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The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART

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ClinicalTrials.gov Identifier: NCT01319383
Recruitment Status : Completed
First Posted : March 21, 2011
Results First Posted : June 29, 2017
Last Update Posted : June 29, 2017
Sponsor:
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

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV-1 Infection
Intervention Drug: Vorinostat
Enrollment 25
Recruitment Details Potential HIV infected participants who were durably suppressed (<50 copies/mL) on stable ART with a CD4 count >300/μL were recruited from the UNC ID clinic and UNC AIDS Clinical Trials Unit. Twenty seven (27) participants were screened for both study periods, 25 unique individuals enrolled between February 2011 and March 31, 2016.
Pre-assignment Details Participants were recruited into the single and multiple dose Vorinostat (VOR) Arm alone, the VOR Interval Dosing Arm alone, or both = 25. Each Arm had multiple steps. Participants without a significant in vitro or in vivo response to VOR did not advance in either Arm; 3 Arm 1 and 13 new participants, enrolled Arm 2.
Arm/Group Title Single and Multiple Dose Interval Dosing
Hide Arm/Group Description There are 3 Steps in this Arm: Step 1 a Baseline leukapheresis was completed to obtain resting CD4+ T cells for quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL); ex-vivo exposure. Step 2 measured the in-vivo response to single dose of VOR; Step 3 measured the in vivo response after each of 2 series of exposure to multiple doses of VOR 400 mg PO. In each series, 11 doses of VOR were administered for 3 days (M-T-W) and no doses for the remaining 4 days. A leukapheresis was completed 4 hours after the 11th dose to measure in vivo response. There are 4 steps in this Arm. Step 1 Baseline leukapheresis (Visit 2) to obtain resting CD4+ T cells for quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL). Ex-vivo exposure to measure RCVL responsiveness to Vorinostat. Step 2 involved measurement of in vivo response to single dose of VOR. Step 3 involved 2 doses separated by 48 or 72 hours. In vivo responsiveness measured for optimal dose interval and step advancement. Step 4 measured significance of response to VOR 400 mg PO taken every 72 hours for 10 doses.
Period Title: Overall Study
Started 12 13
Step 1 [1] 8 11 [2]
Step 2 [3] 8 [4] 4 [5]
Step 2 [6] 4 [7] 0
Step 3 [8] 0 [9] 6 [10]
Step 4 [11] 0 [12] 3 [13]
Completed 0 3
Not Completed 12 10
Reason Not Completed
No ex vivo or in vivo response             4             0
Physician Decision             3             0
Lack of Efficacy             5             9
No in vivo response to interval doses             0             1
[1]
Demonstrating an ex vivo response to VOR, measured in research lab, permitted study advancement
[2]
The 2 participants without an ex vivo response were terminated from the study.
[3]
Demonstrated an in vivo response to a single VOR 400 mg PO in Step 2
[4]
These participants demonstrated an ex vivo response in Step 1
[5]
The 7 participants without an in vivo response to single dose of VOR 400 mg PO were terminated.
[6]
Did not demonstrate an in vivo response to VOR 400 mg PO
[7]
The 4 without ex vivo response (Step 1) took a single dose to see if in vivo response would occur
[8]
Demonstrated an in vivo response to multiple doses of VOR 400 mg PO
[9]
None who qualified for the 2 series of 11 doses of VOR (taken M-T-W & off for 4 days for 4 wks).
[10]
3 Arm 1 participants enrolled here; 6/7 had in vivo response to 2 VOR doses given 72 hours apart.
[11]
Demonstrated an in vivo response to 10 doses taken a designated intervals
[12]
Arm 1 did not have a Step 4
[13]
Only 3/6 completed the study.
Arm/Group Title Single, Multiple and Interval Dosing Of Vorinostat 400 mg PO
Hide Arm/Group Description The study was separated into Arms for reporting purposes required in this report. The data representing the eligibility and baseline measures were the same throughout the study and are therefore reported as a composite of the entire study. Vorinostat 400 mg PO was administered in single and multiple doses in both Arm 1 and 2. The entire cohort is described below and representative of all who were enrolled in the study over the 5 year period.
Overall Number of Baseline Participants 25
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
<=18 years
0
   0.0%
Between 18 and 65 years
25
 100.0%
>=65 years
0
   0.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 25 participants
49
(23 to 65)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Female
0
   0.0%
Male
25
 100.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Hispanic
1
   4.0%
Black or African American
4
  16.0%
Caucasian or White
20
  80.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 25 participants
