing to provide signed informed consent for herself and her infant

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (14)

David Geffen School of Medicine at UCLA NICHD CRS

Los Angeles, California, 90095-1752, United States

Location

Univ. of Colorado Denver NICHD CRS

Aurora, Colorado, 80045, United States

Location

South Florida CDTC Ft Lauderdale NICHD CRS

Fort Lauderdale, Florida, 33316, United States

Location

Univ. of Florida Jacksonville NICHD CRS

Jacksonville, Florida, 32209, United States

Location

Pediatric Perinatal HIV Clinical Trials Unit CRS

Miami, Florida, 33136, United States

Location

Emory University School of Medicine NICHD CRS

Atlanta, Georgia, 30322, United States

Location

Johns Hopkins Univ. Baltimore NICHD CRS

Baltimore, Maryland, 21287, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS

The Bronx, New York, 10457, United States

Location

Jacobi Med. Ctr. Bronx NICHD CRS

The Bronx, New York, 10461, United States

Location

Texas Children's Hospital CRS

Houston, Texas, 77030-2399, United States

Location

San Juan City Hosp. PR NICHD CRS

San Juan, PR, 00936, Puerto Rico

Location

University of Puerto Rico Pediatric HIV/AIDS Research Program CRS

San Juan, 00935, Puerto Rico

Location

Famcru Crs

Tygerberg, Western Cape, 7505, South Africa

Location

Harare Family Care CRS

Harare, Zimbabwe

Location

Related Publications (2)

• Cunningham CK, McFarland EJ, Morrison RL, Capparelli EV, Safrit JT, Mofenson LM, Mathieson B, Valentine ME, Perlowski C, Smith B, Hazra R, Purdue L, Muresan P, Harding PA, Mbengeranwa T, Robinson LG, Wiznia A, Theron G, Lin B, Bailer RT, Mascola JR, Graham BS; IMPAACT P1112 team. Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants. J Infect Dis. 2020 Jul 23;222(4):628-636. doi: 10.1093/infdis/jiz532.

  PMID: 31681963 RESULT

• McFarland EJ, Cunningham CK, Muresan P, Capparelli EV, Perlowski C, Morgan P, Smith B, Hazra R, Purdue L, Harding PA, Theron G, Mujuru H, Agwu A, Purswani M, Rathore MH, Flach B, Taylor A, Lin BC, McDermott AB, Mascola JR, Graham BS; International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1112 Team. Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants. J Infect Dis. 2021 Dec 1;224(11):1916-1924. doi: 10.1093/infdis/jiab229.

  PMID: 34009371 RESULT

Related Links

• Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 - July 2017)
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Coleen Cunningham, MD

  Duke University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2014
• First Posted: October 3, 2014
• Study Start: June 30, 2015
• Primary Completion: June 17, 2020
• Study Completion: December 16, 2021
• Last Updated: February 8, 2023
• Results First Posted: August 23, 2021

Record last verified: 2023-01

Locations

US (10); ZA (1); ZI (1); PR (2)