Clinical trial NCT05719441: A Clinical Trial of Combination HIV-Specific Broadly Neutralizing Monoclonal Antibodies Combined With ART Initiation During Acute HIV Infection to Induce HIV Remission
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
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Acute HIV Infection
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2023-02-09
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Occurrence of Grade ≥2 AE or SAE that are possibly, probably, or definitely related to the study bNAbs during Step 1
timeFrame: Week 0 to end of Step 1
measure: Time from ART discontinuation to HIV-1 RNA ≥1,000 copies/mL for 4 consecutive weeks during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
Secondary outcomes:
measure: Time from ART discontinuation to first documented HIV-1 RNA viral rebound of ≥50 copies/mL during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: Time from ART discontinuation to first documented HIV-1 RNA viral rebound of ≥200 copies/mL during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: Time from ART discontinuation to first documented HIV-1 RNA viral rebound of ≥1000 copies/mL during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: 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
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: Time from ART discontinuation to ART restart for an HIV-related reason (virologic, immunologic and clinical criteria) during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: Frequency of participants maintained off ART at each visit during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: Change in CD4+/CD8+ T-cell counts during Step 2
timeFrame: From Step 2 entry through 24 weeks after ART interruption
measure: Area under the curve (AUC) of VRC07-523LS and PGT121.414.LS when administered together
timeFrame: Week 0 to end of Step 3
measure: Half-life of VRC07-523LS and PGT121.414.LS when administered together
timeFrame: Week 0 to end of Step 3
measure: Cmax of VRC07-523LS and PGT121.414.LS when administered together
timeFrame: Week 0 to end of Step 3
measure: Cmin of VRC07-523LS and PGT121.414.LS when administered together
timeFrame: Week 0 to end of Step 3
measure: Clearance (Cl/F) of VRC07-523LS and PGT121.414.LS when administered together
timeFrame: Week 0 to end of Step 3
measure: Volume of distribution of VRC07-523LS and PGT121.414.LS when administered together
timeFrame: Week 0 to end of Step 3
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788, Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: 1201, University of Southern California CRS
state: California
city: Los Angeles
country: United States
facility: 601, University of California, Los Angeles CARE Center CRS
state: California
city: San Diego
country: United States
facility: 701, UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: 801, University of California, San Francisco HIV/AIDS CRS
state: California
city: Torrance
country: United States
facility: 603, Harbor University of California Los Angeles Center CRS
state: California
city: Aurora
country: United States
facility: 6101, University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: 31791, Whitman-Walker Institute, Inc. CRS
state: District of Columbia
city: Atlanta
country: United States
facility: 5802, The Ponce de Leon Center CRS
state: Georgia
city: Chicago
country: United States
facility: 2701, Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: 2702, Rush University CRS
state: Illinois
city: Baltimore
country: United States
facility: 201, Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: 101, Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Boston
country: United States
facility: 107, Brigham and Women's Hospital Therapeutics (BWH TCRS) CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: 2101, Washington University Therapeutics (WT) CRS
state: Missouri
city: Newark
country: United States
facility: 31786, New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: New York
country: United States
facility: 7804, Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: 30329, Columbia Physicians & Surgeons (P&S) CRS
state: New York
city: New York
country: United States
facility: 7803, Weill Cornell Uptown CRS
state: New York
city: Rochester
country: United States
facility: 31787, University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Chapel Hill
country: United States
facility: 3201, Chapel Hill CRS
state: North Carolina
city: Greensboro
country: United States
facility: 3203, Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: 2401, Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: 2501, Case CRS
state: Ohio
city: Columbus
country: United States
facility: 2301, Ohio State University CRS
state: Ohio
city: Philadelphia
country: United States
facility: 6201, Penn Therapeutics CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: 1001, University of Pittsburgh CRS
state: Pennsylvania
city: Providence
country: United States
facility: 2951, The Miriam Hospital (TMH) CRS
state: Rhode Island
city: Nashville
country: United States
facility: 3652, Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Dallas
country: United States
facility: 31443, Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: 31473, Houston AIDS Research Team CRS
state: Texas
city: Seattle
country: United States
facility: 1401, University of Washington Positive Research CRS
state: Washington
city: Porto Alegre
country: Brazil
facility: 12201, Hospital Nossa Senhora da Conceicao CRS
city: Rio De Janeiro
country: Brazil
facility: 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: San Miguel
country: Peru
facility: 11302, San Miguel CRS
state: Lima
city: Lima
country: Peru
facility: 11301, Barranco CRS
Study officials:
affiliation: U.S. Military HIV Research Program CTU
name: Trevor Crowell, MD, PhD
role: STUDY_CHAIR
References: