|First Submitted Date ICMJE||March 17, 2011|
|First Posted Date ICMJE||March 21, 2011|
|Results First Submitted Date||February 9, 2017|
|Results First Posted Date||June 29, 2017|
|Last Update Posted Date||June 29, 2017|
|Start Date ICMJE||February 2011|
|Primary Completion Date||March 31, 2016 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
||To compare HIV RNA expression within resting CD4+ cells in HIV-infected patients on stable ART before and after a single exposure to VOR [ Time Frame: 3 years ]
The frequency of detectable HIV RNA expression within resting CD4+ T cells will increase after VOR exposure in vivo.
|Change History||Complete list of historical versions of study NCT01319383 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
||a) safety, tolerability, and PK profile of VOR; b) alterations in global histone acetylation and histone acetylation of the host p21 gene promoter, c) changes on plasma HIV-1 RNA. [ Time Frame: 3 years ]
A single oral administration of VOR in combination with ART to patients with HIV-1 infection will be safe and tolerable.
|Current Other Outcome Measures ICMJE
||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.
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART|
|Official Title ICMJE||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|
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.
This is a Phase I-II single-center study in participants (ppts) with HIV-1 infection receiving stable ART, with plasma HIV RNA < 50 copies/mL. Baseline ART will be maintained throughout the study. Participants will be screened for study entry, and then undergo an initial leukapheresis evaluation at study entry to obtain resting CD4+ T cells for quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL) at a baseline evaluation. All 1st time leukapheresis participants, and others as requested based on prior latent pool determinations, will have HIV-1 DNA PCR done. All participants who enter the study will receive VOR at assigned study visits, and undergo repeat leukapheresis to measure the effects of VOR exposure.
Period One - Single and Multiple Dose Vorinostat (protocol versions (v) 3.0 and 5.0)
After signing the informed consent, completing screening and meeting all eligibility requirements, participants are enrolled and undergo a baseline leukapheresis (Visit 2). Participants exhibiting or not exhibiting a response [quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL)] to an ex vivo exposure to VOR will be evaluated for an in vivo response to a single dose of VOR 400 mg. Additionally participants complete a modified 24 hour pharmacokinetics (PK) analysis. All are monitored for adverse events (AEs) especially those that are dose-limiting. Safety monitoring included clinical labs, physical exams and assessment of medications and the onset of new signs and symptoms at all study visits.
Participants demonstrating in vivo a significant increase in the resting CD4+ T cell- associated HIV RNA (RCVL) after the single dose of VOR (protocol v3.0 and v5.0) are eligible to advance into Step 2. In Step 2 (protocol v5.0), participants are administered multiple doses of VOR. Each participant receives 22 total doses of VOR via 2 cycles of 11 doses each. Each cycle is 4 weeks in length. VOR 400 mg is administered on Monday, Tuesday and Wednesday followed by 4 days of no drug during the 1st 3 weeks. The 4th week of the cycle will have VOR administered on Monday and Tuesday, followed by a leukapheresis approximately 4 hours after the 11th dose (estimated peak drug level). Participants will be monitored throughout the 4 weeks for safety which includes the documentation of AEs, especially dose-limiting AEs, and other AEs associated with study procedures and events. After a rest period (approximately 5 - 8 weeks), participants repeat the 4 week cycle. Each cycle is analyzed for significant increase in resting CD4+ T cell- associated HIV RNA (RCVL) as compared to baseline (ex-vivo) and step 1 (single dose in-vivo) responses.
Period Two - Single, Paired Interval and Multiple Interval Doses of VOR (protocol v6.0)
Step 1: Enrollment into this study period was similar to the procedures in Period 1. Participants were consented to protocol v6.0, completed screening and after meeting eligibility, enrolled on the study at Visit 2. The leukapheresis, scheduled for Visit 2, was optional based on prior ascertainment of baseline parameters. Omission of this leukapheresis was determined by study PI, after analysis of lab data from previous leukapheresis procedures. Regardless of the completion of the leukapheresis procedure at Visit 2, study enrollment and collection of required research assays was completed at Visit 2. Participant were screened and enrolled into Step 1 until 12 evaluable participants successfully completed the multiple doses of VOR (Step 4), or until the study-stopping rules are met. It is estimated that up to 30 eligible participants may be screened and enrolled to provide a total of 12 evaluable participants who complete Step 3.
Step 2 included several visits: administration of VOR (visit 3), modified/abbreviated 8 hour PK analysis, leukapheresis procedure and safety follow up (Visit 4). After assessment and ascertainment of safe to proceed clinical status, each participant receive a single dose of VOR 400 mg. Participant remained in the clinic for observation and the collection of samples for the abbreviated PK. Four hours after the dose, the leukapheresis procedure was initiated. It was anticipated that the completion of Step 1 and 2 would occur over a minimum of 8 weeks. All participants must complete Step 2 prior to moving to Step 3. All participants are assessed after the Visit 3 leukapheresis for an in vivo response to the 400 mg of VOR.
Progression from Step 2 (single dose) to Step 3 (paired doses) was based on each participant's increase in RCVL following their first dose of 400 mg VOR (Visit 3), compared to that measured at baseline (Visit 2). Progression from Step 3 (paired doses) to Step 4 (multiple doses) will be based on each participant's increase in RCVL following the 2nd in a paired dose VOR 400 mg (total doses = 3, Visit 6), compared to that measured at baseline (Visit 2).
The goal of protocol v6.0 is to determine the optimal interval between two doses of VOR (Step 2), and the response of RCI (and secondarily RCLV) to repeated doses at this interval (Step 3).
Step 3 will be initiated at least 4 weeks after the completion of the Step 2 safety follow up visit (Visit 4). If greater than 60 days elapse between Visit 4 and Visit 5, participants will repeat screening Visit labs to qualify for continued study participation. In Step 3, two paired doses of VOR 400 mg will be administered. The interval between the 2 paired doses can be as short as 48 hours (2 days), and as much as 96 hours (4 days) apart from each other. Participants were assessed for in vivo response via a 3rd leukapheresis after the second of the paired doses of 400 mg VOR. The first three (3) participants will first be assessed for an in-vivo response after the 2nd dose of the paired doses given 48 hours (2 days) apart. Subsequent participants will be assessed for responses to paired doses separated by 48 hours, or the interval may be lengthened to as much 96 hours (4 days), as dictated by the accumulated responses observed in subsequent participants.
If at least 2 of the 3 participants with 48-hour intervals respond (defined as a significant within-subject increase in cell-associated HIV RNA), then 3 subsequent participants will receive 48-hour intervals. If 2 of these 3 respond (4 of 6 total), then 3 additional participants will receive 48-hour intervals. If among the first 6 evaluable participants receiving 48-hour intervals there are 3 non-responders, then subsequent participants will receive 72-hour intervals. Participants receiving 72-hour intervals will then be assessed in the same way as those receiving 48-hour intervals, to either continue additional participants at 72-hour intervals or to increase to 96-hour intervals. Step 3 will enroll until a total of 12 evaluable subjects with a measureable increase in cell-associated HIV RNA are obtained, and these participants have advanced to Step 4.
Our preliminary results from protocol version 5.0 (period 1) are consistent with the hypothesis that the complex cellular effects of HDAC inhibitor exposure require more than 24 hours to resolve. We observed what appears to be an antagonistic effect where a VOR dose blunts the effect of the next dose when two doses are given within 24 hours of each other. The purpose of Step 3 is to establish the optimal dosing interval in which a response to Vorinostat is sustained. Step 3 will study dosing intervals; starting with a 48-hour interval and moving to longer intervals between doses depending on the effect observed with the ultimate goal to determine the shortest interval that yields an optimal effect of VOR.
If a participant fails to respond in their initial Step 3 dosing interval, they can be eligible to repeat Step 3. They can re-enter or repeat Step 3 one time only. They will only re-enter Step 3 to test a longer dosing interval. Again, if > 60 days elapses between the final safety visit of step 3 (Visit 7) and their re-entry to Step 3, they will re-screen (visit 1 only) to qualify to continue in the study.
Step 4: After a period of at least 6 weeks, to allow data analysis, participants who demonstrate an in vivo response to the 2nd of the paired dose of VOR will proceed to Step 4 and receive 10 doses of VOR 400 mg administered at the same interval at which cell-associated HIV-RNA induction was observed in Step 3. If greater than 60 days elapse between Visit 7 and Visit 8, participants will repeat the screening visit labs to qualify for continued participation in the study. At the completion of 10 doses, participants will then be assessed via a 4th and final leukapheresis for in vivo response to the serial dosing of VOR.
It is anticipated that Step 4 will occur over a minimum of 4 weeks; however this may vary among participants based on their Step 3 dosing interval stage. Accumulated blood volumes and the timing between leukapheresis procedures will determine the length of time between each step. Participants completing this protocol (version 6.0), who respond initially in Step 3 will receive a total of 5200 mg of Vorinostat. Participant completing the study, who repeat Step 3, will receive a total of 6000 mg of Vorinostat. For reference, participants who completed the previous version (5.0) received a total of 10,000 mg of Vorinostat without clear evidence of any durable drug-associated toxicity thus far.
The change in the frequency of HIV-1 infection per million resting CD4 + cells will be measured after repeated short interval dosing with VOR in Step 4. The 4th leukapheresis (Visit 12) will be compared to the baseline leukapheresis done at Visit 2. If the VOR 400 mg dosing in Step 4 is interrupted due to toxicity or intolerance, then the leukapheresis will be performed as soon as possible after the VOR interruption. This is justified as if a depletion of resting cell infection can occur; new resting cell infection is unlikely to occur in the presence of ART. Test dosing in this Step will continue until the study's stopping (lack of response in five) or toxicity rules are met.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Intervention Model: Single Group Assignment
Intervention Model Description:
All participants eligible for study received the same open label drugMasking: None (Open Label)
Open labelPrimary Purpose: Treatment
|Condition ICMJE||HIV-1 Infection|
|Intervention ICMJE||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
|Study Arms||Experimental: Open Label, Translational Research
Vorinostat will be administered to all eligible participants in each step of each phase (period) of the study
Intervention: Drug: Vorinostat
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||March 31, 2016|
|Primary Completion Date||March 31, 2016 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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.
|Ages||18 Years to 65 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01319383|
|Other Study ID Numbers ICMJE||CID 0807
1U01AI095052-01 ( U.S. NIH Grant/Contract )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||University of North Carolina, Chapel Hill|
|Study Sponsor ICMJE||University of North Carolina, Chapel Hill|
|PRS Account||University of North Carolina, Chapel Hill|
|Verification Date||April 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP