Clinical trial NCT02716675: Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men
Official title: A Phase 2b Study to Evaluate the Safety and Efficacy of VRC01 Broadly Neutralizing Monoclonal Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV-1 Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2016-03-23
Enrollment: 2699
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study will evaluate the safety and efficacy of the human monoclonal antibody (mAb) VRC-HIVMAB060-00-AB (VRC01) in preventing HIV-1 infection among men and transgender (TG) persons who have sex with men, in North America, South America, and Switzerland.

Detailed description: This study will evaluate the safety, tolerability, and efficacy of the VRC01 antibody in preventing HIV-1 infection in men and transgender (TG) persons who have sex with men, in North America, South America, and Switzerland.

Participants will be randomized to receive VRC01 mAb by intravenous (IV) infusion at a dose of 10 mg/kg or 30 mg/kg every 8 weeks, or to receive control infusions every 8 weeks. All participants will receive the VRC01 antibody or placebo by IV infusion at Weeks 0 (study entry), 8, 16, 24, 32, 40, 48, 56, 64, and 72. For 3 days following each infusion, participants will be asked to record and report any symptoms to study researchers.

In addition to the infusion visits, participants will attend study visits at Weeks 4, 8 + 5 days, 12, 20, 28, 36, 44, 52, 60, 68, 76, 80, 88, 96, and 104. All study visits will include blood collection and HIV testing and counseling. Select study visits will include a medical history review, physical exam, urine collection, pregnancy testing for participants capable of becoming pregnant, risk reduction counseling, and an interview/questionnaire.

Eligibility criteria: Inclusion Criteria:

General and Demographic Criteria

* Age of 18 to 50 years
* Access to a participating clinical research site (CRS) and willingness to be followed for the planned duration of the study
* Ability and willingness to provide informed consent
* Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first infusion with verbal demonstration of understanding of all questionnaire items answered incorrectly
* Agrees not to enroll in another study of an investigational research agent for the duration of the participant's trial participation
* Good general health as shown by medical history, physical exam, and screening laboratory tests

HIV-Related Criteria

* Willingness to receive HIV test results
* Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling
* Persons born Male or identifying as Transgender (TG) (male-to-female or female-to-male, see HVTN 704/HPTN 085 SSP) who, in the 6 months prior to randomization, experienced 1 or both of the following HIV risk criteria:

  * Condomless anal intercourse with 1 or more male or transgender partner(s)
  * Anal intercourse with 2 or more male or transgender partners
* Male-to-female and female-to-male TG volunteers are eligible. Receipt of hormonal therapy does not make a TG volunteer ineligible.
* Volunteers who have been in a mutually monogamous relationship with an HIV-1 seronegative partner for greater than 1 year are excluded.

Laboratory Inclusion Values:

Hematology

* Hemoglobin (Hgb) greater than or equal to 10.5 g/dL for volunteers who were born female, greater than or equal to 13.0 g/dL for volunteers who were born male (greater than or equal to 12.0 g/dL for transgender women taking feminizing hormones \[e.g., anti-androgens, estrogens\])
* Platelets greater than or equal to 100,000 cells/mm\^3

Chemistry

* Alanine aminotransferase (ALT) less than 2.5 times the institutional upper limit of normal and creatinine less than or equal to 1.25 times the institutional upper limit of normal

Virology

* HIV uninfected, as defined in the SSP, within 30 days prior to enrollment

Urine

* Negative, trace, or 1+ (30 g/L for semi-quantitative) urine protein by dipstick

Reproductive Status

* Volunteers capable of becoming pregnant: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed at the screening visit and prior to infusion on the day of initial infusion. Persons who are NOT capable of becoming pregnant due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records) are not required to undergo pregnancy testing.
* Reproductive Status: A volunteer who is capable of becoming pregnant must agree to consistently use effective contraception (see the protocol and SSP for more information) for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through the last required protocol clinic visit.
* Volunteers capable of becoming pregnant must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit

Exclusion Criteria:

General

* Investigational research agents received within 30 days before first infusion
* Body mass index (BMI) greater than or equal to 40
* Pregnant or breastfeeding
* Any reactive, indeterminate, or positive HIV test, even if subsequent testing indicates that the individual is not HIV infected, except as permitted by the HVTN 704/HPTN 085 Protocol Safety Review Team (PSRT).

Vaccines

* HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 704/HPTN 085 PSRT will determine eligibility on a case-by-case basis.