25
HIV-1 RNA Categories  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
< 50 copies/mL
25
 100.0%
>= 50 copies/mL
0
   0.0%
CD4 Nadir  
Median (Full Range)
Unit of measure:  cells/µL
Number Analyzed 25 participants
403
(49 to 879)
CD4 Cell Count  
Median (Full Range)
Unit of measure:  cells/µL
Number Analyzed 25 participants
718
(402 to 1302)
1.Primary Outcome
Title 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
Hide Description 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
Time Frame Arm1: Baseline, Visit 5 and Arm 2: Baseline and Visit 3
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title 1/Single & Multiple Dose, Step 2, Visit 5 2/Interval Dosing, Visit 3
Hide Arm/Group Description:
Participants enrolled in Arm 1 were given one dose of VOR 200 mg by mouth (PO), symptoms were assessed over 12 hours and pharmacokinetic samples obtained. Leukapheresis procedure was performed 4 hours after the dose to measure RCVL in-vivo response.
Participants enrolled in Arm 2 receiving a single dose of VOR 400 mg PO after demonstrating an ex vivo response at baseline. Symptoms were assessed over 12 hours and pharmacokinetic samples obtained. Leukapheresis procedure was performed 4 hours after the dose to measure RCVL in-vivo response.
Overall Number of Participants Analyzed 12 11
Measure Type: Count of Participants
Unit of Measure: Participants
8
  66.7%
4
  36.4%
2.Primary Outcome
Title 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)
Hide Description 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.
Time Frame Baseline, Visit 18, Visit 29
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with resting CD4+ T-cell-associated HIV RNA (rc-RNA) increases after receiving daily VOR Monday through Wednesday for 8 weekly cycles were enrolled.
Arm/Group Title Arm 1 - Single and Multiple Dose, Step 3
Hide Arm/Group Description:
Participants without dose-limiting symptoms and exhibiting an in vivo response to single VOR doses were eligible to receive multiple doses of VOR 400 mg. The first dose was administered in clinic with observation for symptoms for 1 hour post dose. Symptoms were assessed daily and on the third day 4 hours after the dose. These participants took VOR 400 mg (PO) in the AM for 3 days each week (dose every M-T-W) for 3 weeks. On the 4th week, the participant took 2 doses of VOR 400 mg (M-T) in the AM. A leukapheresis was completed 4 hours after the 2nd dose of VOR to measure RCVL in-vivo response. After a 4 - 8 week rest period, participants without dose-limiting symptoms repeated the 4 week cycle.
Overall Number of Participants Analyzed 5
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
3.Primary Outcome
Title Number of Participants With a Significant in Vivo Response in Resting Cell Infection (RCI) and HIV RNA After Paired Doses
Hide Description 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
Time Frame Baseline, Visit 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants showing an in vivo response in resting CD4+ T cell- associated HIV RNA (RCVL) after a single dose of VOR were administered 2 doses of VOR 400 mg separated by either 48 or 72 hours to determine the optimal interval/spacing to observe a significant in vivo response in the RCVL after the paired doses.
Arm/Group Title Interval Dosing , Step 3 (48 hr Interval) Interval Dosing, Step 3 (72 Hour Interval)
Hide Arm/Group Description:
Participants without dose-limiting symptoms and exhibiting an in vivo response to single VOR dose were eligible to receive 2 doses of VOR 400 mg PO, given at the pre-determined interval of 48 hours. Participant took the PO doses at home per schedule with daily telephone assessment of symptoms. Leukapheresis procedure performed 4 hours after the 2nd dose to measure RCVL in-vivo response.
Participants without dose-limiting symptoms and exhibiting an in vivo response to single VOR dose were eligible to receive 2 doses of VOR 400 mg PO, given at the pre-determined interval of 72 hours. Participant took the PO doses at home per schedule with daily telephone assessment of symptoms. Leukapheresis procedure performed 4 hours after the 2nd dose to measure RCVL in-vivo response.
Overall Number of Participants Analyzed 1 7
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
6
  85.7%
4.Primary Outcome
Title Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Multiple (n = 10) Interval Doses
Hide Description 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.
Time Frame Baseline, Visit 9
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who demonstrated a significant in vivo response after taking 2 doses of VOR 400 mg PO, each dose taken 72 hours apart were administered 10 doses of VOR based on the optimal dosing of 72 hours.
Arm/Group Title Interval Doses (Multiple) Step 4
Hide Arm/Group Description:

