The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART
Verified March 2014 by University of North Carolina, Chapel Hill
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
David Margolis, MD, University of North Carolina, Chapel Hill
First received: March 17, 2011
Last updated: March 18, 2014
Last verified: March 2014
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.
- 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
- That repeated exposure to VOR will reduce the frequency of HIV infection within resting CD4+ T cells (RCI)
||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||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
Primary Outcome Measures:
- To compare RCVL in HIV-infected patients on stable ART, before and after a single exposure to VOR, after a pair of exposures to VOR, and after multiple exposures to VOR. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
HIV RNA expression per 1 million resting CD4+ cells (RCVL) after the second of a pair of VOR doses, in participants who exhibited an increase in HIV RNA expression per 1 million resting CD4+ cells after a single 400 mg dose of VOR (HIV RNA per million resting CD4+ T cells). We will compare the HIV RNA expression per 1 million resting CD4+ cells obtained at the leukapheresis after paired VOR doses to the level obtained at baseline leukapheresis on stable ART.
Secondary Outcome Measures:
- To compare the change in HIV RNA expression per million resting CD4 + cells after multiple (10) VOR doses. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
HIV RNA per million resting CD4+ T cells at leukapheresis after ten 400 mg VOR doses vs. level at baseline leukapheresis on stable ART.
- Changes on plasma HIV-1 RNA [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
By standard assay and single copy assay.
- To assess safety, tolerability, and PK profile of VOR [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
- To assess the alterations in global histone acetylation within resting lymphocytes [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To compare the frequency of resting CD4+ T cell infection (RCI) after multiple (10) repeated short interval dosing with VOR [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
Leukapheresis on ART and VOR vs. leukapheresis on baseline ART
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||March 2015 (Final data collection date for primary outcome measure)
Step 1 - Screening (Visit 1), Enrollment (Visit 2) and Single Dose Vorinostat 400 mg (Visits 3 & 4)
Step 2 - Visits 5 and 6 - Paired Doses of Vorinostat 400 mg and Leukapheresis.
Step 3: Visits 8 - 13 Multiple Doses of Vorinostat 400 mg and Leukapheresis
Drug administration - Step 1 - 400mg Vorinostat will be given as single doses by mouth at visits 2 and 5.
Step II - 400 mg VOR for 3 consecutive days a week (for a maximum of 8 weeks).
- SAHA, or MK-0683
|Ages Eligible for Study:
||18 Years to 65 Years
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- HIV-1 infection
- Men, women age ≥18 years.
- Ability, willingness to give written informed consent.
- Able, willing to provide adequate locator information.
- Karnofsky performance status >70.
- Able, willing to adhere to therapy and adherent to ART.
- Able,willing to comply with time requirements for study visits and evaluations.
- 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.
- Adequate vascular access for leukapheresis.
- Able to swallow pills without difficulty.
- Plasma HIV-1 RNA never > 50 copies/ml on 2 consecutive occasions for ≥ 6 months while on ART.
- CD4 cell count ≥ 300 cells/µl at screening.
- All male study volunteers must agree not to participate in a conception process.
- Must be seronegative for Hep C RNA, Hep B sAg within 90 days of entry
- 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.
- Received blood transfusions or hematopoetic growth factors within 90 days.
- All women unless there is written documentation of menopause (absence of a period for ≥ one year), hysterectomy, oophorectomy, or tubal ligation.
- The study PI is unable to construct a fully active alternative regimen based on previous resistance testing and/or treatment history
- Use of atazanavir and raltegravir in background antiretroviral regimens.
- 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.
- 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.
- 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.
- 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.
- Treatment for an active AIDS-defining opportunistic infection within 90 days prior to screening.
- Any history of cardiac rhythm disturbance requiring medical or surgical therapy.
- Any history of acute or chronic pancreatitis.
- 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.
- 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.
- Known hypersensitivity to the components of VOR or its analogs.
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Pregnancy or breast feeding, or expecting to father children within the projected duration of the study.
- Inability to communicate effectively with study personnel.
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, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01319383
|The University of North Carolina at Chapel Hill
|Chapel Hill, North Carolina, United States, 27514 |
|Contact: JoAnn Kuruc, MSN, RN 919-966-8533 email@example.com |
|Principal Investigator: David Margolis, MD |
|Sub-Investigator: Joseph Eron, MD |
|Sub-Investigator: Christopher Hurt, MD |
University of North Carolina, Chapel Hill
Merck Sharp & Dohme Corp.
||David Margolis, MD
||University of North Carolina, Chapel Hill
No publications provided by University of North Carolina, Chapel Hill
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286. Erratum in: Nature. 2012 Sep 20;489(7416):460.
||David Margolis, MD, Principal Investigator, University of North Carolina, Chapel Hill
History of Changes
|Other Study ID Numbers:
||CID 0807, 1U01AI095052-01
|Study First Received:
||March 17, 2011
||March 18, 2014
||United States: Food and Drug Administration
United States: Institutional Review Board
United States: Federal Government
Keywords provided by University of North Carolina, Chapel Hill:
HIV RNA <50 copies/mL
Resting CD4+ T cells
HIV RNA expression
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on August 21, 2014
RNA Virus Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action