Immune System

* Serious adverse reactions to VRC01 formulation components such as sodium citrate, sodium chloride, and L-arginine hydrochloride, including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.
* Autoimmune disease, including Type I diabetes mellitus (Not excluded from participation: Volunteer with mild, stable and uncomplicated autoimmune disease that does not require consistent immunosuppressive medication and that, in the judgment of the site investigator, is likely not subject to exacerbation and likely not to complicate reactogenicity and AE assessments)
* Immunodeficiency syndrome

Clinically Significant Medical Conditions

* Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to:

  * Any contraindication to repeated infusions or blood draws, including inability to establish venous access;
  * A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period; or
  * A condition or process for which signs or symptoms could be confused with reactions to VRC01.
* Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or infusion reactions, or a volunteer's ability to give informed consent
* Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.
* Asthma, other than mild, well-controlled asthma
* Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions)
* Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study)
* Seizure disorder: History of seizure(s) within past three years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.
* History of hereditary angioedema, acquired angioedema, or idiopathic angioedema
* History of receiving transplantation of life-saving organs or tissues (includes heart, kidney, pancreas, lungs, liver, and intestines)
* Known hepatic or renal dysfunction

Primary outcomes:
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness
timeFrame: Measured through 3 days after each infusion at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration
timeFrame: Measured through 3 days after each infusion at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms
timeFrame: Measured through 3 days after each infusion at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Chemistry and Hematology Laboratory Measures - Alanine Aminotransferase (ALT)
timeFrame: Measured at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Chemistry and Hematology Laboratory Measures - Creatinine
timeFrame: Measured at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Chemistry and Hematology Laboratory Measures - Hemoglobin
timeFrame: Measured at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Chemistry and Hematology Laboratory Measures - Lymphocyte Count, Neutrophil Count
timeFrame: Measured at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Chemistry and Hematology Laboratory Measures - Platelets, White Blood Cells (WBC)
timeFrame: Measured at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Chemistry and Hematology Laboratory Measures Meeting Grade 3 AE Criteria or Above
timeFrame: Measured at Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72.
measure: Number of Participants With Early Infusion Discontinuation and Reasons for Discontinuation
timeFrame: Measured through Week 72 (the last infusion visit).
measure: Incidence Rate of Early Infusion Discontinuation
timeFrame: Measured through Week 72 (the last infusion visit).
measure: Number of Participants With Documented HIV-1 Infection by the Week 80 Visit
timeFrame: Measured through Week 80.
Secondary outcomes:
measure: Serum Concentration of VRC01 in Participants Assigned to Receive the mAb
timeFrame: Day 61 (5 days post infusion #2), Midpoint (4-weeks post infusion visits): Weeks 4, 12, 16, 28, 36, 44, 52, 60, 68, 76 and Trough (infusion visits): Pre dose at Weeks 0 (study entry), 8, 16, 24, 32, 40, 48, 56, 64, and 72.
measure: VRC01 Clinical Lot Neutralization of Founder Viruses (IC80)
timeFrame: Measured through Week 80.
measure: VRC01 Serum Neutralization of Autologous Founder Viruses (ID50, ID80)
timeFrame: First RNA+ Sample detected from baseline up to Week 104.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Vine Street Clinic CRS
state: California
city: San Francisco
country: United States
facility: Bridge HIV CRS
state: California
city: Washington
country: United States
facility: George Washington Univ. CRS
state: District of Columbia
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS
state: Georgia
city: Decatur
country: United States
facility: The Hope Clinic of the Emory Vaccine Center CRS
