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

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
Overall Status
Not yet recruiting
CT.gov ID
NCT05719441
Collaborator
(none)
48
Enrollment
36
Locations
2
Arms
66.1
Anticipated Duration (Months)
1.3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: VRC07-523LS
  • Biological: PGT121.414.LS
  • Other: Placebo
  • Drug: ART
 Phase 2

Study Design

Study Type:
Interventional
Anticipated Enrollment :
48 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
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
Anticipated Study Start Date :
Mar 6, 2023
Anticipated Primary Completion Date :
Sep 6, 2025
Anticipated Study Completion Date :
Sep 6, 2028

Arms and Interventions

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

    Other: Placebo
    Sodium Chloride for Injection USP, 0.9%

    Drug: ART
    Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablet orally once daily with or without food
    Other Names:
  • Biktarvy

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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]

    2. 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

    1. 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]

    2. 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]

    3. 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]

    4. 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]

    5. 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]

    6. Frequency of participants maintained off ART at each visit during Step 2 [From Step 2 entry through 24 weeks after ART interruption]

    7. Change in CD4+/CD8+ T-cell counts during Step 2 [From Step 2 entry through 24 weeks after ART interruption]

    8. Area under the curve (AUC) of VRC07-523LS and PGT121.414.LS when administered together [Week 0 to end of Step 3]

    9. Half-life of VRC07-523LS and PGT121.414.LS when administered together [Week 0 to end of Step 3]

    10. Cmax of VRC07-523LS and PGT121.414.LS when administered together [Week 0 to end of Step 3]

    11. Cmin of VRC07-523LS and PGT121.414.LS when administered together [Week 0 to end of Step 3]

    12. Clearance (Cl/F) of VRC07-523LS and PGT121.414.LS when administered together [Week 0 to end of Step 3]

    13. Volume of distribution of VRC07-523LS and PGT121.414.LS when administered together [Week 0 to end of Step 3]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    Step 1:

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

    2. 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

    3. 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

    4. 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

    5. 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

    6. 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

    7. 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

    8. 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

    1. For persons who are able to become pregnant, negative urine or serum pregnancy test within 24 hours prior to study entry.

    2. 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.

    3. 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.

    4. 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.

    5. Age ≥18 and ≤70 years.

    6. Ability and willingness to initiate ART at enrollment.

    7. Ability and willingness to participate in scheduled study visits, including during the ATI, per Schedule of Evaluations (SOE).

    8. 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

    1. Currently breastfeeding or pregnant.

    2. Weight >115 kg.

    3. 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.

    4. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 31788, Alabama CRS Birmingham Alabama United States 35222
    2 1201, University of Southern California CRS Los Angeles California United States 90033-1079
    3 601, University of California, Los Angeles CARE Center CRS Los Angeles California United States 90035
    4 701, UCSD Antiviral Research Center CRS San Diego California United States 92103
    5 801, University of California, San Francisco HIV/AIDS CRS San Francisco California United States 94110
    6 603, Harbor University of California Los Angeles Center CRS Torrance California United States 90502
    7 6101, University of Colorado Hospital CRS Aurora Colorado United States 80045
    8 31791, Whitman-Walker Institute, Inc. CRS Washington District of Columbia United States 20005
    9 5802, The Ponce de Leon Center CRS Atlanta Georgia United States 30308-2012
    10 2701, Northwestern University CRS Chicago Illinois United States 60611
    11 2702, Rush University CRS Chicago Illinois United States 60612
    12 201, Johns Hopkins University CRS Baltimore Maryland United States 21205
    13 101, Massachusetts General Hospital CRS (MGH CRS) Boston Massachusetts United States 02114
    14 107, Brigham and Women's Hospital Therapeutics (BWH TCRS) CRS Boston Massachusetts United States 02115
    15 2101, Washington University Therapeutics (WT) CRS Saint Louis Missouri United States 63110-1010
    16 31786, New Jersey Medical School Clinical Research Center CRS Newark New Jersey United States 07103
    17 7804, Weill Cornell Chelsea CRS New York New York United States 10010
    18 30329, Columbia Physicians & Surgeons (P&S) CRS New York New York United States 10032-3732
    19 7803, Weill Cornell Uptown CRS New York New York United States 10065
    20 31787, University of Rochester Adult HIV Therapeutic Strategies Network CRS Rochester New York United States 14642
    21 3201, Chapel Hill CRS Chapel Hill North Carolina United States 27599-7215
    22 3203, Greensboro CRS Greensboro North Carolina United States 27401
    23 2401, Cincinnati CRS Cincinnati Ohio United States 45267-0405
    24 2501, Case CRS Cleveland Ohio United States 44106
    25 2301, Ohio State University CRS Columbus Ohio United States 43210-1282
    26 6201, Penn Therapeutics CRS Philadelphia Pennsylvania United States 19104
    27 1001, University of Pittsburgh CRS Pittsburgh Pennsylvania United States 15213
    28 2951, The Miriam Hospital (TMH) CRS Providence Rhode Island United States 02904
    29 3652, Vanderbilt Therapeutics (VT) CRS Nashville Tennessee United States 37204
    30 31443, Trinity Health and Wellness Center CRS Dallas Texas United States 75208
    31 31473, Houston AIDS Research Team CRS Houston Texas United States 77030
    32 1401, University of Washington Positive Research CRS Seattle Washington United States 98104
    33 12201, Hospital Nossa Senhora da Conceicao CRS Porto Alegre Brazil 91350-200
    34 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS Rio De Janeiro Brazil
    35 11302, San Miguel CRS San Miguel Lima Peru 32
    36 11301, Barranco CRS Lima Peru 4

    Sponsors and Collaborators

    • National Institute of Allergy and Infectious Diseases (NIAID)

    Investigators

    • Study Chair: Trevor Crowell, MD, PhD, U.S. Military HIV Research Program CTU

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Institute of Allergy and Infectious Diseases (NIAID)
    ClinicalTrials.gov Identifier:
    NCT05719441
    Other Study ID Numbers:
    • A5388
    • 38662
    First Posted:
    Feb 9, 2023
    Last Update Posted:
    Feb 9, 2023
    Last Verified:
    Jan 1, 2023
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Infections
    Communicable Diseases
    HIV Infections
    Acquired Immunodeficiency Syndrome

    Study Results

    No Results Posted as of Feb 9, 2023