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

HIV-1-infection Clinical Trial

Official title:

A Phase I/IIa Randomized, Placebo-Controlled Trial of Conserved-Mosaic T-cell Vaccine in a Regimen With Vesatolimod and Broadly Neutralizing Antibodies in Adults Initiated on Suppressive Antiretroviral Therapy During Acute HIV-1

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06071767
• Other study ID #: A5374
• Secondary ID: 12025HIV-CORE 00
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 1, 2024
• Est. completion date: April 29, 2026

Study information

• Verified date: April 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: April 29, 2026
• Est. primary completion date: April 29, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

• Provision of written informed consent.

• History of Initiation of combination ART within 28 days of acute HIV diagnosis

• No known ART interruption >14 consecutive days since initiation of ART.

• ART with an integrase inhibitor-based regimen with two NRTIs or dolutegravir/lamivudine regimen for at least 6 weeks prior to study entry.

• Willingness to participate in the ATI and willingness to restart ART according to study guidelines.

• Willingness to adhere to protocol therapy and complete all study visits.

• Weight =50 kg and =115 kg at Screening.

• CD4 cell count =500 cells/mm3 obtained within 60 days prior to study Entry.

• HIV-1 RNA <50 copies/mL since initial viral suppression on ART and for at least 1 year and within 60 days prior to study Entry.

• Select laboratory results within 60 days of study entry

• For cisgender women and transgender men of reproductive potential, negative urine or serum pregnancy test within 48 hours prior to or at study Entry.

• Participants who are able to become pregnant and who are engaging in sexual activity that could lead to pregnancy must agree to use two methods of contraception, one of which must be a highly effective methods for contraception. Barrier methods of contraception are required for the second method of contraception.

• Availability of results of HLA typing (required for randomization).

• Completion of pre-entry leukapheresis or LVBD.

Exclusion Criteria

• Currently pregnant or breastfeeding or planning to become pregnant during study participation.

• Prior receipt of monoclonal antibody therapy (except for COVID treatment).

• Prior receipt of a latency-reversing agent (LRA).

• Receipt of HIV-1 or other investigational vaccines within 6 months prior to study Entry.

• Receipt of a live-virus vaccine within 60 days or any vaccination within 14 days prior to entry.

• Prior receipt of any simian adenovirus-vectored vaccine (e.g., anti-COVID-19 AZD1222).

• Known allergy/sensitivity or any hypersensitivity to components of study treatments or their formulations.

• Known severe chicken egg allergy.

• Known history of a severe reaction or anaphylaxis to prior vaccinations or antibody preparations (e.g., intravenous immunoglobulin).

• Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity).

• Any history of anaphylaxis and related symptoms such as hives, respiratory difficulty, or angioedema.

• Previous or current history of bleeding factor deficiency, coagulopathy or platelet disorder or on chronic anticoagulation.

• History of inflammatory neurologic diseases.

• History of pregnancy, head trauma or major surgery within 90 days prior to study Entry.

• History of use of any immunomodulatory medications within the 6 months prior to study entry.

• Significant serious skin disease, such as but not limited to active rash, eczema, psoriasis, or urticaria.

• Autoimmune disease (e.g., lupus, multiple sclerosis, and others) requiring ongoing immunosuppression.

• Known history of CDC Stage 3 opportunistic infection (OI).

• Any history of an HIV-associated malignancy.

• Known or suspected active or untreated latent Mycobacterium tuberculosis infection.

• Active or recent non-HIV-associated malignancy.

• Serious illness requiring systemic treatment and/or hospitalization within 90 days prior to study entry.

• Known resistance to one or more drugs in two or more ARV drug classes.

• History of or current clinical atherosclerotic cardiovascular disease

• Current advanced liver disease.

• Use of complementary or alternative medicines within 14 days prior study entry.

Related Conditions & MeSH terms

• HIV-1-infection

Intervention

Biological:
• ChAdOx1.tHIVconsv1
Administered as 0.4 mL intramuscularly (IM) at Week 0
• ChAdOx1.HIVconsv62
Administered as 0.3 mL IM at Week 0
• MVA.tHIVconsv3
Administered as 0.3 mL IM at Week 4
• MVA.tHIVconsv4
Administered as 0.5 mL IM at week 4

Drug:
• Vesatolimod (VES)
VES 6 mg administered orally once every 2 weeks for two doses, then VES 8 mg once every 2 weeks for 8 doses. Dose escalation may be held or the 8 mg dose may be reduced for intolerability for weeks 6 through 24.
• GS-5423
Administered via intravenous (IV) infusion at week 7
• GS-2872
Administered via IV infusion at week 7

Biological:
• MVA.tHIVconsv4
Administered 0.5 mL IM at week 60
• Placebo
Placebos for vaccines, VES, and bnAbs

Locations

Country	Name	City	State
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio De Janeiro
United States	Ponce de Leon Center CRS	Atlanta	Georgia
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	Cincinnati CRS	Cincinnati	Ohio
United States	Ohio State University CRS	Columbus	Ohio
United States	Greensboro CRS	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS	Houston	Texas
United States	Columbia Physicians & Surgeons CRS	New York	New York
United States	Penn Therapeutics CRS	Philadelphia	Pennsylvania
United States	Washington University Therapeutics CRS	Saint Louis	Missouri
United States	University of California, San Diego AntiViral Research Center CRS	San Diego	California

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Gilead Sciences, University of Oxford

Countries where clinical trial is conducted

United States,  Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Change in cell-associated HIV-1 RNA and DNA levels		Weeks 0 to Week 24 on Step 2
Secondary	Change in plasma HIV-1 RNA viral load as measured by single copy assay (SCA)		Weeks 0 to Week 24 on Step 2
Secondary	Change in intact proviral DNA levels (IPDA)		Weeks 0 to Week 24 on Step 2
Secondary	HIV-1-specific T-cell responses to the conserved regions present in the vaccines as measured by IFN-? ELISPOT - total frequency and breadth (number of recognized peptide pools out of 10).		Week 0 to Week 24 on Step 2
Secondary	Change in soluble markers of systemic inflammation and immune activation: sCD163 (pg/mL)		Weeks 0 to Week 24 on Step 2
Secondary	Change in soluble markers of systemic inflammation and immune activation: sCD14 (pg/mL)		Weeks 0 to Week 24 on Step 2
Secondary	Change in soluble markers of systemic inflammation and immune activation: IL-6 (pg/mL)		Weeks 0 to Week 24 on Step 2
Secondary	Change in soluble markers of systemic inflammation and immune activation: sTNFaR (pg/mL)		Weeks 0 to Week 24 on Step 2
Secondary	Changes in soluble markers of systemic inflammation and immune activation: hsCRP (pg/mL)		Weeks 0 to Week 24 on Step 2
Secondary	Time to first HIV-1 RNA =1000 copies/mL after ATI.		Week 0 to Week 24 on Step 2
Secondary	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
Secondary	Occurrence of Medically Attended Adverse Events (MAAEs)		Week 0 on Step 1 to 12 months following the last dose of study vaccination
Secondary	Occurrence of Adverse Events of Special Interest (AESIs)		Week 0 on Step 1 to 12 months following the last dose of study vaccination