Clinical trial NCT02411539: Evaluating the Safety, Tolerability, and Effect of a Human Monoclonal Antibody (VRC01) on Markers of HIV Persistence in HIV-Infected Adults Receiving Antiretroviral Therapy (ART)
Official title: A Phase I Study to Evaluate the Safety, Tolerability, and Effect of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), on Markers of HIV Persistence in ART-treated, HIV-infected Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: HIV
VRC01
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
First posted: 2015-04-08
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the safety, tolerability, and effect of an experimental human monoclonal antibody (mAb), VRC-HIVMAB060-00-AB (VRC01), in adults infected with HIV who were receiving antiretroviral therapy (ART).

Detailed description: Monoclonal antibodies (mAbs) have been developed as treatment for a variety of conditions including cancer, autoimmune disorders, and infections. mAbs may also be a potential treatment for people infected with HIV. The purpose of this study was to evaluate the safety and tolerability of an experimental human mAb, VRC-HIVMAB060-00-AB (VRC01), in HIV-infected adults receiving ART. Study researchers will also evaluate the effect of VRC01 on the number of infected cells containing unspliced HIV-1 transcripts in the blood in participants.

This study enrolled HIV-infected people 18 to 65 years old, who had been receiving ART for at least 2 years and who had a CD4+ count of 200 cells/mm\^3 or greater. Participants were randomly assigned to Arm A or Arm B. Participants in Arm A received an intravenous (IV) infusion of VRC01 at Day 0 and Week 3 and an IV infusion of placebo (normal saline) at Weeks 6 and 9. Participants in Arm B received an IV infusion of placebo (normal saline) at Day 0 and Week 3 and an IV infusion of VRC01 at Weeks 6 and 9. Participants recorded their temperature and symptoms for 3 days after each infusion. Study visits occured at study entry (Day 0), and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, and 30. Study visits included physical examinations, clinical assessments, and blood collection.

The primary safety outcome for this study was descriptive and assessed the occurrence of Grade ≥ 3 AEs including signs/symptoms, lab toxicities, and/or clinical events that are possibly, probably, or definitely related to study treatment (as judged by the core team, blinded to treatment arm) at any time from the initial dose of study treatment to the end of study follow-up. Since this outcome is descriptive, no statistical significance testing was performed.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection, documented by any FDA-approved rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV or E/CIA tests, or by HIV-1 antigen, or plasma HIV-1 RNA assay. More information on this criterion is available in the protocol.
* Received continuous ART for at least 2 years (defined as no interruptions longer than 14 consecutive days) and with no changes in the components of the ART for at least 90 days prior to study entry
* CD4+ cell count greater than or equal to 200 cells/mm\^3 obtained within 60 days prior to study entry in a clinical laboratory improvement amendments (CLIA)-certified laboratory
* Plasma HIV-1 RNA below the limit of detection of the FDA-approved assays (limit of detection: 75, 50, 40 or 20 copies/mL) for greater than or equal to 2 years on ART. Participants must have had at least one documented HIV-1 RNA less than the limit of detection 12-24 months prior to study entry and at least one HIV-1 RNA less than the limit of detection within 12 months prior to study entry. All available HIV-1 RNA measurements must have been below the assay limit of detection during the 2 years prior to study entry except as allowed by the following note. NOTE: A single unconfirmed plasma HIV-1 RNA greater than the limit of detection but less than 200 copies/mL within 6-24 months was allowed if followed by a subsequent value below the limit of detection.
* Plasma HIV-1 RNA level of less than 40 copies/mL obtained by the Abbott Real-time HIV assay (m2000) or less than 20 copies/mL obtained by the Roche COBAS Taqman HIV-1 v2.0 assay within 60 days prior to entry
* The following laboratory values obtained within 60 days prior to entry by any U.S. laboratory that has a CLIA certification or its equivalent.

  * Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm\^3
  * Hemoglobin greater than or equal to 11.0 g/dL for men and greater than or equal to 10.0 g/dL for women
  * Platelet count greater than or equal to 100,000/mm\^3
  * Creatinine clearance greater than or equal to 60 mL/min estimated by the Cockcroft-Gault equation. NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault method is available on www.fstrf.org.
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (SGPT) less than or equal to 2.0 times upper limit of normal (ULN)
* Hepatitis C virus (HCV) antibody negative result within 60 days prior to study entry or, if the HCV antibody result is positive, a negative HCV RNA result within 60 days prior to study entry
* Negative HBsAg result obtained within 60 days prior to study entry
* Ability and willingness of participant to provide informed consent
* Females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy, or bilateral oophorectomy and/or bilateral salpingectomy), needed a negative serum or urine pregnancy test within 48 hours prior to study entry. NOTE: Acceptable documentation of hysterectomy and bilateral oophorectomy, bilateral salpingectomy, tubal micro-inserts, partner who has undergone vasectomy, and menopause is participant-reported history.
* All participants must have agreed not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the participant/partner must use at least one reliable form of contraception (condoms, with or without a spermicidal agent; a diaphragm or cervical cap with spermicide; an intrauterine device (IUD); or hormone-based contraceptive), while receiving study treatment and for 12 weeks after stopping study treatment
* Documentation of the availability of the following stored samples from the screening visit: peripheral blood mononuclear cell (PBMC) for CD4+ T-cell associated HIV-1 RNA, DNA assay and plasma for HIV-1 SCA. Sites must receive confirmation from the processing lab via phone, email, or fax, that specimens have been entered into the AIDS Clinical Trials Group (ACTG) Laboratory Data Management System (LDMS).

Exclusion Criteria:

* Previous receipt of humanized or human monoclonal antibody (licensed or investigational)
* Weight greater than 115 kg or less than 53 kg
* Acute or ongoing AIDS-defining illness within 60 days prior to study entry
* History of a severe allergic reaction with generalized urticarial, angioedema, or anaphylaxis within 2 years of study entry
* Currently breastfeeding or pregnant
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
* Acute or serious illness that, in the opinion of the site investigator, requires systemic treatment and/or hospitalization within 60 days prior to entry
* Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry. NOTE: Participants receiving stable physiologic doses of glucocorticoids, defined as the equivalent of prednisone less than or equal to 10 mg/day, will not be excluded. Stable physiologic glucocorticoid doses should not be discontinued for the duration of the study. In addition, participants receiving inhaled or topical corticosteroids will not be excluded.
* Treatment for hepatitis C within 24 weeks of study entry
* Vaccinations within 7 days prior to the screening, pre-entry, or study entry visits. NOTE: Participants are encouraged to get routine vaccinations, such as seasonal influenza vaccine more than 7 days prior to screening or between screening and pre-entry visits (outside of the 7-day window above).
* Initiation of ART during acute HIV-1 infection (as determined by the site investigator by history and/or available medical records)

