Safety and Efficacy of Neutralizing Antibodies and Vaccination for Induction of HIV Remission

NCT05769569 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: RV 582
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

This is a phase I, randomized, open-label trial to investigate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-Bavarian Nordic (BN)-HIV and A244d11gp120/ALFQ vaccination, and the impact on time to sustained viral rebound of ≥1000 copies/mL for 4 consecutive weeks during analytic treatment interruption (ATI) in people living with human immunodeficiency virus-1 (HIV-1, PLWH) who initiated antiretroviral therapy (ART) during acute HIV-1 infection (AHI).

Conditions

HIV-1-infection

Keywords

human immunodeficiency virus-1; PLWH; AHI; ART; HIV-1; antiretroviral therapy; acute HIV-1 infection

Outcome Measures

Primary Outcomes (2)

• To evaluate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination in PLWH who initiated ART during AHI.

  Occurrence of ≥ grade 3 AE or SAE that are possibly, probably, or definitely related to the IPs during the study. Adverse events will be graded using "DAIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS (DAIDS AE SEVERITY GRADING TABLE) V2.1, JULY 2017" (https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf), where grade 1 is mild and grade 4 is potentially life threatening.

  Through month 31

• To evaluate the treatment combination on time to sustain viral rebound to ≥1000 copies/mL for 4 consecutive weeks AND has not declined by >0.2 log10

  Time (days) from ATI to sustained viral rebound of ≥1000 copies/mL for 4 consecutive weeks AND has not declined by \>0.2 log10 from the previous measurement.

  Through month 31

Secondary Outcomes (20)

• To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to first documented HIV-1 RNA viral rebound of ≥50 copies/mL following ATI.

  Through month 31

• To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to first documented HIV-1 RNA viral rebound of ≥1000 copies/mL following ATI.

  Through month 31

• To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on the number of participants with plasma HIV RNA <1000 copies/mL at 12 and 24 weeks of ATI.

  Through month 31

• To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to ART resumption for an HIV-related (virologic, immunologic, or clinical) reason during Step 2.

  Through month 31

• To measure the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on HIV RNA levels while on ART.

  Through month 31

Study Arms (2)

Antiretroviral therapy + Investigational Products

EXPERIMENTAL

Active Group (ART with the addition of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV, A244d11 gp120 and ALFQ vaccination)

Biological: VRC07-523LS; Biological: PGDM1400LS; Biological: N-803; Biological: Ad26.Mos4.HIV; Biological: MVA-BN-HIV; Biological: A244d11 gp120; Biological: ALFQ; Combination Product: Antiretroviral Therapy (ART)

Antiretroviral therapy only

ACTIVE COMPARATOR

Control Group (continue only with ART without further interventions)

Combination Product: Antiretroviral Therapy (ART)

Interventions

VRC07-523LS BIOLOGICAL

VRC07-523LS is a recombinant human immunoglobulin G1 (IgG1) broadly neutralizing monoclonal antibody (bNAb) directed against the HIV-1 CD4 binding site. Intravenous infusion of 10 mg/kg VRC07-523LS will be administered on Week 0.

Also known as: VRC-HIVMAB075-00-AB

Antiretroviral therapy + Investigational Products

PGDM1400LS BIOLOGICAL

PGDM1400LS is a recombinant human IgG1 bNAb targeted against the HIV-1 V2 apex epitope region. Intravenous infusion of 20 mg/kg PGDM1400LS will be administered on Week 0.

Antiretroviral therapy + Investigational Products

N-803 BIOLOGICAL

N-803 is a recombinant human superagonist interleukin-15 (IL-15) complex. N-803 at 6 ug/kg will be administered via subcutaneous injection to the trunk on Weeks 1, 4, 7, 39, 42 and 45.

Antiretroviral therapy + Investigational Products

Ad26.Mos4.HIV BIOLOGICAL

Ad26.Mos4.HIV is a tetravalent vaccine comprising Ad26.Mos1.Env, Ad26.Mos2S.Env, Ad26.Mos1.Gag-Pol, and Ad26.Mos2.Gag-Pol. Ad26.Mos4.HIV at 5x1010 viral particles (per 0.5 mL dose) will be administered through intramuscular injection in the quadriceps muscle at Week 11.

Antiretroviral therapy + Investigational Products

MVA-BN-HIV BIOLOGICAL

MVA-BN-HIV is a single vector recombinant Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN®) expressing Mos1.Env, Mos2S.Env, Mos1.Gag-Pol, and Mos2.Gag-Pol. MVA-BN-HIV at 2x108 infectious unit (per 0.5mL dose) will be administered through intramuscular injection in the quadriceps muscle at Week 35.

Antiretroviral therapy + Investigational Products

A244d11 gp120 BIOLOGICAL

A244d11 gp120, consists of the gp120 envelope glycoprotein HIV-1 subtype CRF\_01AE A244 derived from the CM244 CRF\_01AE strain, with an 11 amino N-terminal deletion. It is a modification of the A244 rgp120 immunogen from the AIDSVAX®B/E vaccine. A244d11 gp120 at 300 ug will be administered as an intramuscular injection in the quadriceps muscle at week 11 and week 35.

Antiretroviral therapy + Investigational Products

ALFQ BIOLOGICAL

ALFQ (Army Liposome Formulation, ALF) is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (MPLA, 3D-PHAD®) with the addition of QS-21. ALFQ at 200 ug will be administered as an intramuscular injection in the quadriceps muscle at week 11 and week 35.

