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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT06071767

Collaborator

University of Oxford (Other), Gilead Sciences (Industry)

Enrollment

Locations

Arms

29.9

Anticipated Duration (Months)

3.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
HIV-1-infection	Biological: ChAdOx1.tHIVconsv1 Biological: ChAdOx1.HIVconsv62 Biological: MVA.tHIVconsv3 Biological: MVA.tHIVconsv4 Drug: Vesatolimod (VES) Drug: GS-5423 Drug: GS-2872 Biological: MVA.tHIVconsv4 Biological: Placebo	Phase 1/Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Oct 31, 2023

Anticipated Primary Completion Date :

Apr 29, 2026

Anticipated Study Completion Date :

Apr 29, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	Biological: ChAdOx1.tHIVconsv1 Administered as 0.4 mL intramuscularly (IM) at Week 0 Biological: ChAdOx1.HIVconsv62 Administered as 0.3 mL IM at Week 0 Biological: MVA.tHIVconsv3 Administered as 0.3 mL IM at Week 4 Biological: 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. Drug: GS-5423 Administered via intravenous (IV) infusion at week 7 Other Names: 3BNC117-LS Drug: GS-2872 Administered via IV infusion at week 7 Other Names: 10-1074-LS Biological: MVA.tHIVconsv4 Administered 0.5 mL IM at week 60
Placebo Comparator: Arm B: Placebos for vaccines, vesatolimod and bnAbs	Biological: Placebo Placebos for vaccines, VES, and bnAbs

Arm

Intervention/Treatment

Experimental: Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs

Biological: ChAdOx1.tHIVconsv1

Administered as 0.4 mL intramuscularly (IM) at Week 0

Biological: ChAdOx1.HIVconsv62

Administered as 0.3 mL IM at Week 0

Biological: MVA.tHIVconsv3

Administered as 0.3 mL IM at Week 4

Biological: 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.

Drug: GS-5423

Administered via intravenous (IV) infusion at week 7

Other Names:

3BNC117-LS

Drug: GS-2872

Administered via IV infusion at week 7

Other Names:

10-1074-LS

Biological: MVA.tHIVconsv4

Administered 0.5 mL IM at week 60

Placebo Comparator: Arm B: Placebos for vaccines, vesatolimod and bnAbs

Biological: Placebo

Placebos for vaccines, VES, and bnAbs

Outcome Measures

Primary Outcome Measures

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

Change in cell-associated HIV-1 RNA and DNA levels [Weeks 0 to Week 24 on Step 2]
Change in plasma HIV-1 RNA viral load as measured by single copy assay (SCA) [Weeks 0 to Week 24 on Step 2]
Change in intact proviral DNA levels (IPDA) [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 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]
Time to first HIV-1 RNA ≥1000 copies/mL after ATI. [Week 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]
Occurrence of Adverse Events of Special Interest (AESIs) [Week 0 on Step 1 to 12 months following the last dose of study vaccination]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego AntiViral Research Center CRS	San Diego	California	United States	92103
2	Ponce de Leon Center CRS	Atlanta	Georgia	United States	30308
3	Northwestern University CRS	Chicago	Illinois	United States	60611
4	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts	United States	02114
5	Washington University Therapeutics CRS	Saint Louis	Missouri	United States	63110
6	Columbia Physicians & Surgeons CRS	New York	New York	United States	10032
7	Chapel Hill CRS	Chapel Hill	North Carolina	United States	27599
8	Greensboro CRS	Greensboro	North Carolina	United States	27401
9	Cincinnati CRS	Cincinnati	Ohio	United States	45267
10	Penn Therapeutics CRS	Philadelphia	Pennsylvania	United States	19104
11	Houston AIDS Research Team CRS	Houston	Texas	United States	77004
12	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio De Janeiro		Brazil