A Clinical Trial of Combination HIV-Specific Broadly Neutralizing Monoclonal Antibodies Combined With ART Initiation During Acute HIV Infection to Induce HIV Remission

A Double-Blind, Randomized, Placebo-Controlled Clinical Trial of Combination HIV-Specific Broadly Neutralizing Monoclonal Antibodies Combined With ART Initiation During Acute HIV Infection to Induce HIV Remission

A5388 is a phase II, two-arm, randomized, double-blind, placebo-controlled study that will enroll 48 antiretroviral therapy (ART)-naïve adults with acute HIV infection (AHI) in order to determine whether:

• Administration of combination HIV-specific broadly neutralizing antibody (bNAb) therapy in addition to ART during acute HIV infection (AHI) will be safe.
• Participants who receive combination bNAb therapy in addition to ART during AHI will be more likely to demonstrate a delay in time to HIV-1 RNA ≥1,000 copies/mL for 4 consecutive weeks compared to participants who receive placebo plus ART.
• Participants who receive combination bNAb therapy in addition to ART during AHI will demonstrate lower viral reservoirs and enhanced HIV-specific immunity compared to participants who receive placebo plus ART.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute HIV Infection
• Intervention / Treatment: Biological: VRC07-523LS; Biological: PGT121.414.LS; Drug: ART; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil, 91350-200
    • 12201, Hospital Nossa Senhora da Conceicao CRS
    • Contact: Rita de Cassia Alves Lira; Phone Number: +55 51-33572603; Email: lrita@ghc.com.br
  • Rio De Janeiro, Brazil
    • 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
• Peru
  • Lima, Peru, 4
    • 11301, Barranco CRS
    • Contact: María del Pilar Estrella Caballero; Phone Number: +51 206-7800; Email: mestrella@impactaperu.org
  • Lima
    • San Miguel, Lima, Peru, 32
      • 11302, San Miguel CRS
      • Contact: Helen B. Chapa; Phone Number: 653 51-1-562-1600; Email: hchapa@impactaperu.org
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35222
      • 31788, Alabama CRS
      • Contact: Faye Heard; Phone Number: 205-996-4405; Email: fhoward@uabmc.edu
  • California
    • Los Angeles, California, United States, 90033-1079
      • 1201, University of Southern California CRS
      • Contact: Luis Mendez; Phone Number: 323-409-8283; Email: lmendez@usc.edu
    • Los Angeles, California, United States, 90035
      • 601, University of California, Los Angeles CARE Center CRS
      • Contact: Aleen Khodabakhshian; Phone Number: 310-557-3798; Email: akhodabakhshian@mednet.ucla.edu
    • San Diego, California, United States, 92103
      • 701, UCSD Antiviral Research Center CRS
      • Contact: Steven Hendrickx; Phone Number: 619-543-6968; Email: smhendrickx@health.ucsd.edu
    • San Francisco, California, United States, 94110
      • 801, University of California, San Francisco HIV/AIDS CRS
      • Contact: Elvira Gomez; Phone Number: 415-476-4082; Email: elvira.gomez@ucsf.edu
    • Torrance, California, United States, 90502
      • 603, Harbor University of California Los Angeles Center CRS
      • Contact: Mario Guerrero; Phone Number: 7318 424-201-3000; Email: mguerrero@lundquist.org
  • Colorado
    • Aurora, Colorado, United States, 80045
      • 6101, University of Colorado Hospital CRS
      • Contact: Nicola Haakonsen; Phone Number: 303-724-5931; Email: nicola.haakonsen@cuanschutz.edu
  • District of Columbia
    • Washington, District of Columbia, United States, 20005
      • 31791, Whitman-Walker Institute, Inc. CRS
      • Contact: Avery Wimpelberg; Phone Number: 202-797-3589; Email: awimpelberg@whitman-walker.org
  • Georgia
    • Atlanta, Georgia, United States, 30308-2012
      • 5802, The Ponce de Leon Center CRS
      • Contact: Ericka R. Patrick; Phone Number: 404-616-6313; Email: erpatri@emory.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • 2701, Northwestern University CRS
      • Contact: Baiba Berzins; Phone Number: 312-695-5012; Email: baiba@northwestern.edu
    • Chicago, Illinois, United States, 60612
      • 2702, Rush University CRS
