Safety and Therapeutic Efficacy of the VRC01 Antibody in Patients Who Initiated Antiretroviral Therapy During Early Acute HIV Infection

Study Overview
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Brief Summary
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The study will evaluate the safety and therapeutic efficacy of the human monoclonal antibody (mAb) VRC-HIVMAB060-00-AB (VRC01), when administered during analytic treatment interruption (ATI), in adults who began antiretroviral therapy (ART) during early acute HIV infection.

Detailed Description
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Human monoclonal antibodies (mAbs) may have the potential to treat HIV infection by preventing the spread of the virus. This study will evaluate an experimental mAb known as VRC-HIVMAB060-00-AB (VRC01). The purpose of this study is to evaluate the safety and therapeutic efficacy of VRC01, when administered during analytic treatment interruption (ATI), in adults who began antiretroviral therapy (ART) during early acute HIV infection. The study will enroll participants from the RV 254 study who were diagnosed during early acute HIV infection and who have been on ART. At study entry, participants will stop taking their antiretroviral (ARV) medications. They will be randomly assigned to receive an intravenous (IV) infusion of VRC01 or placebo at Weeks 0 (study entry), 3, 6, 9, 12, 15, 18, 21, and 24. For 7 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 follow-up visits for 48 weeks. Study visits may include physical examinations, blood collection, and urine collection. Neurocognitive testing will take place at select study visits. Some participants may take part in optional study procedures including mucosal secretion collection, MRI brain scan, colon biopsy, lymph node biopsy, leukapheresis, and lumbar puncture. Study staff will monitor participants' HIV throughout the study, and participants will end their participation in the study and restart their ARV medications, if needed.

Official Title
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Safety and Therapeutic Efficacy of the Broadly Neutralizing HIV-1 Specific Monoclonal Antibody VRC01 During Analytic Treatment Interruption in Patients Who Initiated Antiretroviral Therapy During Early Acute HIV Infection