state: Georgia
city: Boston
country: United States
facility: Brigham and Women's Hospital Vaccine CRS (BWH VCRS)
state: Massachusetts
city: Boston
country: United States
facility: Fenway Health (FH) CRS
state: Massachusetts
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx Prevention Research Center CRS
state: New York
city: New York
country: United States
facility: Harlem Prevention Center CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: New York Blood Center CRS
state: New York
city: Rochester
country: United States
facility: University of Rochester Vaccines to Prevent HIV Infection CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Cleveland
country: United States
facility: Case Clinical Research Site
state: Ohio
city: Philadelphia
country: United States
facility: Penn Prevention CRS
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Vaccine (VV) CRS
state: Tennessee
city: Seattle
country: United States
facility: Seattle Vaccine and Prevention CRS
state: Washington
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: Bellavista
country: Peru
facility: CITBM - UNIDEC, Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales CRS
state: Callao
city: Iquitos
country: Peru
facility: ACSA CRS
state: Maynas
city: Lima
country: Peru
facility: Barranco CRS
city: Lima
country: Peru
facility: San Miguel CRS
city: Lima
country: Peru
facility: Via Libre CRS
city: Lausanne
country: Switzerland
facility: Lausanne Vaccine and Immunotherapy Center CRS
state: Vaud
Study officials:
affiliation: HVTN; FHCRC
name: Lawrence Corey
role: STUDY_CHAIR
affiliation: HPTN; University of North Carolina
name: Myron Cohen
role: STUDY_CHAIR
References:
citation: Edupuganti S, Mgodi N, Karuna ST, Andrew P, Rudnicki E, Kochar N, deCamp A, De La Grecca R, Anderson M, Karg C, Tindale I, Greene E, Broder GB, Lucas J, Hural J, Gallardo-Cartagena JA, Gonzales P, Frank I, Sobieszczyk M, Gomez Lorenzo MM, Burns D, Anderson PL, Miner MD, Ledgerwood J, Mascola JR, Gilbert PB, Cohen MS, Corey L; HVTN 704/HPTN 085 study group. Feasibility and Successful Enrollment in a Proof-of-Concept HIV Prevention Trial of VRC01, a Broadly Neutralizing HIV-1 Monoclonal Antibody. J Acquir Immune Defic Syndr. 2021 May 1;87(1):671-679. doi: 10.1097/QAI.0000000000002639.
citation: Mgodi NM, Takuva S, Edupuganti S, Karuna S, Andrew P, Lazarus E, Garnett P, Shava E, Mukwekwerere PG, Kochar N, Marshall K, Rudnicki E, Juraska M, Anderson M, Karg C, Tindale I, Greene E, Luthuli N, Baepanye K, Hural J, Gomez Lorenzo MM, Burns D, Miner MD, Ledgerwood J, Mascola JR, Donnell D, Cohen MS, Corey L; HVTN 703/HPTN 081 Team. A Phase 2b Study to Evaluate the Safety and Efficacy of VRC01 Broadly Neutralizing Monoclonal Antibody in Reducing Acquisition of HIV-1 Infection in Women in Sub-Saharan Africa: Baseline Findings. J Acquir Immune Defic Syndr. 2021 May 1;87(1):680-687. doi: 10.1097/QAI.0000000000002649.
citation: Huang Y, Naidoo L, Zhang L, Carpp LN, Rudnicki E, Randhawa A, Gonzales P, McDermott A, Ledgerwood J, Lorenzo MMG, Burns D, DeCamp A, Juraska M, Mascola J, Edupuganti S, Mgodi N, Cohen M, Corey L, Andrew P, Karuna S, Gilbert PB, Mngadi K, Lazarus E. Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials. EBioMedicine. 2021 Feb;64:103203. doi: 10.1016/j.ebiom.2020.103203. Epub 2021 Jan 23.
citation: Huang Y, Zhang L, Eaton A, Mkhize NN, Carpp LN, Rudnicki E, DeCamp A, Juraska M, Randhawa A, McDermott A, Ledgerwood J, Andrew P, Karuna S, Edupuganti S, Mgodi N, Cohen M, Corey L, Mascola J, Gilbert PB, Morris L, Montefiori DC. Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected Antibody Mediated Prevention (AMP) trial participants. Hum Vaccin Immunother. 2022 Dec 31;18(1):1908030. doi: 10.1080/21645515.2021.1908030. Epub 2021 Jul 2.
citation: Corey L, Gilbert PB, Juraska M, Montefiori DC, Morris L, Karuna ST, Edupuganti S, Mgodi NM, deCamp AC, Rudnicki E, Huang Y, Gonzales P, Cabello R, Orrell C, Lama JR, Laher F, Lazarus EM, Sanchez J, Frank I, Hinojosa J, Sobieszczyk ME, Marshall KE, Mukwekwerere PG, Makhema J, Baden LR, Mullins JI, Williamson C, Hural J, McElrath MJ, Bentley C, Takuva S, Gomez Lorenzo MM, Burns DN, Espy N, Randhawa AK, Kochar N, Piwowar-Manning E, Donnell DJ, Sista N, Andrew P, Kublin JG, Gray G, Ledgerwood JE, Mascola JR, Cohen MS; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams. Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N Engl J Med. 2021 Mar 18;384(11):1003-1014. doi: 10.1056/NEJMoa2031738.