      • Contact: Ben Xu; Phone Number: 312-942-5865; Email: Ben_Xu@rush.edu
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • 201, Johns Hopkins University CRS
      • Contact: Rebecca L. Becker; Phone Number: 410-614-4036; Email: rbecke22@jhmi.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • 101, Massachusetts General Hospital CRS (MGH CRS)
      • Contact: Amy Sbrolla; Phone Number: 617-726-5598; Email: asbrolla@mgh.harvard.edu
    • Boston, Massachusetts, United States, 02115
      • 107, Brigham and Women's Hospital Therapeutics (BWH TCRS) CRS
      • Contact: Cheryl Keenan; Phone Number: 617-732-5635; Email: CKeenan@BWH.Harvard.edu
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1010
      • 2101, Washington University Therapeutics (WT) CRS
      • Contact: Michael Klebert; Phone Number: 314-454-0058; Email: mklebert@wustl.edu
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • 31786, New Jersey Medical School Clinical Research Center CRS
      • Contact: Rondalya DeShields; Phone Number: 973-972-3729; Email: deshierd@njms.rutgers.edu
  • New York
    • New York, New York, United States, 10010
      • 7804, Weill Cornell Chelsea CRS
      • Contact: Rebecca Fry; Phone Number: 212-746-7204; Email: ref2007@med.cornell.edu
    • New York, New York, United States, 10032-3732
      • 30329, Columbia Physicians & Surgeons (P&S) CRS
      • Contact: Mascha Elskamp; Phone Number: 212-305-2201; Email: me2500@cumc.columbia.edu
    • New York, New York, United States, 10065
      • 7803, Weill Cornell Uptown CRS
      • Contact: Jonathan Berardi; Phone Number: 212-746-7864; Email: jlb4002@med.cornell.edu
    • Rochester, New York, United States, 14642
      • 31787, University of Rochester Adult HIV Therapeutic Strategies Network CRS
      • Contact: Susan Hulse; Phone Number: 585-275-0529; Email: susan_hulse@urmc.rochester.edu
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7215
      • 3201, Chapel Hill CRS
      • Contact: Susan Pedersen; Phone Number: 919-966-6713; Email: spederse@med.unc.edu
    • Greensboro, North Carolina, United States, 27401
      • 3203, Greensboro CRS
      • Contact: Kelly Phillips; Phone Number: 336-832-7297; Email: kelly.phillips@conehealth.com
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • 2401, Cincinnati CRS
      • Contact: Sharon Kohrs; Phone Number: 513-584-6383; Email: kohrssd@ucmail.uc.edu
    • Cleveland, Ohio, United States, 44106
      • 2501, Case CRS
      • Contact: Julie Pasternak; Phone Number: 216-844-2738; Email: pasternak.julie@clevelandactu.org
    • Columbus, Ohio, United States, 43210-1282
      • 2301, Ohio State University CRS
      • Contact: Lindsay Summers; Phone Number: 614-293-8529; Email: lindsay.summers@osumc.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • 6201, Penn Therapeutics CRS
      • Contact: Jamie Doyle; Phone Number: 215-615-2316; Email: jamie.doyle1@pennmedicine.upenn.edu
    • Pittsburgh, Pennsylvania, United States, 15213
      • 1001, University of Pittsburgh CRS
      • Contact: Dawn Renee Weinman; Phone Number: 412-383-1748; Email: drw38@pitt.edu
  • Rhode Island
    • Providence, Rhode Island, United States, 02904
      • 2951, The Miriam Hospital (TMH) CRS
      • Contact: Helen B. Patterson; Phone Number: 401-793-4771; Email: hpatterson@lifespan.org
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • 3652, Vanderbilt Therapeutics (VT) CRS
      • Contact: Beverly Woodward; Phone Number: 615-936-8516; Email: beverly.o.woodward@vumc.org
  • Texas
    • Dallas, Texas, United States, 75208
      • 31443, Trinity Health and Wellness Center CRS
      • Contact: Melvina Seay; Phone Number: 972-807-7370; Email: melvina.seay@prismntx.org
    • Houston, Texas, United States, 77030
      • 31473, Houston AIDS Research Team CRS
      • Contact: Maria Laura Martinez; Phone Number: 713-500-6718; Email: maria.l.martinez@uth.tmc.edu
  • Washington
    • Seattle, Washington, United States, 98104
      • 1401, University of Washington Positive Research CRS
      • Contact: Christine Jonsson; Phone Number: 206-744-8886; Email: cjonsson@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Step 1:

