Evaluating the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of the Monoclonal Antibody PGT121.414.LS Administered Alone and in Combination With VRC07-523LS Via Intravenous or Subcutaneous Infusions in Healthy, HIV-uninfected Adult Participants
- Conditions
- HIV Infections
- Interventions
- Biological: PGT121.414.LSBiological: VRC07-523LS
- Registration Number
- NCT04212091
- Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous or subcutaneous infusions in healthy, HIV-uninfected adult participants.
- Detailed Description
This study will evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous (IV) or subcutaneous (SC) infusions in healthy, HIV-uninfected adult participants.
The study will be conducted in two parts (Part A and B). Part A will include four groups (Groups 1, 2, 3, and 4) and Part B will include two groups (Groups 5 and 6).
In Part A of the study, PGT121.414.LS will be administered via IV infusion at 3, 10, or 30 mg/kg (Groups 1-3) or via SC infusion at 5 mg/kg (Group 4). Participants in Part B will receive consecutive administration of PGT121.414.LS followed by VRC07-523LS, at 20 mg/kg IV each per dose (Group 5) or 5 mg/kg SC each per dose (Group 6). Participants will be followed for 32 weeks after the last study product administration via IV infusion and 24 weeks after the last study product administration via SC infusion.
Participants in Groups 1, 2, and 3 will attend 8 months of study visits. Participants in Group 4 will attend 6 months of study visits. Part B participants will attend 16 months of study visits. Study visits may include physical examinations, blood and urine collection, and questionnaires.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 33
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 study product administration with verbal demonstration of understanding of all questionnaire items answered incorrectly
- Agrees not to enroll in another study of an investigational research agent until completion of the last required protocol clinic visit
- 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.
- Assessed by the clinic staff as being at "low risk" for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit (see study protocol).
Laboratory Inclusion Values:
Hemogram/Complete Blood Count
- Hemoglobin ≥11.0 g/dL for participants who were assigned female sex at birth, ≥13.0 g/dL for participants who were assigned male sex at birth. For transgender participants who have been on feminizing hormone therapy for more than 6 consecutive months, determine hemoglobin eligibility based on the gender with which they identify (ie, a transgender female who has been on hormone therapy for more than 6 consecutive months should be assessed for eligibility using the hemoglobin parameters for persons assigned female sex at birth).
- White blood cell (WBC) count = 2,500 to 12,000 cells/mm^3
- WBC differential either within institutional normal range or with site clinician approval
- Platelets = 125,000 to 550,000 cells/mm^3
Chemistry
- Chemistry panel: alanine aminotransferase (ALT) <1.25 times the institutional upper limit of normal; creatinine ≤ institutional upper limit of normal
Virology
- Negative HIV-1 and -2 blood test: US volunteers must have a negative Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA).
- Negative Hepatitis B surface antigen (HBsAg)
- Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive
Urine
- Negative or trace urine protein
Reproductive Status
-
Volunteers who were assigned female sex at birth: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to study product administration on the day of initial study product administration. Persons who are NOT of reproductive potential 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 was assigned female sex at birth must:
- Agree to use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through the last required protocol clinic visit. Effective contraception is defined as using the following methods:
- Condoms (male or female) with or without a spermicide,
- Diaphragm or cervical cap with spermicide,
- Intrauterine device (IUD),
- Hormonal contraception,
- Tubal ligation, or
- Any other contraceptive method approved by the HIV Vaccine Trials Network (HVTN) 136/HIV Prevention Trials Network (HPTN) 092 Protocol Safety Review Team (PSRT)
- Successful vasectomy in any partner assigned male sex at birth (considered successful if a volunteer reports that a male partner has [1] documentation of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy);
- Or not be of reproductive potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy, bilateral oophorectomy;
- Or be sexually abstinent.
-
Volunteers who were assigned female sex at birth 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
General
- Weight >115 kg
- Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 136/HPTN 092 PSRT
- Investigational research agents received within 30 days before first study product administration
- Intent to participate in another study of an investigational research agent or any other study that requires non-Network HIV antibody testing during the planned duration of the study
- Pregnant or breastfeeding
Vaccines and other Injections
- HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 136/HPTN 092 PSRT will determine eligibility on a case-by-case basis.
- Previous receipt of humanized or human mAbs, whether licensed or investigational; the HVTN 136/HPTN 092 PSRT will determine eligibility on a case-by-case basis.
- Previous receipt of monoclonal antibodies VRC01, VRC01LS, VRC07-523LS, or PGT121
Immune System
- Immunosuppressive medications received within 30 days before first study product administration (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatological condition; or [4] a single course of oral/parenteral prednisone or equivalent at doses <20 mg/day and length of therapy <14 days.)
- Serious adverse reactions to VRC07-523LS or PGT121.414.LS formulation components (acetate, sucrose, polysorbate 80, histidine, and sorbitol; see study protocol), including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain
- Immunoglobulin received within 90 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 136/HPTN 092 PSRT (for mAb see criterion above)
- Autoimmune disease (Not excluded from participation: Participant with mild, stable and uncomplicated autoimmune disease that does not require immunosuppressive medication and that, in the judgment of the site investigator, is likely not subject to exacerbation and likely not to complicate Solicited and Unsolicited AE assessments)
- Immunodeficiency
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:
- A process that would affect the immune response,
- A process that would require medication that affects the immune response,
- Any contraindication to repeated infusions, or blood draws, including inability to establish venous or subcutaneous 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,
- A condition or process (eg, chronic urticaria or recent injection or infusion with evidence of residual inflammation) for which signs or symptoms could be confused with reactions to the study product, or
- Any condition specifically listed among the exclusion criteria.
-
Any medical, psychiatric, occupational, or skin condition (eg, tattoos) that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety, Solicited AEs, or a participant'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.
-
Current anti-tuberculosis (TB) therapy
-
Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program (NAEPP) Expert Panel report).
-
Exclude a volunteer who:
- Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
- Uses moderate/high-dose, inhaled corticosteroids, or
-
In the past year has either of the following:
- Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids;
- Needed emergency care, urgent care, hospitalization, or intubation for asthma.
-
Diabetes mellitus type 1 or type 2 (Not excluded: type 2 cases controlled with diet alone or a history of isolated gestational diabetes.)
-
Hypertension:
- If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined as consistently ≤140 mm Hg systolic and ≤90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤150 mm Hg systolic and ≤100 mm Hg diastolic. For these volunteers, blood pressure must be ≤140 mm Hg systolic and ≤90 mm Hg diastolic at enrollment.
- If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure ≥150 mm Hg at enrollment or diastolic blood pressure ≥100 mm Hg at enrollment.
-
Bleeding disorder diagnosed by a clinician (eg, 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 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.
-
Asplenia: any condition resulting in the absence of a functional spleen
-
History of generalized urticaria, angioedema, or anaphylaxis.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part A (Group 3): PGT121.414.LS (30 mg/kg) PGT121.414.LS Participants will receive 30 mg/kg of PGT121.414.LS by IV infusion at Month 0. Part A (Group 2): PGT121.414.LS (10 mg/kg) PGT121.414.LS Participants will receive 10 mg/kg of PGT121.414.LS by IV infusion at Month 0. Part B (Group 6): PGT121.414.LS + VRC07-523LS (5 mg/kg) PGT121.414.LS Participants will receive 5 mg/kg of PGT121.414.LS and 5 mg/kg of VRC07-523LS by SC infusion sequentially in this order at Months 0, 4, and 8. Part A (Group 1): PGT121.414.LS (3 mg/kg) PGT121.414.LS Participants will receive 3 mg/kg of PGT121.414.LS by intravenous (IV) infusion at Month 0. Part B (Group 5): PGT121.414.LS + VRC07-523LS (20 mg/kg) VRC07-523LS Participants will receive 20 mg/kg of PGT121.414.LS and 20 mg/kg of VRC07-523LS by IV infusion sequentially in this order at Months 0, 4, and 8. Part B (Group 6): PGT121.414.LS + VRC07-523LS (5 mg/kg) VRC07-523LS Participants will receive 5 mg/kg of PGT121.414.LS and 5 mg/kg of VRC07-523LS by SC infusion sequentially in this order at Months 0, 4, and 8. Part A (Group 4): PGT121.414.LS (5 mg/kg) PGT121.414.LS Participants will receive 5 mg/kg of PGT121.414.LS by subcutaneous (SC) infusion at Month 0. Part B (Group 5): PGT121.414.LS + VRC07-523LS (20 mg/kg) PGT121.414.LS Participants will receive 20 mg/kg of PGT121.414.LS and 20 mg/kg of VRC07-523LS by IV infusion sequentially in this order at Months 0, 4, and 8.
- Primary Outcome Measures
Name Time Method Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness Measured through 3 days after each vaccine dose at T1-T4: Day 0; T5-T6: Days 0, 112, 224 Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration Measured through 3 days after each vaccine dose at T1-T4: Day 0; T5-T6: Days 0, 112, 224 Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Measured through 3 days after each vaccine dose at T1-T4: Day 0; T5-T6: Days 0, 112, 224 Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The following symptoms are considered as systemic reactogenicity if the onset date was within the periods of assessment specified in the protocol: malaise and/or fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, and body temperature. The item Max. Systemic Symptoms is the maximum of the individual systemic reactogenicities excluding body temperature for a participant
Chemistry and Hematology Laboratory Measures - Alkaline Phosphatase, AST, ALT in U/L Measured during Screening, Days 0, 112, 168 For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Number of Participants Reporting Unsolicited Adverse Events (AEs) Measured through Month 24 The number (percentage) of Participants Reporting Unsolicited Adverse Events (AEs) was summarized by arm
Number of Participants With Early Discontinuation of Vaccinations and Reason for Discontinuation Measured through Month 8 The number (percentage) of participants with early discontinuation of vaccinations and reason for discontinuation was summarized by arm
Chemistry and Hematology Laboratory Measures - Creatinine in mg/dL Measured during Screening, Days 0, 112, 168 For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Chemistry and Hematology Laboratory Measures - Hemoglobin in g/dL Measured during Screening, Days 0, 112, 168 For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Chemistry and Hematology Laboratory Measures - Lymphocyte Count, Neutrophil Count in 1000 Cells/Cubic mm Measured during Screening, Days 0, 112, 168 For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Chemistry and Hematology Laboratory Measures - Platelets, WBC in 1000 Cells/Cubic mm Measured during Screening, Days 0, 112, 168 For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population
Number of Participants With Early Study Termination and Reason for Early Study Termination Measured through Month 16 The number (percentage) of participants with early study termination and reason for early study termination was summarized by arm
PGT121.414.LS and VRC07523LS Serum Concentrations Days 0, 0.0417, 1, 2, 3, 6, 14, 28, 56, 84, 112, 112.0417, 140, 168, 196, 224, 224.0417, 252, 280, 336, 392, 448 Serum concentrations of PGT121.414.LS and VRC07-523LS at prespecified timepoints among participants who received all scheduled product administrations
Magnitude of Serum Neutralizing Activity Measured With mAb-specific Env-pseudotyped Viruses in TZM-bl Cells Day 3, Months 1, 2, 4, 6, 8, 10, 12 Level of ID50 and ID80 titer data from the TZMbl neutralizing antibody assays against 1 bnAb-specific virus (CH505TF.N334S.N160A.N280D.1, sensitive to PGT121, resistant to VRC07) for all Part A participants (IV or SC administration of PGT121.414.LS alone), and 1 bnAb-specific virus (CNE55.N160K, sensitive to VRC07, resistant to PGT121) for all Part B participants (IV or SC administration of PGT121.414.LS in combination with VRC07523LS) at all expected timepoints.
- Secondary Outcome Measures
Name Time Method Occurrence of Antidrug Antibodies (ADA) Day 0, 112, 196, 224, 336, 392, 448 Antidrug antibodies (ADA) are most typically detected and characterized using a tiered testing strategy. In Tier I, a sensitive binding assay is used to determine if samples may have ADA present. In Tier II, the response is confirmed, typically by establishing the specificity of the response by competition with free drug. In Tier III, the response is characterized, typically with a neutralization reduction assay and/or a titering assay.
Magnitude and Breadth of Neutralizing Antibody Responses Against Autologous Viral Isolates as Assessed by Area Under the Magnitude-breadth Curves at Months 1, 4, and 9 Months 1, 4, and 9 Magnitude-breadth characterize the magnitude (ID50 or ID80 titers) and breadth (number of virus isolates) of each individual serum sample assayed against a panel of virus isolates. MB curves show, for each possible magnitude threshold, the fraction of assays with magnitudes greater than this threshold. The area under the magnitude-breadth curve (AUC-MB) is calculated as the average of the log10-based ID50 or ID80 titers over the panel of isolates. Isolates includes: 0330.v4.c3, 3426.v5.c17, 377.v4.c09, AC10.0.29, Ce1176_A3, DU156.12, DU172.17, PVO.4, RHPA4259.7, SC422661.8, T2638, andTRO.11.
Trial Locations
- Locations (5)
George Washington Univ. CRS
🇺🇸Washington, District of Columbia, United States
Columbia P&S CRS
🇺🇸New York, New York, United States
The Hope Clinic of the Emory Vaccine Center CRS
🇺🇸Decatur, Georgia, United States
UCLA CARE Center CRS
🇺🇸Los Angeles, California, United States
Brigham and Women's Hospital Vaccine CRS (BWH VCRS)
🇺🇸Boston, Massachusetts, United States