Evaluation of Safety, Immunogenicity and Efficacy of a Triple Immune Regimen in Adults Initiated on ART During Acute HIV-1

Phase 1

Recruiting

• Conditions: HIV-1-infection
• Interventions: Biological: Placebo; Biological: ChAdOx1.tHIVconsv1; Biological: ChAdOx1.HIVconsv62; Biological: MVA.tHIVconsv3; Biological: MVA.tHIVconsv4; Drug: Vesatolimod (VES); Drug: GS-5423; Drug: GS-2872

• Registration Number: NCT06071767
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, and efficacy of therapeutic vaccination with chimpanzee adenovirus (ChAdV)- and poxvirus modified vaccinia Ankara (MVA)-vectored conserved mosaic T-cell vaccines in a sequential regimen with the Toll-like Receptor 7 (TLR7) agonist vesatolimod (VES) and two broadly neutralizing antibodies (bNAbs) compared to placebo, to induce HIV-1 control during analytic treatment interruption (ATI).

Detailed Description

A5374 is a phase I/IIa randomized, two-arm, double-blind placebo-controlled, multi-step strategy trial to evaluate safety and efficacy of therapeutic vaccination with chimpanzee adenovirus (ChAdV)- and poxvirus modified vaccinia Ankara (MVA)-vectored conserved mosaic T-cell vaccines in a sequential regimen with the Toll-like Receptor 7 (TLR7) agonist vesatolimod (VES) and two broadly neutralizing antibodies (bNAbs) of the CD4 binding site and V3-loop base classes in individuals with HIV-1 who started suppressive antiretroviral therapy (ART) during acute HIV-1.

Participants will be screened for eligibility and have a pre-entry visit. After determination of eligibility, participants will be randomized prior to entry to either the active intervention arm (Arm A) or the placebo arm (Arm B) in a 2:1 ratio.

The study consists of four steps including an analytical treatment interruption (ATI).

* Step 1: Study Intervention and ART (67 weeks)

* Step 2: Analytic Treatment Interruption (up to 24 weeks)

* Step 3: ART Restart (24 weeks)

* Step 4: Continuation of ATI (up to 24 weeks) Each participant will complete Step 1 and Step 2. At the end of Step 2, participants who have experienced virologic rebound will enter Step 3 and resume ART. Participants with continued virologic control for 24 weeks in Step 2 will enter Step 4 for an extended ATI.

Each participant will be enrolled for up to approximately 110 weeks. The total time on study for each participant is dependent on the time spent in the treatment interruption steps (Step 2 and 4).

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2023-09-05
• Study First Submitted QC: 2023-10-04
• Study First Posted: 2023-10-06
• Status Verified: 2024-04
• Study Start: 2024-04-01
• Last Update Submitted: 2024-04-08
• Last Update Posted: 2024-04-09
• Primary Completion: 2026-04-29
• Study Completion: 2026-04-29

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: Placebos for vaccines, vesatolimod and bnAbs	Placebo	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	ChAdOx1.tHIVconsv1	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	GS-2872	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	ChAdOx1.HIVconsv62	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	MVA.tHIVconsv3	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	MVA.tHIVconsv4	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	Vesatolimod (VES)	-
Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	GS-5423	-

Primary Outcome Measures

Name	Time	Method
Occurrence of any serious adverse event (AE), Grade 3 or higher AE, or AE that leads to permanent discontinuation of study treatment regardless of grade, that is related to ChAdOx1-MVA/HIVconsvX vaccines, VES, GS-5423 or GS-2872	Week 0 to Week 64
Proportion of participants with viral control during an ATI defined as remaining off ART with HIV-1 RNA <1,000 copies/mL at Week 16 following ATI.	Week 0 to Week 16 on Step 2

Secondary Outcome Measures

Name	Time	Method
Change in plasma HIV-1 RNA viral load as measured by single copy assay (SCA)	Weeks 0 to Week 24 on Step 2
HIV-1-specific T-cell responses to the conserved regions present in the vaccines as measured by IFN-γ ELISPOT - total frequency and breadth (number of recognized peptide pools out of 10).	Week 0 to Week 24 on Step 2
Change in cell-associated HIV-1 RNA and DNA levels	Weeks 0 to Week 24 on Step 2
Change in intact proviral DNA levels (IPDA)	Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: sCD163 (pg/mL)	Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: sCD14 (pg/mL)	Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: IL-6 (pg/mL)	Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: sTNFαR (pg/mL)	Weeks 0 to Week 24 on Step 2
Changes in soluble markers of systemic inflammation and immune activation: hsCRP (pg/mL)	Weeks 0 to Week 24 on Step 2
Change in HIV-specific CD8+ T-cell-mediated viral inhibition as measured by in vitro virus inhibition assay (VIA) using representative viruses from major HIV-1 clades of group M.	Weeks 0 to Week 24 on Step 2
Occurrence of Medically Attended Adverse Events (MAAEs)	Week 0 on Step 1 to 12 months following the last dose of study vaccination
Time to first HIV-1 RNA ≥1000 copies/mL after ATI.	Week 0 to Week 24 on Step 2
Occurrence of Adverse Events of Special Interest (AESIs)	Week 0 on Step 1 to 12 months following the last dose of study vaccination

Trial Locations

Locations (13)

Ponce de Leon Center CRS; 🇺🇸 Atlanta, Georgia, United States

Penn Therapeutics CRS; 🇺🇸 Philadelphia, Pennsylvania, United States

Columbia Physicians & Surgeons CRS; 🇺🇸 New York, New York, United States

University of California, San Diego AntiViral Research Center CRS; 🇺🇸 San Diego, California, United States

Ohio State University CRS; 🇺🇸 Columbus, Ohio, United States

Washington University Therapeutics CRS; 🇺🇸 Saint Louis, Missouri, United States

Greensboro CRS; 🇺🇸 Greensboro, North Carolina, United States

Cincinnati CRS; 🇺🇸 Cincinnati, Ohio, United States

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS; 🇧🇷 Rio De Janeiro, Brazil

Houston AIDS Research Team CRS; 🇺🇸 Houston, Texas, United States

Massachusetts General Hospital CRS (MGH CRS); 🇺🇸 Boston, Massachusetts, United States

Chapel Hill CRS; 🇺🇸 Chapel Hill, North Carolina, United States

Northwestern University CRS; 🇺🇸 Chicago, Illinois, United States