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Safety and Therapeutic Efficacy of mAb VRC01 During ATI in Early Treatment During Acute HIV Infection

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ClinicalTrials.gov Identifier: NCT03036709
Recruitment Status : Recruiting
First Posted : January 30, 2017
Last Update Posted : January 30, 2017
Sponsor:
Information provided by (Responsible Party):
Nittaya Phanuphak, MD, PhD, South East Asia Research Collaboration with Hawaii

Brief Summary:
This is a placebo-controlled clinical trial of VRC01 administration and analytic treatment interruption (ATI) in adults who began antiretroviral therapy (ART) during early acute HIV infection (Fiebig stage I to III). Eligible volunteers will be randomized in a 3:1 ratio to either VRC01 or placebo, with randomization stratified by Fiebig stage. Volunteers who are receiving ART with a non-nucleoside reverse transcriptase inhibitor (NNRTI) will undergo 4 weeks of protease inhibitor (PI) substitution for their NNRTI prior to randomization. ATI will begin the day of the first dose of either VRC01 or placebo. Participants will be monitored closely for HIV viremia and other pre-defined criteria for ART resumption. Administration of the study agent (VRC01) every three weeks will be discontinued after 24 weeks or if ART is resumed, whichever occurs first. Volunteers who remain virally suppressed without laboratory or clinical indication for ART resumption at 24 weeks will continue intensive monitoring for ART resumption criteria for an additional 24 weeks, during which time no VRC01 or placebo will be administered.

Condition or disease Intervention/treatment Phase
HIV Drug: VRC-HIVMAB01060-00-AB (VRC01) Other: Sodium Chloride for Injection USP, 0.9% Phase 2

Detailed Description:

The study agent, VRC-HIVMAB060-00-antibody (AB), was manufactured for the VRC by the Vaccine Pilot Plant operated by Leidos Biomedical Research, Inc, formerly SAIC-Frederick, Inc, Frederick, MD. Specific manufacturing information is included on the product vial labels and Certificates of Analysis and can be found in the Investigator's Brochure (IB). Quality Assurance (QA) lot release testing by the manufacturer and ongoing stability programs verify conformance to product specifications prior to use in clinical trials.

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing human monoclonal antibody (mAb) targeted against the HIV-1 CD4 binding site. It was developed by the VRC/NIAID/NIH. VRC01 is of the IgG1 subtype and is highly somatically mutated from its germ-line precursor. The heavy chain CDR3 region is 14 amino acids long, which is an average length relative to natural antibodies, and the glycosylation pattern is derived from its production in a Chinese Hamster Ovary (CHO) mammalian cell line.

This is a placebo-controlled clinical trial of VRC01 administration and ATI in adults who began ART during early acute HIV infection (Fiebig stage I to III). Eligible volunteers will be randomized in a 3:1 ratio to either VRC01 or placebo. Participants will undergo randomization stratified by Fiebig stage. Volunteers who are receiving ART with an NNRTI will undergo 4 weeks of PI substitution prior to randomization. ATI will begin the day of the first dose of either VRC01 or placebo. Participants will be monitored closely for HIV viremia and other pre-defined criteria for ART resumption. Administration of the study agent (VRC01) every 3 weeks will be discontinued after 24 weeks or at the time ART resumed, whichever occurs first. Volunteers who remain virally suppressed without laboratory or clinical indication for ART resumption at 24 weeks will continue intensive monitoring for ART resumption criteria for an additional 24 weeks, during which time no VRC01 or placebo will be administered. Clinical study visits will take place at the Thai Red Cross AIDS Research Centre, and the optional procedures may occur at the King Chulalongkorn Memorial Hospital.

This study will recruit 24 adults aged 20-50 years who were diagnosed during acute HIV infection (Fiebig stage I to III) and initiated on ART in Bangkok, Thailand. Participants will be recruited from protocol RV 254 (SEARCH 010, WRAIR 1494). This ongoing parent study cohort enrolls participants with documented acute HIV infection at the Thai Red Cross AIDS Research Center in Bangkok, Thailand. All participants in RV 254 are offered ART at the time of enrollment through a separately funded protocol.

Study agent:

VRC01 will be administered at a dose of 40 mg/kg intravenously every three weeks to participants assigned to the intervention arm of the trial for a total duration of 24 weeks or until ART resumption criteria are met, whichever comes first.

Placebo:

Normal saline (Sodium Chloride for Injection USP, 0.9%) will be administered intravenously every three weeks to participants assigned to the placebo arm of the trial for a total duration of 24 weeks or until ART resumption criteria are met, whichever comes first.

ANALYTIC TREATMENT INTERRUPTION (ATI) Analytic treatment interruption will begin on the day of administration of the first dose of either VRC01 or placebo. During the ATI, participants will be monitored closely for clinical and laboratory indications to resume ART. These criteria are designed to protect the subjects from clinical, immunological, or virological adverse effects during the ATI.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : August 2016
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arm Intervention/treatment
Experimental: VRC-HIVMAB01060-00-AB (VRC01)

VRC01 is a monoclonal antibody directed towards the site of CD4 attachment on the HIV-1 gp120 envelope (Env) glycoprotein.

VRC01 will be administered at a dose of 40 mg/kg intravenously every three weeks to participants assigned to the intervention arm of the trial for a total duration of 24 weeks or until ART resumption criteria are met, whichever comes first.

Drug: VRC-HIVMAB01060-00-AB (VRC01)

VRC01 will be administered at a dose of 40 mg/kg intravenously every 3 weeks for a total duration of 24 weeks or until ART resumption criteria are met, whichever comes first.