1. Appropriate documentation from medical records of diagnosis of AHI prior to enrollment that includes one of the following:

   1. A detectable HIV-1 RNA within 28 days prior to study entry AND a non-reactive HIV-1 antibody within 7 days prior to entry; OR
   2. A detectable HIV-1 RNA or a reactive HIV-1 antibody within 28 days prior to study entry AND a negative/indeterminate Western Blot (WB) or negative/indeterminate Geenius HIV-1/HIV-2 Supplemental Assay within 7 days prior to entry; OR
   3. A documented non-reactive HIV-1 antibody or negative HIV-1 RNA within 90 days prior to study entry AND a documented reactive HIV-1 antibody or positive WB that is negative for p31 band or a positive Geenius HIV-1/HIV-2 Supplemental Assay that is negative for p31 band within 7 days prior to entry; OR
   4. ARCHITECT or GSCOMBO S/CO ≥10 within 7 days prior to entry AND a non-reactive HIV-1 antibody within 7 days prior to entry; OR
   5. ARCHITECT or GSCOMBO S/CO ≥1 within 7 days prior to entry AND a non-reactive HIV-1 antibody within 7 days prior to entry AND a known prior S/CO <0.5 within 90 days prior to entry; OR
   6. ARCHITECT or GSCOMBO S/CO >0.5 but <10 within 7 days prior to entry AND a non-reactive HIV-1 antibody within 7 days prior to entry AND detectable HIV-1 RNA within 7 days prior to entry

2. The following laboratory values obtained within 21 days prior to entry:

   • Absolute neutrophil count (ANC) ˃1,000/mm3

   • Hemoglobin:

     • >10 g/dL for cisgender men and transgender women
     • >9 g/dL for cisgender women and transgender men
   • Platelet count ˃100,000/mm3
   • Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation, with consideration for lower rates in special circumstances.
   • ALT (SGPT) ≤2.5 x ULN
   • AST (SGOT) ≤2.5 x ULN
   • Total bilirubin <1.5 x ULN
3. For persons who are able to become pregnant, negative urine or serum pregnancy test within 24 hours prior to study entry.
4. Persons who are able to become pregnant must agree to use two methods of contraception throughout Step 1 if participating in sexual activity that could lead to pregnancy. One contraceptive method must be a highly effective method and the second method of contraception must be a barrier method.
5. Participants of reproductive potential who engage in sexual activity that could lead to their partner's becoming pregnant must agree to use a barrier method of contraception throughout Step 1.
6. Ability and willingness to use a barrier method or abstinence from sexual intercourse with all partners who are vulnerable to HIV or whose HIV serostatus is unknown in order to prevent HIV transmission during Step 2, Step 3, and until plasma HIV-1 RNA is less than the limit of detection after ART restart in Step 4.
7. Age ≥18 and ≤70 years.
8. Ability and willingness to initiate ART at enrollment.
9. Ability and willingness to participate in scheduled study visits, including during the ATI, per Schedule of Evaluations (SOE).
10. Ability and willingness of participant to provide informed consent.

Step 2:

1. Documented negative hepatitis B virus (HBV) surface antigen (HBsAg) obtained within 16 weeks prior to Step 2 registration.
2. Documented negative hepatitis C virus (HCV) antibody (anti-HCV) or negative HCV RNA PCR obtained within 16 weeks prior to Step 2 registration.
3. Receipt of full doses of study infusions at enrollment (VRC07-523LS + PGT121.414.LS or placebo [Sodium Chloride for Injection USP, 0.9%]).
4. HIV-1 RNA <200 copies/mL obtained within 6 weeks prior to Step 2 registration.
5. CD4+ T-cell count ≥450 cells/mm3 obtained within 6 weeks prior to Step 2 registration.
6. For participants who are able to become pregnant, negative serum or urine pregnancy test within 48 hours prior to Step 2 entry.
7. To avoid pregnancy, participants who are able to become pregnant must agree to use contraception or practice abstinence from sexual activity that could lead to pregnancy throughout Step 2.
8. Ability and willingness to use a barrier method or abstinence from sexual intercourse with partners who are vulnerable to HIV or whose HIV serostatus is unknown in order to prevent HIV transmission throughout Step 2.
9. Ability and willingness to interrupt ART.
10. Completion of Step 1.