Primary outcomes:
measure: Number of Participants Who Experienced Grade 3 or Greater, Treatment Related, Adverse Event (AE)
timeFrame: Measured from study treatment initiation to study discontinuation (study duration is 30 weeks)
measure: Change in Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells
timeFrame: Screening, entry and week 6
Secondary outcomes:
measure: Number of Participants With Premature Treatment Discontinuation, for Reasons Related to Study Treatment
timeFrame: Measured from study treatment initiation to study treatment discontinuation (study treatment dispensed through week 12)
measure: Change in Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells - Last Value Carried Forward (LVCF)
timeFrame: Screening, entry, week 3 and week 6 (week 3 used as LVCF if necessary)
measure: Change in Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells - Across Arms
timeFrame: Screening, entry and weeks 6 and 12
measure: Cell-associated HIV-1 RNA in Total CD4+ Cells
timeFrame: Measured at screening, entry, weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Cell-associated HIV-1 DNA in Total CD4+ Cells
timeFrame: Measured at screening, entry, weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Cell-associated HIV-1 RNA/DNA Ratio in Total CD4+ Cells
timeFrame: Measured at screening, entry, weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Number of Participants With Plasma HIV-1 RNA by Single Copy Assay (SCA) Below Assay Lower Limit
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: CD4+ T-cell Counts
timeFrame: Measured at screening, entry and weeks 6, 12, 18 and 30
measure: CD8+ T-cell Counts
timeFrame: Measured at screening, entry and weeks 6, 12, 18 and 30
measure: Total/Inducible Virus Recovery - Stimulated HIV-1 RNA
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Total/Inducible Virus Recovery - Unstimulated HIV-1 RNA
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Total/Inducible Virus Recovery - Stimulated to Unstimulated HIV-1 RNA Ratio
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Total/Inducible Virus Recovery - Stimulated Cell Fluor
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Total/Inducible Virus Recovery - Unstimulated Cell Fluor
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Total/Inducible Virus Recovery - Stimulated to Unstimulated Cell Fluor Ratio
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Total/Inducible Virus Recovery - Percentage of Total CD4 Yield
timeFrame: Measured at pre-entry, week 6 and week 12
measure: Change in Total/Inducible Virus Recovery - Stimulated HIV-1 RNA
timeFrame: Measured at pre-entry, week 6
measure: Change in Total/Inducible Virus Recovery - Unstimulated HIV-1 RNA
timeFrame: Measured at pre-entry, week 6
measure: Change in Total/Inducible Virus Recovery - Stimulated to Unstimulated HIV-1 RNA Ratio
timeFrame: Measured at pre-entry and week 6
measure: Change in Total/Inducible Virus Recovery - Stimulated Cell Fluor
timeFrame: Measured at pre-entry, week 6
measure: Change in Total/Inducible Virus Recovery - Unstimulated Cell Fluor
timeFrame: Measured at pre-entry, week 6
measure: Change in Total/Inducible Virus Recovery - Stimulated to Unstimulated Cell Fluor Ratio
timeFrame: Measured at pre-entry, week 6
measure: Change in Total/Inducible Virus Recovery - Percentage of Total CD4 Yield
timeFrame: Measured at pre-entry, week 6
measure: VRC01 Antibody Level
timeFrame: Measured at entry and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18 and 30
measure: Detectability of Antibody to VRC01 as Measured in Serum
timeFrame: Measured at week 30
measure: Levels of T-cell Activation
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Levels of NK Cell Activation
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Plasma Levels of sCD163
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Plasma Levels of sCD14
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Plasma Levels of Interleukin-6 (IL-6)
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Plasma Levels of Human Soluble Tumor Necrosis Factor Alpha-receptor (sTNFαR)
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Plasma Levels of Tumor Necrosis Factor Alpha (TNFα)
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: Plasma Levels of High-sensitivity C-reactive Protein (hsCRP)
timeFrame: Measured at screening, entry and weeks 1, 3, 4, 6, 7, 9, 10, 12, 15, 18 and 30
measure: VRC01 Antibody Level Relative to Infusion Timing
timeFrame: Measured immediately after first infusion (and 1, 2, and 3 weeks after), and immediately after second infusion (and 1, 2, 3, 6 and 9 weeks after)
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University CRS
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
affiliation: Pitt CRS
name: Sharon Riddler, MD, MPH
role: STUDY_CHAIR
References:
citation: Riddler SA, Zheng L, Durand CM, Ritz J, Koup RA, Ledgerwood J, Bailer RT, Koletar SL, Eron JJ, Keefer MC, Macatangay BJC, Cyktor JC, Mellors JW; AIDS Clinical Trials Group A5342 Protocol Team. Randomized Clinical Trial to Assess the Impact of the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 on HIV-1 Persistence in Individuals on Effective ART. Open Forum Infect Dis. 2018 Oct 20;5(10):ofy242. doi: 10.1093/ofid/ofy242. eCollection 2018 Oct.