Safety and Tolerability of AAV8 Delivery of a Broadly Neutralizing Antibody in Adults Living With HIV: a Phase 1, Dose-escalation Trial

NCT03374202 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: 18003018-I-0030
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The Human Immunodeficiency Virus (HIV) attacks the immune system. Scientists have created a gene that could be transferred to the cells of people with HIV. The gene should tell the cells to make an antibody called VRC07. This antibody fights HIV. The VRC07 gene is packaged into a man-made version of a virus called AAV8. Objectives: To see if AAV8-VRC07 is safe. To study if it causes cells to produce the VRC07 antibody. Eligibility: Adults ages 18-65 who are HIV infected but in general good health and have been taking the same HIV medicine for at least 3 months Design: Participants were screened in a different protocol. Participants received the study product on day 1. It was injected one or more times in the upper arm or thigh using a needle. Participants weight was measured to calculate the dose. Women may have had a pregnancy test. For 7 days after getting the study product, participants checked their temperature with a thermometer. They noted any symptoms in an electronic or paper diary. Participants will have study visits. At each one, they will have a physical exam and medical history. They will have blood drawn and may have saliva collected. The study visit schedule is as follows: For 12 weeks: 1 visit a week For the next 12 weeks: 1 visit every other week Then about 1 visit a month After 1 year in the study: a visit every 6 months for the next 4 years. Total study participation is 5 years.

Conditions

HIV-1 Infected Adults With Controlled Viremia

Keywords

ARV Therapy; Broadly Neutralizing; Gene Transfer; Monoclonal Antibody; AAV8

Outcome Measures

Primary Outcomes (10)

• Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of AAV8-VRC07 Product Administration

  Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.

  7 days after AAV8-VRC07 product administration, at approximately Week 1

• Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of AAV8-VRC07 Product Administration

  Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.

  7 days after AAV8-VRC07 product administration, at approximately Week 1

• Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following AAV8-VRC07 Product Administration

  Unsolicited adverse event (AE) data collection included AEs of all severities from the date of product administration through the Day 56 (8 weeks) post-product administration visit. After the Day 56 (8 weeks) post-product administration visit, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that require ongoing medical management (reported as a separate outcome) will be recorded through the last study visit. The relationship between a non-serious AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

  Day 0 through 8 weeks after AAV8-VRC07 product administration

• Number of Participants With Abnormal Laboratory Measures of Safety Following AAV8-VRC07 Product Administration

  Abnormal laboratory results recorded as unsolicited adverse events (AEs) are summarized. Safety lab parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, and neutrophil, lymphocyte, monocyte, eosinophil and basophil counts) and chemistry (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine). Complete Blood Count (CBC) with differential and chemistry (ALT, AST and creatinine) results were collected at different timepoints throughout the study per the protocol's schedule of evaluations. Institutional laboratory normal ranges as well as the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 were used.

  Day 0 through 8 weeks after AAV8-VRC07 product administration

• Geometric Mean Endpoint Titer of Anti-AAV8 Antibodies

  Anti-AAV8 antibodies were analyzed by enzyme-linked immunosorbent assay (ELISA) using a vector-matched AAV8 capsid as the capture agent. Group geometric means and 95% confidence intervals (CIs) for the endpoint titers for the AAV8 ELISA assay are reported at baseline, week 12 for the peak response, and week 44 for durability. Values below the lower limit of detection (LOD) were imputed to the lower LOD (30) and values above the assay upper LOD were imputed to the upper LOD (21870).

  Day 0 through 44 Weeks after AAV8-VRC07 product administration

• Number of Participants Who Attained A 50 mcg/mL VRC07 Serum Concentration

  In order to determine the optimal AAV8-VRC07 dose, participants must have attained a 50 mcg/mL VRC07 Serum Concentration. If no participants attained at least 50 mcg/mL VRC07 serum concentration, then the optimal AAV8-VRC07 dose cannot be determined.