Participants without dose-limiting symptoms and exhibiting an in vivo response to the paired doses of VOR 400 mg PO were eligible to receive 10 doses of VOR, given at the pre-determined interval. Participant took the PO doses at home per schedule with daily telephone assessment of symptoms and clinical assessments at after the 3rd, 5th, 8th and 10th doses. Participant were only given the required doses for administration between visits.

Leukapheresis procedure performed 4 hours after the 10th dose to measure RCVL in-vivo response.

Overall Number of Participants Analyzed 3
Measure Type: Count of Participants
Unit of Measure: Participants
3
 100.0%
5.Secondary Outcome
Title Number of Participants With Measurable Changes in Plasma HIV-1 RNA
Hide Description 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.
Time Frame 1 week after last VOR dose
Hide Outcome Measure Data
Hide Analysis Population Description
All participants receiving one or more doses of VOR in any and all Arms of the study.
Arm/Group Title 1/Single & Multiple Dose, Steps 2 and 3 2/Interval Dosing, Steps 2, 3 and 4
Hide Arm/Group Description:
All eligible participants in the Single and Multiple Group Arm who received at least one dose of VOR 400 mg PO
All eligible participants in the Interval Dosing Arm who received at least one dose of VOR 400 mg PO
Overall Number of Participants Analyzed 12 13
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
6.Secondary Outcome
Title Number of Participants With Confirmed Non-hematologic Toxicity >/= Grade 3 and Related to VOR Per Division of AIDS (DAIDS) Grading Table
Hide Description 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.
Time Frame 24 hrs following single dose and 1 week after last of multiple dose sequence
Hide Outcome Measure Data
Hide Analysis Population Description
All participants receiving one or more doses of VOR 400 mg PO in any and all Arms of the study.
Arm/Group Title 1/Single & Multiple Dose, Steps 2 and 3 2/Interval Dosing, Steps 2, 3 and 4
Hide Arm/Group Description:
All eligible participants in the Single and Multiple Group Arm who received at least one dose of VOR 400 mg PO.
All eligible participants in the Interval Dosing Arm who received at least one dose of VOR 400 mg PO.
Overall Number of Participants Analyzed 12 13
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
7.Secondary Outcome
Title Number of Participants With Confirmed Hematologic Toxicity >/= Grade 2 and Related to VOR Per Division of AIDS (DAIDS) Grading Table
Hide Description 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.
Time Frame 24 hrs following single dose and 1 week after last of multiple dose sequence
Hide Outcome Measure Data
Hide Analysis Population Description
All participants receiving one or more doses of VOR 400 mg PO in any and all Arms of the study.
Arm/Group Title 1/Single & Multiple Dose, Steps 2 and 3 2/Interval Dosing, Steps 2, 3 and 4
Hide Arm/Group Description:
All eligible participants in the Single and Multiple Arm who received at least one dose of VOR 400 mg PO.
All eligible participants in the Interval Dosing Arm who received at least one dose of VOR 400 mg PO..
Overall Number of Participants Analyzed 12 13
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
8.Other Pre-specified Outcome
Title Number of Participants Developing Cancer Within 5 Years Following >/= 8 Vorinostat Dose Exposures
Hide Description 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.
Time Frame From last dose Vorinostat to 5 years afterwards
Hide Outcome Measure Data
Hide Analysis Population Description
At end of study, participants receiving >/= 8 doses of Vorinostat are enrolled in a 5-year cancer incidence database to be monitored for the occurrence of cancer.
Arm/Group Title 1/Single and Multiple Dose, Step 3 2/Interval Doses (Multiple) Step 4
Hide Arm/Group Description:
Participants without dose-limiting symptoms and exhibiting an in vivo response to single VOR doses were eligible to receive multiple doses of VOR 400 mg. The first dose was administered in clinic with observation for symptoms for 1 hour post dose. Symptoms were assessed daily and on the third day 4 hours after the dose. These participants took VOR 400 mg (PO) in the AM for 3 days each week (dose every M-T-W) for 3 weeks. On the 4th week, the participant took 2 doses of VOR 400 mg (M-T) in the AM. A leukapheresis was completed 4 hours after the 2nd dose of VOR to measure RCVL in-vivo response. After a 4 - 8 week rest period, participants without dose-limiting symptoms repeated the 4 week cycle.

Participants without dose-limiting symptoms and exhibiting an in vivo response to the paired dose of VOR dose were eligible to receive 10 doses of VOR 400 mg PO, given at the pre-determined interval. Participant took the PO doses at home per schedule with daily telephone assessment of symptoms and clinical assessments at after the 3rd, 5th, 8th and 10th doses. Participant were only given the required doses for administration between visits.

Leukapheresis procedure performed 4 hours after the 10th dose to measure RCVL in-vivo response.

Overall Number of Participants Analyzed 5 3
Measure Type: Count of Participants
Unit of Measure: Participants
0 0
Time Frame Period One: February 1, 2011 through December 31, 2013. Period Two: January 1, 2014 through March 31, 2016.
Adverse Event Reporting Description Data were analyzed for all participants in one arm.
 
Arm/Group Title Open Label - Translational Research Study
Hide Arm/Group Description

Period One: Step 1 (ex-vivo), Step 2 (single dose) and Step 3 (multiple dose). Advancement to each step required demonstration of significant HIV-1 RNA expression per 1 million RCVL response to VOR. Step 1: All participants had an ex-vivo exposure to VOR. Step 2: Participants with and without an ex-vivo response received 1 single dose VOR. Step 3: Participants demonstrating an in vivo response received multiple doses consisting of 2 series of 11 VOR doses each; with in vivo response measured after each series. Period One was stopped due to lack of significant in-vivo response to the multiple doses.

Period Two: Step 1, Step 2 and advancement criteria are the same as above. Step 3 (interval paired dose) and Step 4 (multiple interval doses). Participants without an ex-vivo response did not progress past Step 1. Step 3: Responders received 2 doses separated by 48 or 72 hours. Step 4: Responders then received 10 doses of VOR at pre-determined interval.

All-Cause Mortality
Open Label - Translational Research Study
Affected / at Risk (%)
Total   0/25 (0.00%)    
Hide Serious Adverse Events
Open Label - Translational Research Study
Affected / at Risk (%) # Events
Total   0/25 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Open Label - Translational Research Study
Affected / at Risk (%) # Events
Total   21/25 (84.00%)    
Cardiac disorders   
Bradycardia * 1  1/25 (4.00%)  1
Ear and labyrinth disorders   
Tinnitus * 1  1/25 (4.00%)  1
Eye disorders   
Visual Impairment * 1  1/25 (4.00%)  1
Gastrointestinal disorders   
Abdominal Discomfort * 1  1/25 (4.00%)  2
Abdominal Pain * 1  1/25 (4.00%)  1
Constipation * 1  2/25 (8.00%)  3
Diarrhoea * 1  3/25 (12.00%)  3
Dyspepsia * 1  1/25 (4.00%)  1
Nausea * 1  4/25 (16.00%)  13
General disorders   
Asthenia * 1  1/25 (4.00%)  1
Fatigue * 1  7/25 (28.00%)  9
Thirst * 1  1/25 (4.00%)  1
Vessel Puncture Site Erythema * 1  1/25 (4.00%)  1
Vessel Puncture Site Haematoma * 1  1/25 (4.00%)  1
Injury, poisoning and procedural complications   
Post Procedural Hematoma * 1  2/25 (8.00%)  2
Post Procedural Oedema * 1  1/25 (4.00%)  1
Procedural Anxiety * 1  1/25 (4.00%)  1
Procedural Complication * 1  1/25 (4.00%)  1
Procedural Dizziness * 1  1/25 (4.00%)  1
Procedural Headache * 1  2/25 (8.00%)  2
Procedural Hypertension * 1  17/25 (68.00%)  44
Procedural Nausea * 1  1/25 (4.00%)  1
Procedural Pain * 1  2/25 (8.00%)  2
Procedural Site Reaction * 1  9/25 (36.00%)  15
Vascular Access Site Haematoma * 1  4/25 (16.00%)  4
Vascular Access Site Haemorrhage * 1  6/25 (24.00%)  7
Vascular Access Site Pain * 1  8/25 (32.00%)  8
Vascular Access Site Rupture * 1  4/25 (16.00%)  5
Vascular Access Site Swelling * 1  4/25 (16.00%)  4
Investigations   
Blood Albumin Decreased * 1  2/25 (8.00%)  2
Blood Calcium Decreased * 1  1/25 (4.00%)  1
Blood Calcium Increased * 1  1/25 (4.00%)  1
Blood Creatinine Increased * 1  2/25 (8.00%)  3
Blood Glucose Increased * 1  9/25 (36.00%)  16
Blood Potassium Decreased * 1  3/25 (12.00%)  3
Blood Sodium Increased * 1  1/25 (4.00%)  1
Haemoglobin Decreased * 1  1/25 (4.00%)  2
Neutrophil Count Decreased * 1  2/25 (8.00%)  4
Platelet Count Decreased * 1  3/25 (12.00%)  5
Metabolism and nutrition disorders   
Decreased Appetite * 1  2/25 (8.00%)  2
Musculoskeletal and connective tissue disorders   
Musculoskeletal Chest Pain * 1  1/25 (4.00%)  1
Myalgia * 1  1/25 (4.00%)  1
Nervous system disorders   
Dizziness * 1  6/25 (24.00%)  8
Dizziness Postural * 1  1/25 (4.00%)  1
Headache * 1  5/25 (20.00%)  10
Memory Impairment * 1  1/25 (4.00%)  1
Mental Impairment * 1  1/25 (4.00%)  1
Presyncope * 1  1/25 (4.00%)  1
Psychiatric disorders   
Euphoric Mood * 1  1/25 (4.00%)  1
Insomnia * 1  1/25 (4.00%)  1
Irritability * 1  1/25 (4.00%)  1
Skin and subcutaneous tissue disorders   
Hyperhidrosis * 1  1/25 (4.00%)  1
Night Sweats * 1  1/25 (4.00%)  1
Vascular disorders   
Pallor * 1  1/25 (4.00%)  1
1
Term from vocabulary, MedDRA 20.0
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. David Margolis
Organization: UNC Chapel Hill School of Medicine
Phone: 919-966-6388
EMail: dmargo@med.unc.edu
Layout table for additonal information
Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01319383    
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