Antiretroviral therapy + Investigational Products

Antiretroviral Therapy (ART) COMBINATION_PRODUCT

This study will enroll PLWH aged 18-50 years who initiated ART during Fiebig I-V AHI and are virologically suppressed (HIV RNA \<50 copies/ml for ≥48 weeks) on uninterrupted ART, who meet study inclusion criteria in Bangkok, Thailand.

Antiretroviral therapy + Investigational Products; Antiretroviral therapy only

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants are eligible to be included in the protocol Step 1 only if all of the following criteria are met:
• Thai National
• Age ≥18 and ≤50 years of age
• Can read and write Thai or English
• Able and willing to provide written informed consent
• Participant of the RV254 study
• Confirmed HIV-1 infection (nucleic acid testing \[NAT\] and/or HIV serology positive with confirmatory quantitative HIV viral load) and started ART during acute infection (Fiebig stage I-V)
• Uninterrupted treatment with ART (no interruption of ART for ≥7 consecutive days or longer) since ART initiation, for ≥ 48 weeks.
• Currently on integrase inhibitor-based ART regimen (excluding long-acting injectable regimens) and no recent (≤8 weeks prior to screening) changes to ART regimen.
• a. There must be at least one documented plasma HIV RNA \<50 cps/mL after the last ART change prior to screening
• Must be medically stable as confirmed by medical history, physical examination, vital signs, and clinical laboratory tests performed at screening, and as per the Investigator's discretion.
• The following laboratory values at screening:
• Absolute neutrophil count (ANC) ˃1,000/mm3
• Hemoglobin \>11.5 g/dL
• Platelet count ˃150,000/mm3

You may not qualify if:

• Participants who meet any of the following criteria will be excluded from the study:
• Weight \<50 kg or \> 115 kg
• Presence of HLA allele associated with viral control including HLA B\*57:01 or HLA B\*58:01 (based on archived data from RV254)
• Anyone with contraindication to intramuscular injections, placement of intravenous lines, and blood draws
• Acute or serious illness requiring systemic treatment and/or hospitalization within 90 days prior to entry.
• Any clinically significant acute or chronic medical condition, that in the opinion of the investigator would preclude participation including cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological disorders, that in the opinion of the investigator would preclude participation (e.g., history of seizure disorders, cardiovascular disease, bleeding/clotting disorder, autoimmune disease, malignancy, poorly controlled asthma, active tuberculosis or other systemic infections, etc.)
• Participants with acute illness (this does not include minor illnesses such as diarrhea or mild upper respiratory tract infection) including untreated syphilis, gonorrhea or chlamydia infection or temperature ≥38.0ºC within 24 hours prior to the first dose of IP will not enter baseline. Participant will be referred for treatment, and participant is eligible for repeat screening and potential study entry once treatment is successfully completed
• Major surgery (per the Investigator's judgment) within 12 weeks before screening or plan to have major surgery during the time of study participation
• surgical procedures to be conducted under local or loco-regional anesthesia and not judged as major by the Investigator may participate.
• Current or history of an HIV-associated malignancy (including Kaposi's sarcoma), and any type of lymphoma, or virus-associated cancers
• Current or history of non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the 36 months prior to screening
• Current or history of clinical atherosclerotic cardiovascular disease, as defined by 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, including a previous diagnosis of any of the following: acute myocardial infarction, acute coronary syndromes, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), peripheral arterial disease presumed to be of atherosclerotic origin
• Current or history of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with permanent sequelae, clinically significant arrhythmia (including any arrhythmia requiring medication, treatment, or clinical follow-up)
• Current or history of advanced liver disease (non-alcoholic fatty liver disease, steatohepatitis, or alcoholic liver disease) with known or suspected cirrhosis or fibrosis score ≥F2.
• Current or history of TTS, or heparin-induced thrombocytopenia and thrombosis syndrome.

Sponsors & Collaborators

• Henry M. Jackson Foundation for the Advancement of Military Medicine: lead
• US Military HIV Research Program: collaborator
• Janssen Vaccines & Prevention B.V.: collaborator

Study Sites (2)

Thai Red Cross AIDS Research Centre (TRCARC)

Pathum Wan, Bangkok, 10330, Thailand

Location

The Faculty of Medicine, Chulalongkorn University/ King Chulalongkorn Memorial Hospital

Pathum Wan, Bangkok, 10330, Thailand

Location

MeSH Terms

Interventions

ALT-803; Antiretroviral Therapy, Highly Active

Intervention Hierarchy (Ancestors)

Drug Therapy, Combination; Drug Therapy; Therapeutics

Study Officials

• Donn Colby, M.D., M.P.H.

  US Military HIV Research Program

  STUDY CHAIR

• Kiat Ruxrungtham, MD

  King Chulalongkorn Memorial Hospital

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: This is a phase I, randomized, open-label trial to investigate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination, and the impact on time to sustained viral rebound of ≥1000 copies/mL for 4 consecutive weeks during ATI in PLWH who initiated ART during AHI. The study will involve 35 adults who initiated ART during Fiebig I-V acute HIV infection, with plasma HIV RNA \<50 copies/mL for ≥48 weeks, CD4 T-cell counts ≥450 cells/mm3, viruses susceptible to both VRC07-523LS and PGDM1400LS and the absence of known protective HLA allele.

Study Record Dates

• First Submitted: February 15, 2023
• First Posted: March 15, 2023
• Study Start: September 1, 2023
• Primary Completion: July 1, 2025
• Study Completion: July 1, 2025
• Last Updated: May 3, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

TH (2)