Phase 1, Open-label, Single Dose Study to Examine Safety, Tolerability, Pharmacokinetics and Virologic Impact of VRC01LS or VRC07-523LS in HIV-infected Viremic Adults

Study Overview
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Brief Summary
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Background: The human body uses antibodies as one way to help fight infection. VRC01LS and VRC07-523LS are antibodies directed against the HIV virus. Researchers want to see if they are safe and well tolerated. In Part A of the study, the researchers studied VRC01LS. Part A of the study was completed in 2017. In Part B, the researchers studied VRC07-523LS. Depending on which antibody received, researchers studied the amount of VRC01LS or VRC07-523LS in the body and how it changes over time. They evaluated the effect of antibodies on CD4+ (Cluster of Differentiation 4) lymphocyte count and HIV viral load, and checked to see if people who get VRC01LS or VRC07-523LS develop an immune response to it. Objective: To see if VRC01LS and VRC07-523LS are safe and well tolerated. Eligibility: Adults ages 18-70 who are HIV infected but otherwise healthy. Design: Participants received the study drug one time by IV infusion. A needle guided a thin tube into a vein. The study drug mixed with salt water was dripped into the vein over about 30 minutes. Participants were monitored for 30 minutes after the infusion. Blood samples were taken at the following times: Once before the infusion 5 times in the 4 hours after the infusion 1 time 24 hours after infusion. Some participants may have had 3 optional blood draws in the time period between 4 and 24 hours. For 3 days after the infusion, participants recorded their temperature and reactogenicity symptoms in a diary. There were a total of 23 study visits over 48 weeks. Ten visits were in the first 4 weeks. At all visits, participants answered health questions and gave blood samples.

Detailed Description
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Study Design: Open-label, single dose study to examine safety, tolerability, pharmacokinetics and virologic impact of VRC01LS or VRC07-523LS in HIV-infected viremic adults. Study Hypotheses: This is the first study of VRC01LS or VRC07-523LS in HIV-infected viremic adults. The primary hypothesis is that both VRC01LS and VRC07-523LS will be safe for intravenous administration to HIV-1-infected adults. The secondary hypothesis is that VRC01LS and VRC07-523LS will be detectable in human sera with a definable half-life. Product Description: VRC-HIVMAB080-00-AB (VRC01LS) and VRC-HIVMAB075-00-AB (VRC07-523LS) are human monoclonal antibodies (MAbs) targeted to the CD4+ binding site of HIV-1. Both MAbs are modifications of the VRC01 MAb (which has been shown to be safe and to have antiviral activity in human studies) with the addition of the LS, a 2-amino acid mutation designed to improve the half-life of the antibody. These MAbs were developed and manufactured by VRC/NIAID/NIH under current Good Manufacturing Practice (cGMP) at the VRC Vaccine Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick, MD. Vials were provided at 100 mg/mL. Participants: HIV-1-infected viremic adults; 18-70 years of age. Study Plan: This study assessed VRC01LS or VRC07-523LS administered at 40 mg/kg IV in HIV-infected viremic participants. Participants enrolled in one of two parts: Part A (VRC01LS) or Part B (VRC07-523LS). A total of 7 participants were enrolled in Part A and received VRC01LS and a total of 9 participants were enrolled in Part B and received VRC07-523LS. Safety lab samples, HIV viral load, CD4+ lymphocyte count, pharmacokinetic (PK) samples, and blood samples for detection of human anti-VRC01LS antibody (Part A) and human anti-VRC07-523LS antibody (Part B) were drawn at baseline and intervals throughout the study. Participants recorded in a daily diary reactogenicity symptoms for 3 days after study product administration and were queried at each study visit for adverse events. Participants were strongly encouraged to initiate 3-drug anti-retroviral therapy (ART), prescribed by their primary HIV clinician; not study-provided, any time after completing the day 14 study evaluations. VRC 607/A5378 Study Schema: Part: A; Participants: 7; Product: VRC01LS; Administration Schedule (Day 0): 40 mg/kg IV. Part: B; Participants: 9; Product: VRC07-523LS; Administration Schedule (Day 0): 40 mg/kg IV. Total Participants: 16 Study Duration: Participants were followed for 48 weeks after study product administration.

Official Title
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VRC 607-ACTG A5378: A Phase 1, Single Dose Study of the Safety and Virologic Effect of an HIV-1 Specific Broadly Neutralizing Human Monoclonal Antibody, VRC-HIVMAB080-00-AB (VRC01LS) or VRC-HIVMAB075-00-AB (VRC07-523LS), Administered Intravenously to HIV-Infected Adults.