Step 3:

1. Has not met ART restart criteria.
2. Completion of Step 2.
3. Willing to continue ATI.
4. To avoid pregnancy, participants who are able to become pregnant must agree to use contraception or practice abstinence from sexual activity that could lead to pregnancy throughout Step 3.
5. Ability and willingness to use a barrier method or abstinence from sexual intercourse with all partners who are vulnerable to HIV or whose HIV serostatus is unknown in order to prevent HIV transmission throughout Step 3.

Step 4:

1. Has met any of the ART restart criteria during Step 2 or Step 3. -OR- Has completed Step 3 and is not enrolling to ACTG A5385.
2. To avoid pregnancy, participants who are able to become pregnant must agree to use contraception or practice abstinence from sexual activity that could lead to pregnancy throughout Step 4.
3. Ability and willingness to use a barrier method or abstinence from sexual intercourse with all partners who are vulnerable to HIV or whose HIV serostatus is unknown in order to prevent HIV transmission until plasma HIV-1 RNA is less than the limit of detection after ART restart.

Exclusion Criteria:

Step 1:

1. Previous receipt of immunoglobulin (IgG) therapy.
2. Previous receipt of humanized or human monoclonal antibody whether licensed or investigational (other than for the prevention and/or treatment of SARS-CoV-2/COVID-19).
3. History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis in the 2 years prior to enrollment.
4. History of chronic urticaria requiring daily treatment.
5. Receipt of investigational study agent within 28 days prior to enrollment.
6. Past participation in an investigational study of a candidate HIV vaccine or immune prophylaxis for HIV-1 infection with receipt of active product or with receipt of active product or placebo and remains blinded to what they actually received.
7. Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months.
8. Use of any immunomodulatory medications within 6 months of study entry including systemic corticosteroids (long-term), immunosuppressants, anti-cancer, interleukins, systemic interferons, systemic chemotherapy, or other medications that the site investigator feels could have an immune modulatory effect.
9. Use of ART for any reason, including pre- or post-exposure prophylaxis, within 60 days prior to study entry.
10. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
11. Known history of active Hepatitis B or Hepatitis C infection.
12. Any acute, chronic, or recent and clinically significant medical condition that, in the opinion of the site investigator, would interfere with adherence to study requirements or jeopardize the safety or rights of the participant.

13. History of or current clinical atherosclerotic cardiovascular disease (ASCVD) 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
    • TIA
    • Peripheral arterial disease presumed to be of atherosclerotic origin
14. Currently breastfeeding or pregnant.
15. Weight >115 kg.
16. Use of prohibited medications for bictegravir, emtricitabine, and tenofovir alafenamide (refer to protocol section 5.8) within 7 days prior to entry, or planned use of prohibited medications during the period of study participation.
17. Absence of adequate venous access for the administration of infusion or for phlebotomy to assess for the primary study endpoint.

Step 2:

1. Viral failure, as defined in protocol section 6.2.4, after Step 1 week 24.
2. Failure to initiate ART in Step 1.
3. Receipt of any non-nucleoside reverse transcriptase inhibitor (NNRTI) or long-acting ART (any therapy dosed at an interval less than daily), such as cabotegravir or rilpivirine injections, after Step 1 entry.
4. Receipt of any immunoglobulin therapy or immunomodulatory medications after Step 1 entry including systemic corticosteroids (long-term), immunosuppressants, anti-cancer, interleukins, systemic interferons, systemic chemotherapy, or other medications that the site investigator feels could have an immune modulatory effect.
5. Does not have HIV-1.
6. Participant was in Fiebig stage VI at the time of study entry.
7. Failure by the participant to attend three consecutive Step 1 study visits.
8. Intercurrent illness, new medical diagnosis, laboratory abnormality, sign, or symptom that, in the opinion of the site investigator, would place participant at higher risk of morbidity during ATI.
9. Pregnancy or breastfeeding.
10. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Step 3:

1. Transfer to A5385 (The Post-Intervention Cohort Study).
2. ART restart in Step 2.
3. Intercurrent illness, new medical diagnosis, laboratory abnormality, sign, or symptom that, in the opinion of the site investigator, would place participant at higher risk of morbidity during analytic treatment interruption.
4. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Step 4:

1. Unwillingness or inability to restart ART after meeting an ART restart criterion in Step 2 or Step 3.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: VRC07-523LS + PGT121.414.LS + ART	Biological: VRC07-523LS; 10 mg/kg intravenous infusion over approximately 15 to 30 minutes once at entry; Other Names: VRC-HIVMAB075-00-AB; Biological: PGT121.414.LS; 5 mg/kg intravenous infusion over approximately 30 to 60 minutes once at entry; Other Names: VRC-HIVMAB0107-00-AB; Drug: ART; Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet orally once daily with or without food; Other Names: Biktarvy
Placebo Comparator: Arm 2: Placebo + ART	Drug: ART; Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet orally once daily with or without food; Other Names: Biktarvy; Other: Placebo; Sodium Chloride for Injection USP, 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Occurrence of Grade ≥2 AE or SAE that are possibly, probably, or definitely related to the study bNAbs during Step 1	Week 0 to end of Step 1
Time from ART discontinuation to HIV-1 RNA ≥1,000 copies/mL for 4 consecutive weeks during Step 2	From Step 2 entry through 24 weeks after ART interruption

Secondary Outcome Measures

Outcome Measure	Time Frame
Time from ART discontinuation to first documented HIV-1 RNA viral rebound of ≥50 copies/mL during Step 2	From Step 2 entry through 24 weeks after ART interruption
Time from ART discontinuation to first documented HIV-1 RNA viral rebound of ≥200 copies/mL during Step 2	From Step 2 entry through 24 weeks after ART interruption
Time from ART discontinuation to first documented HIV-1 RNA viral rebound of ≥1000 copies/mL during Step 2	From Step 2 entry through 24 weeks after ART interruption
Proportion of study participants who undergo ATI with HIV-1 RNA <200 copies/mL at 24 weeks after ART interruption, without indication of ART restart	From Step 2 entry through 24 weeks after ART interruption
Time from ART discontinuation to ART restart for an HIV-related reason (virologic, immunologic and clinical criteria) during Step 2	From Step 2 entry through 24 weeks after ART interruption
Frequency of participants maintained off ART at each visit during Step 2	From Step 2 entry through 24 weeks after ART interruption
Change in CD4+/CD8+ T-cell counts during Step 2	From Step 2 entry through 24 weeks after ART interruption
Area under the curve (AUC) of VRC07-523LS and PGT121.414.LS when administered together	Week 0 to end of Step 3
Half-life of VRC07-523LS and PGT121.414.LS when administered together	Week 0 to end of Step 3
Cmax of VRC07-523LS and PGT121.414.LS when administered together	Week 0 to end of Step 3
Cmin of VRC07-523LS and PGT121.414.LS when administered together	Week 0 to end of Step 3
Clearance (Cl/F) of VRC07-523LS and PGT121.414.LS when administered together	Week 0 to end of Step 3
Volume of distribution of VRC07-523LS and PGT121.414.LS when administered together	Week 0 to end of Step 3

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Trevor Crowell, MD, PhD, U.S. Military HIV Research Program CTU

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2024
• Primary Completion (Estimated): September 6, 2025
• Study Completion (Estimated): September 6, 2028

Study Registration Dates

• First Submitted: January 30, 2023
• First Submitted That Met QC Criteria: January 30, 2023
• First Posted (Actual): February 9, 2023

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: A5388; 38662 (Other Identifier: DAIDS-ES ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.

IPD Sharing Access Criteria

With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.

For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.

By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/aboutactg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No