  Day 0 through 52 Weeks after AAV8-VRC07 product administration

• Geometric Mean Concentration of VRC07 Serum Antibodies (PK ELISA)

  For the pharmacokinetic (PK) primary outcome analysis, PK ELISA detected VRC07 serum antibodies in mcg/mL, using the VRC01 anti-idiotype Fab specific 5C9 monoclonal antibody (mAb). Only visits that had detectable PK ELISA concentrations for any participant are reported. Results are reported in group geometric mean mcg/mL concentrations with 95% CIs. The protocol specifies that a more sensitive assay can also be used; the more sensitive Singulex assay results are reported later in the secondary outcome measure. Values below the lower limit of detection (LOD) were imputed to the lower LOD (1 mcg/mL) with no 95% CI.

  Day 0 through 52 Weeks after AAV8-VRC07 product administration

• Number of Participants With Serious Adverse Events (SAEs) Following AAV8-VRC07 Product Administration

  SAEs are recorded from receipt of study product through the last expected study visit at Year 5 (260 weeks). The relationship between a SAE and the study product is assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

  Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration

• Number of Participants With New Chronic Medical Conditions Following AAV8-VRC07 Product Administration

  New chronic medical conditions are recorded from receipt of study product through the last expected study visit at Year 5 (260 weeks). The relationship between a new chronic medical condition and the study product is assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

  Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration

• Number of Participants Who Produced VRC07 Anti-drug Antibodies (ADA)

  A three-tiered assay was used for ADA evaluation. The tier 1 screening assay measures specific and non-specific binding of serum proteins to VRC07 and the assay membrane. The tier 2 assay is a qualitative competition assay in which exogenously added VRC07 removes any VRC07-binding proteins from the serum prior to the binding assay. If the addition of the exogenous VRC07 results in a reduction of signal, the specificity of VRC07 binding is confirmed. The tier 3 assay is a qualitative assay that assesses the ability of VRC07-binding serum protein to prevent VRC07-mediated neutralization of an HIV pseudovirus in vitro. Only samples positive for a tier will be analyzed in subsequent tiers.

  Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration

Secondary Outcomes (3)

• Geometric Mean Value of CD4 Cell Counts

  Day 0 through 44 Weeks after AAV8-VRC07 product administration

• Viral Load

  Day 0 through 44 Weeks after AAV8-VRC07 product administration

• Concentration of VRC07 Serum Antibodies (Singulex Assay)

  Day 0 through 52 weeks after AAV8-VRC07 product administration

Study Arms (3)

Group 1: AAV8-VRC07 (5 x 10^10 vg/kg IM)

EXPERIMENTAL

AAV8-VRC07 (5 x 10\^10 vg/kg) administered by intramuscular (IM) injection (Day 0)

Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)

Group 2: AAV8-VRC07 (5 x 10^11 vg/kg IM)

EXPERIMENTAL

AAV8-VRC07 (5 x 10\^11 vg/kg) administered by IM injection (Day 0)

Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)

Group 3: AAV8-VRC07 (2.5 x 10^12 vg/kg IM)

EXPERIMENTAL

AAV8-VRC07 (2.5 x 10\^12 vg/kg) administered by IM injection (Day 0)

Genetic: VRC-HIVAAV070-00-GT (AAV8-VRC07)

Interventions

VRC-HIVAAV070-00-GT (AAV8-VRC07) GENETIC

AAV8-VRC07 is a recombinant AAV vector expressing a HIV-1 CD4 binding site-specific neutralizing antibody, VRC07

Group 1: AAV8-VRC07 (5 x 10^10 vg/kg IM); Group 2: AAV8-VRC07 (5 x 10^11 vg/kg IM); Group 3: AAV8-VRC07 (2.5 x 10^12 vg/kg IM)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A volunteer must have met all of the following criteria:
• Able and willing to complete the informed consent process.
• to 65 years of age.
• HIV-1 infected.
• On a stable antiretroviral regimen for greater than or equal to 3 months.
• Available for clinical follow-up through the last study visit.

You may not qualify if:

• Willing to maintain or establish a relationship with a primary health care provider for medical management of HIV infection while participating in the study.
• Willing to have blood samples collected, stored indefinitely, and used for research purposes.
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
• Laboratory tests assessing individual's health will be conducted within 84 days prior to enrollment and values must meet the following criteria:
• White blood cell count (WBC) 2,500-12,000/mm\^3;
• WBC differential either within institutional normal range or accompanied by approval of the Principal Investigator (PI) or designee;
• Platelets = 125,000-400,000/mm\^3;
• Hemoglobin greater than or equal to 10.0 gm/dL;
• Creatinine less than or equal to 1.25 x upper limit of normal (ULN);
• Alanine aminotransferase (ALT) less than or equal to 1.1 x ULN;
• Aspartate aminotransferase (AST) less than or equal to 1.1 x ULN; and,
• Viral Load (VL) less than or equal to 50 copies/mL and a CD4 count greater than or equal to 300/mcL (microliter).
• Male-Specific Criteria:
• Males must agree to use condoms for all sexual activity of any reproductive potential for 52 weeks after receiving the study product.
• Female-Specific Criteria:

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Lynch RM, Boritz E, Coates EE, DeZure A, Madden P, Costner P, Enama ME, Plummer S, Holman L, Hendel CS, Gordon I, Casazza J, Conan-Cibotti M, Migueles SA, Tressler R, Bailer RT, McDermott A, Narpala S, O'Dell S, Wolf G, Lifson JD, Freemire BA, Gorelick RJ, Pandey JP, Mohan S, Chomont N, Fromentin R, Chun TW, Fauci AS, Schwartz RM, Koup RA, Douek DC, Hu Z, Capparelli E, Graham BS, Mascola JR, Ledgerwood JE; VRC 601 Study Team. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015 Dec 23;7(319):319ra206. doi: 10.1126/scitranslmed.aad5752.

  PMID: 26702094 BACKGROUND

• Balazs AB, Ouyang Y, Hong CM, Chen J, Nguyen SM, Rao DS, An DS, Baltimore D. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med. 2014 Mar;20(3):296-300. doi: 10.1038/nm.3471. Epub 2014 Feb 9.

  PMID: 24509526 BACKGROUND

• Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, Novik L, Holman LA, Widge AT, Apte P, Gordon I, Gaudinski MR, Conan-Cibotti M, Lin BC, Nason MC, Trofymenko O, Telscher S, Plummer SH, Wycuff D, Adams WC, Pandey JP, McDermott A, Roederer M, Sukienik AN, O'Dell S, Gall JG, Flach B, Terry TL, Choe M, Shi W, Chen X, Kaltovich F, Saunders KO, Stein JA, Doria-Rose NA, Schwartz RM, Balazs AB, Baltimore D, Nabel GJ, Koup RA, Graham BS, Ledgerwood JE, Mascola JR; VRC 603 Study Team. Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nat Med. 2022 May;28(5):1022-1030. doi: 10.1038/s41591-022-01762-x. Epub 2022 Apr 11.

  PMID: 35411076 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

Limitations and Caveats

The active phase of the study was completed on August 2, 2022 and data collection is complete for the majority of the outcome measures; therefore, those completed measures are being reported after one year of follow up. The primary outcomes for SAEs, NCMCs and VRC07 ADAs will be reported once all participants have completed the Year 5 LTFU study visit.

Results Point of Contact

• Title: VRC Clinical Trials Program Leadership
• Organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health

ctpleadership@mail.nih.gov

301-451-8715

Study Officials

• Joseph P Casazza, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: December 14, 2017
• First Posted: December 15, 2017
• Study Start: January 11, 2018
• Primary Completion (Estimated): August 8, 2026
• Study Completion (Estimated): August 8, 2026
• Last Updated: April 27, 2025
• Results First Posted: October 25, 2023

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)