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: VRC01
* Biological: Placebo for VRC01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent or, in the case of illiteracy, witnessed verbal informed consent with documentation of a thumbprint in lieu of a signature. Passes Test of Understanding. Man or woman aged 20-50 years. Initiated on ART during acute HIV infection (Fiebig Stage I to III at RV 254 enrollment). Prescribed ART for at least 24 months prior to enrollment. HIV-1 RNA less than 50 copies/mL on at least three consecutive measurements within the past 12 months. Integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) below the level of detection (1 copy/10^5 PBMCs) within 6 months prior to enrollment. Last documented peripheral blood CD4 greater than 400 cells/mm^3 within 3 months prior to enrollment. No HIV-related or AIDS-defining illness within 6 months prior to enrollment. In general good health. Able to participate in study visits. Female-Specific Criteria: Agrees not to become pregnant from the time of study enrollment until the last study visit. If a woman is sexually active and has no history of hysterectomy or tubal ligation or menopause, she must agree to use a prescription birth control method or a barrier birth control method. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day of enrollment for any women unless she is post-menopause for 24 consecutive months or has undergone a surgical procedure that precludes pregnancy. Exclusion Criteria: Previous receipt of humanized or human monoclonal antibody whether licensed or investigational. Ongoing AIDS-related opportunistic infection (including oral thrush). Active injection drug use within previous 12 months. History of a severe allergic reaction with generalized urticaria, angioedema, or anaphylaxis in the 2 years prior to enrollment. History of chronic urticaria requiring daily treatment. Physical finding on examination considered indicative of significant disease such as murmur (other than functional), hepatosplenomegaly, or focal neurologic deficit. Hypertension that is not well controlled by medication. Hepatitis B surface antigen positive at any time in the past. Hepatitis C antibody positive at any time in the past. Untreated syphilis. Estimated glomerular filtration rate (GFR) less than 50 ml/min within the past 90 days. Pregnant or breastfeeding. Receipt of licensed vaccine or other investigational study agent within 28 days prior to enrollment or past participation in an investigational HIV vaccine study with receipt of active product. Current or planned participation in another interventional clinical trial during the study period. Chronic or recurrent use of medications that modify host immune response, e.g., oral or parenteral steroids, cancer chemotherapy. Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the volunteer. Including, but not limited to: diabetes mellitus type I, chronic hepatitis, renal failure; OR clinically significant forms of: drug or alcohol abuse, mental illness, severe asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer. Study site employee.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VRC01<br>Participants will receive an intravenous (IV) infusion of 40 mg/kg of VRC01 at Week 0 and every 3 weeks until Week 24 or until criteria for resumption of ART are met. | Biological: VRC01<br>* 40 mg/kg; administered IV<br>* Other names: VRC-HIVMAB060-00-AB;|
| Placebo Comparator: Placebo for VRC01<br>Participants will receive an IV infusion of placebo at Week 0 and every 3 weeks until Week 24 or until criteria for resumption of ART are met. | Biological: Placebo for VRC01<br>* Sodium Chloride for Injection 0.9%, USP; administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Event | Participants were monitored for up to 10 weeks after the last infusion of VRC01 or placebo | Measured up to 10 weeks after last infusion of VRC01 or placebo | 
| Number of Participants With Sustained Virologic Suppression | Number of participants who sustained virologic control (HIV RNA <50 copies/mL), without indication for ART resumption at week 24. | Measured through 24 weeks after ATI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Viral Rebound After Cessation of ART | This is the days from Analytic Treatment Interruption (ATI) to: HIV RNA >= 20 copies/mL. HIV RNA >= 1000 copies/mL | Measured from Baseline ATI through ART resumption. | 
| Level of Rebound Viremia After Cessation of ART | This is the HIV-1 RNA levels (copies/mL) at first detection and ART resumption. | Measured from Baseline ATI through ART resumption. | 
| Time to ART Resumption for Any Reason After Cessation of ART | This is the days from ATI to ART resumptions. | Measured from Baseline ATI through ART resumption. | 
| Number of Participants With Detectable HIV-1 RNA Via Single Copy Assay | This is number of participants who had detectable HIV-1 RNA via the ultrasensitive single copy assay prior to detectability on the routine assay. | Measured from Baseline ATI through ART resumption. | 
| Change in CD4+ T Cell Count From ATI to ART Resumption | This is change in CD4+ T cell count from ATI to ART resumption. | Measured from Baseline ATI through ART resumption | 
| Total HIV DNA in the Peripheral Compartment | This is total HIV DNA levels at baseline ATI, ART resumption and 6 month after ART resumption | Measured from ATI through 6 months after ART resumption | 
| Number of Participants Hospitalized. | Participants were monitored for up to 10 weeks after the last infusion of VRC01 or placebo | Measured up to 10 weeks after the last infusion of VRC01 or placebo | 
| Number of Participants With Acute Retroviral Syndrome (ARS) | This is the number of participants who have developed during ATI. | Measured from Baseline ATI through ART resumption. | 
| Neuropsychological Battery Performance | This is a NPZ-4 score,a 4-test NP battery evaluated fine motor function/manual dexterity [Grooved Pegboard test (GP), non-dominant hand], psychomotor speed [Color Trails 1 (CT1), Trail Making A (TM)], and executive function/set shifting [Color Trails 2 (CT2)]. Individual test raw scores were converted to z-scores. Z-scores range from -3 standard deviations up to +3 standard deviations. Higher scores indicate better test performance and lower cognitive impairment. | Measured from Baseline ATI through ART resumption. | 
| Computed Score on the Control and Attention Task (i.e., Flanker Task) | The Flanker is a measure of executive function, specifically tapping inhibitory control and attention.The scores range from 0 to 10. A higher scores indicate higher levels of ability to attend to relevant stimuli and inhibit attention from irrelevant stimuli. | Measured from Baseline ATI through ART resumption. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Monoclonal Antibody