Conditions
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HIV-1

Intervention / Treatment
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* Biological: VRC-HIVMAB080-00-AB
* Biological: VRC-HIVMAB075-00-AB


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: A participant must meet all of the following criteria: Able and willing to complete the informed consent process. 18-70 years old Available for clinic visits for 48 weeks after study product administration. HIV-1 infected and clinically stable. [Note: Documented HIV-1 infection by HIV enzyme immunoassay (EIA) performed by a Clinical Laboratory Improvement Amendments (CLIA) certified outside lab within 28 days of enrollment is acceptable.] At least one plasma viral load >=500 copies/mL within 28 days of enrollment. A plasma viral load within 28 days and closest to the day of enrollment, that is detectable but not greater than 100,000 copies/mL. [Note: outside laboratory results will be acceptable]. A CD4+ count >=350 cells/microliter (mcL) on 2 of 3 consecutive testing occasions (or on 2 of 2 sequential tests) within 28 days prior to enrollment. [Note: outside laboratory results will be acceptable]. In general good health as assessed by a study clinician and under the care of a primary health care provider for medical management of HIV infection while participating in the study. Willing to give consent to contact and send laboratory results to the participant's primary health provider. Willing to have blood samples collected, stored indefinitely, and used for various research purposes. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. Screening laboratory values within 28 days prior to enrollment must meet the following criteria: Absolute neutrophil count >=800/mcL Platelets >=100,000/mcL Hemoglobin >=10.0 g/dL Creatinine less than or equal to 1.31 mg/dL Alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN) Negative Hepatitis B Surface Antigen (HBsAg) Undetectable Hepatitis C Viral Load (HCV RNA) [Note: Documented negative HBsAg and HCV RNA performed by an outside CLIA certified lab within 28 days of enrollment are acceptable.] Female-Specific Criteria: If a woman is sexually active with a male partner and has no history of hysterectomy, tubal ligation, or menopause, she must agree to use either a prescription birth control method or a barrier birth control method from the time of study enrollment until the last study visit, or have a monogamous partner who has had a vasectomy. Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential. EXCLUSION CRITERIA: A participant will be excluded if one or more of the following conditions apply: Previous receipt of humanized or human monoclonal antibody whether licensed or investigational. Prior use of antiretroviral therapy. Ongoing AIDS-related opportunistic infection (including oral thrush). Active drug or alcohol use or dependence in the opinion of the site investigator that would interfere with adherence to study requirements. Any history of a severe allergic reaction, including generalized urticaria, angioedema or anaphylaxis prior to enrollment, that has a reasonable risk of recurrence during the study. Physical finding on examination considered clinically significant. Hypertension that is not well controlled. Weight >115 kg (253 pounds). Breast-feeding. Receipt of any investigational study product within 28 days prior to enrollment. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: VRC01LS (40 mg/kg)<br>VRC-HIVMAB080-00-AB (VRC01LS) - (40 mg/kg) - administered intravenously (IV) at Day 0 | Biological: VRC-HIVMAB080-00-AB<br>* VRC01LS is an investigational human monoclonal antibody targeted to the CD4+ binding site of HIV-1.<br>* Other names: VRC01LS;|
| Experimental: Part B: VRC07-523LS (40 mg/kg)<br>VRC-HIVMAB075-00-AB (VRC07-523LS) - (40 mg/kg) - administered IV at Day 0 | Biological: VRC-HIVMAB075-00-AB<br>* VRC07-523LS is an investigational human monoclonal antibody targeted to the CD4+ binding site of HIV-1.<br>* Other names: VRC07-523LS;|

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 for 3 Days After VRC01LS or VRC07-523LS Administration | Participants recorded the occurrence of solicited symptoms on a diary card for 3 days after the study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for Any Local Symptom is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 [November 2014]. | 3 days after study product administration | 
| Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms for 3 Days After VRC01LS or VRC07-523LS Administration | Participants recorded the occurrence of solicited symptoms on a diary card for 3 days after the study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for Any Systemic Symptom is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 [November 2014]. | 3 days after study product administration | 
| Number of Participants With Abnormal Laboratory Measures of Safety | Any abnormal laboratory results recorded as unsolicited AEs are summarized. Labs included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, white blood cell (WBC) and red blood cell (RBC) counts, and neutrophil, lymphocyte, monocyte, eosinophil and basophil percents and counts) and chemistry (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and creatinine). Complete blood count (CBC) and platelet results were collected at screening, Day 0 prior to study product administration (baseline), and Days 2 and 7, Weeks 2-8, 12, 16, 20, 24, 36 and 48 after product administration. Creatinine, ALT, AST and ALP results were collected at screening, baseline, and Days 2 and 7, Weeks 2, 4, 12, 24, 36 and 48 after product administration. Institutional laboratory normal ranges as well as the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 [November 2014] were used. | Through 48 weeks after study product administration | 
| Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) | Unsolicited AEs and attribution assessments were recorded in the study database from receipt of the study product administration through the visit scheduled for 56 days (or 8 weeks) after study product administration. At other time periods greater than 56 days (or 8 weeks) after the study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module), and new chronic medical conditions that required ongoing medical management were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity. | Through 56 days after study product administration | 
| Number of Participants With Serious Adverse Events (SAEs) | SAEs were recorded from receipt of the study product administration through the last expected study visit at Week 48. The relationship between a SAE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity. | Through 48 weeks after study product administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve For the Last Study Visit (AUC(Last)) | The AUC(last) represents the area under the curve (AUC) from zero (dosing) to the time of the last measurable drug concentration at the last study visit after study product administration; it is determined based on the summary PK curve for each study group. Serum samples were collected pre-infusion (baseline), end of infusion (0h), 30 min, 1 hr-4 hr, 24 hr, 48 hr and Days 7, 14, 21, 28, 35, 42, 49, 56, 84, 112, 140, 168, 252 and 336 (Week 48) post-infusion. | Administration (0h) to 48 weeks after study product administration | 
| Clearance Rate of VRC01LS or VRC07-523LS Administered at 40 mg/kg IV | Rate of study product elimination divided by the plasma concentration; determined based on the summary PK curve for each study group. Serum samples were collected pre-infusion (baseline), end of infusion (0h), 30 min, 1 hr-4 hr, 24 hr, 48 hr and Days 7, 14, 21, 28, 35, 42, 49, 56, 84, 112, 140, 168, 252 and 336 (Week 48) post-infusion. | Administration (0h) to 48 weeks after study product administration | 
| Maximum Observed Serum Concentration (Cmax) of VRC01LS or VRC07-523LS Administered at 40 mg/kg IV | Cmax is the peak serum concentration that the study product achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group. Serum samples were collected pre-infusion (baseline), end of infusion (0h), 30 min, 1 hr-4 hr, 24 hr, 48 hr and Days 7, 14, 21, 28, 35, 42, 49, 56, 84, 112, 140, 168, 252 and 336 (Week 48) post-infusion. | Through 48 weeks after study product administration | 
| Half-life (T1/2) of VRC01LS or VRC07-523LS Administered at 40 mg/kg IV | Half-life (T1/2) is the time required for half of the study product to be eliminated from the serum. Serum samples were collected pre-infusion (baseline), end of infusion (0h), 30 min, 1 hr-4 hr, 24 hr, 48 hr and Days 7, 14, 21, 28, 35, 42, 49, 56, 84, 112, 140, 168, 252 and 336 (Week 48) post-infusion. | Through 48 weeks after study product administration | 
| Mean Serum Concentration of VRC01LS or VRC07-523LS Administered at 40 mg/kg IV | The mean of individual subject serum concentrations by administered study group. Serum samples were collected pre-infusion (baseline), end of infusion (0h), 30 min, 1 hr-4 hr, 24 hr, 48 hr and Days 7, 14, 21, 28, 35, 42, 49, 56 and 84 post-infusion. | Day 28 and Day 84 after study product administration | 
| Time to Reach Maximum Observed Serum Concentration (Tmax) of VRC01LS or VRC07-523LS Administered at 40 mg/kg IV | Tmax is the time it takes to reach Cmax of study product after it has been administered; it is determined based on the summary PK curve for each study group. Serum samples were collected pre-infusion (baseline), end of infusion (0h), 30 min, 1 hr-4 hr, 24 hr, 48 hr and Days 7, 14, 21, 28, 35, 42, 49, 56, 84, 112, 140, 168, 252 and 336 (Week 48) post-infusion. | Through 48 weeks after study product administration | 
| Number of Participants Who Produced Anti-drug Antibodies to VRC01LS or VRC07-523LS Administered at 40 mg/kg IV | Presence of anti-drug antibodies to VRC01LS or VRC07-523LS was evaluated. | Day 28 and Day 56 after study product administration | 
| Log10 Change in Viral Load (VL) From Baseline to Nadir (Lowest Detectable Value) Prior to Antiretroviral Therapy (ART) Initiation | Baseline VL (log10) was the average of VL (log10) at the enrollment and pre-administration study visits. Nadir (lowest detectable) values were calculated pre-ART. For participants who didn't get ART, nadir was calculated as the minimum VL (log10) from baseline through the last visit. | Baseline through 48 weeks after study product administration | 
| Day of Nadir (Lowest Detectable) VL Prior to ART Initiation | Nadir values were calculated pre-ART. For participants who didn't get ART, nadir was calculated from baseline through the last visit. | Baseline through 48 weeks after study product administration | 
| Overall Change in CD4+ Lymphocyte Count From Baseline to Peak Prior to ART Initiation | The pre-administration study visit was considered the baseline visit. Peak values were calculated pre-ART. For participants who didn't get ART, peak was calculated as the maximum CD4+ lymphocyte counts from baseline through the last visit. | Baseline through 48 weeks after study product administration | 
| Day of Peak CD4+ Lymphocyte Count Prior to ART Initiation | Peak values were calculated pre-ART. For participants who didn't get ART, peak was calculated as the maximum CD4+ counts from baseline through the last visit. | Baseline through 48 weeks after study product administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Viral Load, Antiviral, CD4 Count, HIV-1 Infection, Broadly Neutralizing Antibody