Evaluating the Safety and Serum Concentrations of a Human Monoclonal Antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), Administered in Multiple Doses and Routes to Healthy, HIV-uninfected Adults

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and serum concentrations of a human monoclonal antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), administered in multiple doses and routes to healthy, HIV-uninfected adults.

Detailed Description
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This study will evaluate the safety, tolerability, and serum concentrations of a human monoclonal antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), administered in multiple doses and routes to healthy, HIV-uninfected adults. Participants will be randomly assigned to one of six groups. Participants in Group 1 will receive 2.5 mg/kg of VRC07-523LS by intravenous (IV) infusion at Weeks 0, 16, 32, 48, and 64. Participants in Group 2 will receive 5 mg/kg of VRC07-523LS by IV infusion at Weeks 0, 16, 32, 48, and 64. Participants in Group 3 will receive 20 mg/kg of VRC07-523LS by IV infusion at Weeks 0, 16, 32, 48, and 64. Participants in Group 4 will receive 2.5 mg/kg of VRC07-523LS by subcutaneous (SC) injection at Weeks 0, 16, 32, 48, and 64. Participants in Group 5 will receive 5 mg/kg of VRC07-523LS by SC injection at Weeks 0, 16, 32, 48, and 64. Participants in Group 6 will receive 2.5 mg/kg of VRC07-523LS or placebo by intramuscular (IM) injection at Weeks 0, 16, 32, 48, and 64. Participants will attend numerous study visits throughout the course of the study, beginning at Week 0 through Week 112. Visits may include physical examinations, blood and urine collection, HIV testing, risk reduction counseling, and questionnaires.

Official Title
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A Multicenter, Randomized, Partially Blinded Phase 1 Clinical Trial to Evaluate the Safety and Serum Concentrations of a Human Monoclonal Antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), Administered in Multiple Doses and Routes to Healthy, HIV-uninfected Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: VRC07-523LS
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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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 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 those criteria through the last required protocol clinic visit (see the protocol for more information). Laboratory Inclusion Values Hemogram/Complete Blood Count (CBC) Hemoglobin greater than or equal to 11.0 g/dL for volunteers who were assigned female sex at birth, greater than or equal to 13.0 g/dL for volunteers who were assigned male sex at birth. For transgender participants who have been on 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 volunteers assigned female sex at birth). White blood cell (WBC) count equal to 2,500 to 12,000 cells/mm^3 WBC differential either within institutional normal range or with site physician approval Platelets equal to 125,000 to 550,000/mm^3 Chemistry Chemistry panel: Alanine aminotransferase (ALT) less than 1.25 times the institutional upper limit of normal and creatinine less than or equal to institutional upper limits of normal. Virology Negative HIV-1 and -2 blood test: US volunteers must have a negative US Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA). Non-US sites may use locally available assays that have been approved by HVTN and HIV Prevention Trials Network (HPTN) Laboratory Operations. 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 infusion/injection. 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 (see protocol 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. 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, or Any other contraceptive method approved by the HVTN 127/HPTN 087 Protocol Safety Review Team (PSRT) Successful vasectomy in any partner assigned male sex at birth (considered successful if a volunteer reports that a partner assigned male sex at birth 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 tubal ligation; Or plan to be sexually abstinent until at least 6 months following the last study product administration. 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 Exclusion Criteria: General Weight greater than 115 kg Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 127/HPTN 087 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 HVTN 127/HPTN 087 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 127/HPTN 087 PSRT will determine eligibility on a case-by-case basis. Previous receipt of humanized or human mAbs, whether licensed or investigational; the HVTN 127/HPTN 087 PSRT will determine eligibility on a case-by-case basis. Previous receipt of monoclonal antibodies VRC01, VRC01LS, or VRC07-523LS Immune System Immunosuppressive medications received within 30 days before first injection or infusion (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of oral/parenteral prednisone or equivalent at doses less than 2 mg/kg/day and length of therapy less than 11 days with completion at least 30 days prior to enrollment) Serious adverse reactions to VRC07-523LS formulation components, including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain Immunoglobulin received within 90 days before first injection or infusion, unless eligibility for earlier enrollment is determined by the HVTN 127/HPTN 087 PSRT Autoimmune disease (Not excluded from participation: Volunteer 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 adverse event (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 injections, 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, 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 other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or Solicited AEs, 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. Current anti-tuberculosis (TB) therapy Asthma other than mild or moderate, 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 high dose inhaled corticosteroids, or In the past year has had 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 less than or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be less than or equal to 150 mm Hg systolic and less than or equal to 100 mm Hg diastolic. For these volunteers, blood pressure must be less than or equal to 140 mm Hg systolic and less than or equal to 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 greater than or equal to 150 mm Hg at enrollment or diastolic blood pressure greater than or equal to 100 mm Hg at enrollment. Bleeding disorder diagnosed by a doctor (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 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. Asplenia: any condition resulting in the absence of a functional spleen History of hereditary angioedema, acquired angioedema, or idiopathic angioedema

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: VRC07-523LS<br>Participants in Group 1 will receive 2.5 mg/kg of VRC07-523LS by IV infusion at Weeks 0, 16, 32, 48, and 64. | Biological: VRC07-523LS<br>* Administered by intravenous (IV) infusion, subcutaneous (SC) injection, or intramuscular (IM) injection, depending on which group participants are in<br>* Other names: VRC-HIVMAB075-00-AB;|
| Experimental: Group 2: VRC07-523LS<br>Participants in Group 2 will receive 5 mg/kg of VRC07-523LS by IV infusion at Weeks 0, 16, 32, 48, and 64. | Biological: VRC07-523LS<br>* Administered by intravenous (IV) infusion, subcutaneous (SC) injection, or intramuscular (IM) injection, depending on which group participants are in<br>* Other names: VRC-HIVMAB075-00-AB;|
| Experimental: Group 3: VRC07-523LS<br>Participants in Group 3 will receive 20 mg/kg of VRC07-523LS by IV infusion at Weeks 0, 16, 32, 48, and 64. | Biological: VRC07-523LS<br>* Administered by intravenous (IV) infusion, subcutaneous (SC) injection, or intramuscular (IM) injection, depending on which group participants are in<br>* Other names: VRC-HIVMAB075-00-AB;|
| Experimental: Group 4: VRC07-523LS<br>Participants in Group 4 will receive 2.5 mg/kg of VRC07-523LS by SC injection at Weeks 0, 16, 32, 48, and 64. | Biological: VRC07-523LS<br>* Administered by intravenous (IV) infusion, subcutaneous (SC) injection, or intramuscular (IM) injection, depending on which group participants are in<br>* Other names: VRC-HIVMAB075-00-AB;|
| Experimental: Group 5: VRC07-523LS<br>Participants in Group 5 will receive 5 mg/kg of VRC07-523LS by SC injection at Weeks 0, 16, 32, 48, and 64. | Biological: VRC07-523LS<br>* Administered by intravenous (IV) infusion, subcutaneous (SC) injection, or intramuscular (IM) injection, depending on which group participants are in<br>* Other names: VRC-HIVMAB075-00-AB;|
| Experimental: Group T6 VRC07-523LS<br>Participants in Group T6 will receive 2.5 mg/kg of VRC07-523LS by IM injection at Weeks 0, 16, 32, 48, and 64. | Biological: VRC07-523LS<br>* Administered by intravenous (IV) infusion, subcutaneous (SC) injection, or intramuscular (IM) injection, depending on which group participants are in<br>* Other names: VRC-HIVMAB075-00-AB;|
| Placebo Comparator: Group P6: Placebo<br>Participants in Group P6 will receive 2.5 mg/kg of placebo by IM injection at Weeks 0, 16, 32, 48, and 64. | Biological: Placebo<br>* Sodium Chloride for Injection USP, 0.9%; administered by IM injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness | 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 | Measured through 3 days after each vaccine dose at Weeks 0, 16, 32, 48, 64 | 
| Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration | 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 | Measured through 3 days after each vaccine dose at Weeks 0, 16, 32, 48, 64 | 
| Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms | 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. | Measured through 3 days after each vaccine dose at Weeks 0, 16, 32, 48, 64 | 
| Chemistry and Hematology Laboratory Measures - Alanine Aminotransferase (ALT) | For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population. | Measured during screening, Days 0, 56, 112, 168, 224, 280, 336, 392, 448, 504, 728 | 
| Chemistry and Hematology Laboratory Measures - Creatinine | For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population. | Measured during screening, Days 0, 56, 112, 168, 224, 280, 336, 392, 448, 504, 728 | 
| Chemistry and Hematology Laboratory Measures - Hemoglobin | For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population. | Measured during screening, Days 0, 56, 112, 168, 224, 280, 336, 392, 448, 504, 728 | 
| Chemistry and Hematology Laboratory Measures - Lymphocyte Count, Neutrophil Count | For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population. | Measured during screening, Days 0, 56, 112, 168, 224, 280, 336, 392, 448, 504, 728 | 
| Chemistry and Hematology Laboratory Measures - Platelets, White Blood Cells (WBC) | For each local laboratory measure, summary statistics were presented by treatment group and timepoint for the overall population. | Measured during screening, Days 0, 56, 112, 168, 224, 280, 336, 392, 448, 504, 728 | 
| Number of Lab Grade >= 1 for Alanine Aminotransferase (ALT), Creatinine, Hemoglobin, Lymphocyte Count, Neutrophil Count, Platelets, White Blood Cells (WBC). | The number (percentage) of participants with lab grade >= 1 for alanine aminotransferase (ALT), creatinine, hemoglobin, lymphocyte count, neutrophil count, platelets, white blood cells (WBC) was summarized by arm | Measured during screening, Days 0, 56, 112, 168, 224, 280, 336, 392, 448, 504, 728 | 
| VRC07523LS Serum Concentrations | VRC07523LS serum concentrations measured in healthy human subjects after up to five administrations of the study product via the IV, SC or IM routes at various doses. Serum concentrations between the first and second study product administrations (Target Visit Day 0-112) were measured using ELISA assay in all enrolled participants. Serum concentrations after the second study product administrations (Target Visit Day 168-784) were measured using BAMA (LUMINEX) assay in a subset of participants enrolled in each treatment group and all particiants in plocebo group. serum concentrations below the lower limit of quantification (LLoQ) were replaced by half the LLoQ. Thus, concentrations below the LLoQ when measured by the ELISA assay were replaced by 0.5 ug/ml and concentrations below the LLoQ when measured by the BAMA assay were replaced by 0.02285 ug/ml. | Target Visit Days 0, 3, 6, 28, 56, 84, 112, 168, 224, 280, 336, 392, 448, 504, 560, 616, 672, 728, 784 (i.e., visit numbers 2 through 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Antidrug Antibodies (ADA) | 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. | Day 0, 6, 112, 224, 448 | 
| Magnitude and Breadth of Neutralizing Antibody Responses Against Autologous Viral Isolates as Assessed by Area Under the Magnitude-breadth Curves 8, 72, 88 Weeks After the First Study Product Administration. | 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: H703_0646_051sN, H703_1471_190s, H703_1750_140Es, H704_0726_080sN, H704_1535_030sN, H704_2544_140eN01, PVO.4. | Weeks 8, 72, and 88 following the first study product administration |