The first dose of VRC01 will be administered on the same day that antiretroviral therapy (ART) is interrupted. In the simian model, VRC01 administered intravenously achieved peak serum levels within one hour of infusion and was slowly metabolized with an average half-life of 7.61 days.The second infusion of VRC01 will occur at the midpoint of this highest risk period.

Placebo Comparator: Sodium Chloride for Injection USP, 0.9%
Normal saline (Sodium Chloride for Injection USP, 0.9%) will be administered intravenously every three weeks to participants assigned to the placebo arm of the trial for a total duration of 24 weeks or until ART resumption criteria are met, whichever comes first.
Other: Sodium Chloride for Injection USP, 0.9%
Normal saline (Sodium Chloride for Injection USP, 0.9%) will be administered intravenously every three weeks to participants assigned to the placebo arm of the trial for a total duration of 24 weeks or until ART resumption criteria are met, whichever comes first.



Primary Outcome Measures :
  1. Sustained virologic control (HIV RNA <50 copies/mL) at 24 weeks after analytic treatment interruption (ATI) [ Time Frame: 24 weeks ]
    The rate of virology control will be compared between treatment groups using a two-sided exact unconditional test with a significance level of 0.05.


Secondary Outcome Measures :
  1. the number and percentage of subjects experiencing any serious adverse event (SAE), adverse event (AE), or reactogenicity [ Time Frame: 24 and 48 weeks ]
    To assess safety will be tallied by treatment group and presented along with two-sided exact 95% confidence intervals for the proportion.

  2. Time to viral rebound [ Time Frame: through 48 weeks ]
    - Time to viral load rebound will be described using a Kaplan-Meier estimator to account for possible censoring and compared between treatment groups using an exact log-rank test.

  3. Quantification of rebound viremia after cessation of ART [ Time Frame: through 48 weeks ]
    - Number of HIV RNA copies at the time of rebound viremia will be described using medians and interquartile ranges and compared between treatment groups using a Wilcoxon-Rank Sum test.

  4. Time to ART resumption for any reason after cessation of ART [ Time Frame: baseline through 48 weeks ]
    will be described using a Kaplan-Meier estimator to account for possible censoring and compared between treatment groups using an exact log-rank test.

  5. Detectable HIV RNA via single copy assay [ Time Frame: baseline through 48 weeks ]
    Quantitative HIV RNA will be described using medians and interquartile ranges at baseline, week 24, and week 48 for subjects with HIV RNA <50 copies/mL by standard PCR. Change from baseline will be compared between treatment groups using a Wilcoxon-Rank Sum test.

  6. CD4+ T cell count change [ Time Frame: baseline through 48 weeks ]
    CD4 count will be described using medians and interquartile ranges at baseline, week 24, and week 48. Change from baseline at week 24 and week 48 will be compared between treatment groups using a Wilcoxon-Rank Sum test.

  7. Cell-associated HIV RNA and DNA in the peripheral compartment [ Time Frame: baseline through 48 weeks ]
    will be described using medians and interquartile ranges at baseline, week 24, and week 48. Change from baseline at week 24 and week 48 will be compared between treatment groups using a Wilcoxon-Rank Sum test.

  8. Neuropsychological battery performance at weeks 24 and 48, as compared to baseline at week 0. [ Time Frame: 24 and 48 weeks ]
    will be summarized using z-scores based on age-matched normative data when such data is available or as raw scores when not available.

  9. Frequency of hospitalization [ Time Frame: 48 weeks ]
    Number of hospitalizations can be compared between groups using a Wilcoxon-Rank Sum test

  10. Proportion of subjects experiencing a hospitalization [ Time Frame: 48 weeks ]
    proportion of subjects experiencing a hospitalization will be compared using an exact unconditional test.

  11. Incidence of non-AIDS related conditions [ Time Frame: 48 weeks ]
    Incidence of non-AIDS related conditions can be compared between groups using a Wilcoxon-Rank Sum test

  12. Proportion of subjects experiencing a non-AIDS related conditions [ Time Frame: 48 weeks ]
    proportion of subjects experiencing a non-AIDS related conditions will be compared using an exact unconditional test.



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Ages Eligible for Study:   20 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 < 50 copies/mL on at least three consecutive measurements within the past 12 months.
  • Integrated HIV DNA in PBMCs below the level of detection (1 copy/105 PBMCs) within 6 months prior to enrollment.
  • Last documented peripheral blood CD4 >400 cells/mm3 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 β-HCG (human chorionic gonadotropin) 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 GFR < 50 ml/min within the past 90 days.
  • Pregnant or breast-feeding.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03036709


Contacts
Contact: Nittaya - Phanuphak, MD, PhD +6622542566 nittaya.p@trcarc.org
Contact: Nitiya - Chomchey, MSc +6622542566 ext 111 nitiya.c@searchthailand.org

Locations
Thailand
SEARCH Recruiting
Bangkok, Thailand, 10330
Contact: Nittaya - Phanuphak, MD, PhD    +6622542566    nittaya.p@trcarc.org   
Contact: Nitiya - Chomchey, MSc    +6622542566 ext 111    nitiya.c@searchthailand.org   
Sponsors and Collaborators
Nittaya Phanuphak, MD, PhD
Investigators
Principal Investigator: Nittaya - Phanuphak, MD, PhD South East Asia Research Collaboration with Hawaii

Responsible Party: Nittaya Phanuphak, MD, PhD, MD, PhD, South East Asia Research Collaboration with Hawaii
ClinicalTrials.gov Identifier: NCT03036709     History of Changes
Other Study ID Numbers: SEARCH 024/RV397
First Posted: January 30, 2017    Key Record Dates
Last Update Posted: January 30, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs