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Trial record 1 of 1 for:    NCT01319383
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The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01319383
First Posted: March 21, 2011
Last Update Posted: June 29, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Institutes of Health (NIH)
Merck Sharp & Dohme Corp.
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
  Purpose

The purpose of this study is to compare HIV RNA expression and infection within resting (CD4)+ cells in HIV-infected patients on stable ART before and after a single exposure to Vorinostat (VOR), after exposure to short intervals of VOR, and after repeated short interval exposure to VOR dosed over several weeks.

Hypotheses:

  1. The frequency of resting CD4+ T cell- associated HIV RNA (RCVL) will be increased following single and repeated exposure to VOR when given at appropriate intervals, and
  2. That repeated exposure to VOR will reduce the frequency of HIV infection within resting CD4+ T cells (RCI)

Condition Intervention Phase
HIV-1 Infection Drug: Vorinostat Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Intervention Model Description:
All participants eligible for study received the same open label drug
Masking: None (Open Label)
Masking Description:
Open label
Primary Purpose: Treatment
Official Title: A Phase I/II Investigation of the Effect of Vorinostat (VOR) on HIV RNA Expression in the Resting CD4+ T Cells of HIV-Infected Patients Receiving Stable Antiretroviral Therapy

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Number of Participants Exhibiting an in Vivo Resting CD4+ T Cell- Associated HIV RNA (RCVL) Increase After Receiving a Single Dose of VOR 400 mg PO [ Time Frame: Arm1: Baseline, Visit 5 and Arm 2: Baseline and Visit 3 ]
    Participants in Arm 1 and 2 were analyzed in Step 2 for an in vivo increase in resting CD4+ T cell- associated HIV RNA (RCVL) after administration of a single dose of VOR 400 mg PO

  • Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Each of Two Multiple Dose Cycles (11 Doses/Cycle) [ Time Frame: Baseline, Visit 18, Visit 29 ]
    Participants in Arm 1, Step 3 were analyzed for an in vivo increase in the resting CD4+ T cell- associated HIV RNA (RCVL) after 11 doses of VOR 400 mg PO. This cycle was repeated after a 5 - 8 week rest period for a 2nd series and measurement.

  • Number of Participants With a Significant in Vivo Response in Resting Cell Infection (RCI) and HIV RNA After Paired Doses [ Time Frame: Baseline, Visit 6 ]
    Induction of significant in vivo RCI and RCLV response after 2 doses of VOR 400 mg PO administered 48 hours apart or 72 hours apart

  • Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Multiple (n = 10) Interval Doses [ Time Frame: Baseline, Visit 9 ]
    Participants in Arm 2, Step 4 were analyzed for an in vivo increase in the resting CD4+ T cell- associated HIV RNA (RCVL) after administration of 10 doses of VOR 400 mg PO, given 72 hours apart.


Secondary Outcome Measures:
  • Number of Participants With Measurable Changes in Plasma HIV-1 RNA [ Time Frame: 1 week after last VOR dose ]
    Assess for detectible HIV-1 RNA > 150 copies/mL, confirmed by repeat evaluation, following VOR dose. By standard assay and single copy assay. Pre specified to combine all participants into one arm.

  • Number of Participants With Confirmed Non-hematologic Toxicity >/= Grade 3 and Related to VOR Per Division of AIDS (DAIDS) Grading Table [ Time Frame: 24 hrs following single dose and 1 week after last of multiple dose sequence ]
    DAIDS Grading Table- Grade 1- mild, Grade 2- moderate; Grade 3- severe Grade 4- potentially life-threatening. Pre specified to combine all participants into one arm.

  • Number of Participants With Confirmed Hematologic Toxicity >/= Grade 2 and Related to VOR Per Division of AIDS (DAIDS) Grading Table [ Time Frame: 24 hrs following single dose and 1 week after last of multiple dose sequence ]
    DAIDS Grading Table- Grade 1- mild, Grade 2- moderate; Grade 3- severe Grade 4- potentially life-threatening. Pre specified to combine all participants into one arm.


Other Outcome Measures:
  • Number of Participants Developing Cancer Within 5 Years Following >/= 8 Vorinostat Dose Exposures [ Time Frame: From last dose Vorinostat to 5 years afterwards ]
    Development of a new cancer within the 5 years of taking their last dose of VOR 400 mg PO.All participants receiving one or more doses of VOR 400 mg PO in any and all Arms of the study. Pre-specified to be reported as one group.


Enrollment: 25
Study Start Date: February 2011
Study Completion Date: March 31, 2016
Primary Completion Date: March 31, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Open Label, Translational Research
Vorinostat will be administered to all eligible participants in each step of each phase (period) of the study
Drug: Vorinostat
Vorinostat (VOR) 400mg will be given as single doses by mouth. Participants eligible to advance in study will have opportunity to receive more than one dose of VOR. Each participant will only take one dose of VOR in a 24 hour period. Repeat doses will be administered at least 24 hours apart, with option for dosing at intervals up to 96 hour
Other Names:
  • Zolinza
  • SAHA, or MK-0683
  • VOR

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV-1 infection
  2. Men, women age ≥18 years.
  3. Ability, willingness to give written informed consent.
  4. Able, willing to provide adequate locator information.
  5. Karnofsky performance status >70.
  6. Able, willing to adhere to therapy and adherent to ART.
  7. Able,willing to comply with time requirements for study visits and evaluations.
  8. On potent ART, defined as at least 2 nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, or a protease inhibitor without interruption (defined as missing doses for more than two consecutive days or more than four cumulative days) in the 24 weeks immediately prior to entry. Other potent fully suppressive antiretroviral combinations will be considered on a case-by-case basis. Prior changes in or elimination of medications for easier dosing schedule, intolerance, or other reasons are permitted if an alternative suppression regimen was maintained.
  9. Adequate vascular access for leukapheresis.
  10. Able to swallow pills without difficulty.
  11. On combination ART for ≥ 18 months prior to study entry, no consecutive HIV-1 RNA values >50 copies/mL in that time period
  12. CD4 cell count ≥ 300 cells/µl at screening.
  13. All male study volunteers must agree not to participate in a conception process.
  14. Must be seronegative for Hep C RNA, Hep B sAg within 90 days of entry
  15. Must have adequate organ function as indicated by the following lab values:

Hematological: Absolute Neutrophil Count (ANC) ≥ 1,500/mcL Platelets ≥ 125,000/mcL Hgb ≥ 12 g/dL

Coagulation: Prothrombin Time or International Normalized Ratio (INR) ≤ 1.5x upper limit of normal (ULN)

Chemistry: K+ levels Within normal limits Mg++ levels > Lower limits of normal (LLN) but <1.5 x ULN Glucose Screening serum glucose(fasting/non-fasting) below 120 mg/dl.

Renal: Serum creatinine/calculated creatinine clearance* ≤ 1.3 X ULN OR ≥ 60 mL/min for participants with creatinine levels > 1.3 X ULN

Hepatic: Serum total bilirubin Total bilirubin < 1.5 times ULN. If total bilirubin is elevated, direct bilirubin will be measured and the participant will be eligible if the direct bilirubin is < 2 X ULN.

Aspartate amino transferase (AST) (SGOT) and Alanine amino transferase (ALT) (SGPT)≤ 2.0 X ULN Lipase <1.6 X ULN Alkaline Phosphatase ≤ 2.5 X ULN

*Creatinine clearance should be calculated per institutional standard.

Exclusion Criteria:

  1. Received blood transfusions or hematopoetic growth factors within 90 days.
  2. All women unless there is written documentation of menopause (absence of a period for ≥ one year), hysterectomy, oophorectomy, or tubal ligation.
  3. The study PI is unable to construct a fully active alternative regimen based on previous resistance testing and/or treatment history
  4. Use of atazanavir and raltegravir in background antiretroviral regimens.
  5. Any antiretroviral medications that cannot be co-administered with Vorinostat within the 4 weeks of the first Vorinostat dose and anytime thereafter while on study.
  6. Use of any of the following within 90 days prior to entry: systemic cytotoxic chemotherapy; investigational agents; immunomodulators (colony-stimulating factors, growth factors, systemic corticosteroids, HIV vaccines, immune globulin, interleukins, interferons); coumadin, warfarin, or other Coumadin derivative anticoagulants.
  7. Any serious illness requiring systemic treatment or hospitalization, the subject must either complete therapy or be clinically stable on therapy, in the opinion of the site investigator, for at least 90 days prior to entry.
  8. Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or a physical illness, e.g., infectious disease. Prisoner recruitment and participation is not permitted.
  9. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to screening.
  10. Any history of cardiac rhythm disturbance requiring medical or surgical therapy.
  11. Any history of acute or chronic pancreatitis.
  12. Use of the following medications that carry risk of torsades de pointes: amiodarone, arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, probucol, procainamide, quinidine, sotalol, sparfloxacin, terfenadine, thioridazine.
  13. Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within the last 30 days. Potential participants may enroll after a 30-day washout period.
  14. Known hypersensitivity to the components of VOR or its analogs.
  15. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  16. Pregnancy or breast feeding, or expecting to father children within the projected duration of the study.
  17. Inability to communicate effectively with study personnel.
  Contacts and Locations
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): NCT01319383


Locations
United States, North Carolina
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27514
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institutes of Health (NIH)
Merck Sharp & Dohme Corp.
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: David Margolis, MD University of North Carolina, Chapel Hill
  More Information

Publications:
Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01319383     History of Changes
Other Study ID Numbers: CID 0807
1U01AI095052-01 ( U.S. NIH Grant/Contract )
First Submitted: March 17, 2011
First Posted: March 21, 2011
Results First Submitted: February 9, 2017
Results First Posted: June 29, 2017
Last Update Posted: June 29, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by University of North Carolina, Chapel Hill:
HIV-1 Infection
HIV RNA <50 copies/mL
Stable ART
Resting CD4+ T cells
Leukapheresis
Vorinostat
HIV RNA expression
PK visits

Additional relevant MeSH terms:
Vorinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action