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Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors

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ClinicalTrials.gov Identifier: NCT03382834
Recruitment Status : Active, not recruiting
First Posted : December 26, 2017
Results First Posted : December 18, 2019
Last Update Posted : December 27, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV Infections
Interventions Drug: Tamoxifen
Drug: Vorinostat
Drug: Antiretroviral drugs
Enrollment 31
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Hide Arm/Group Description

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Period Title: Overall Study
Started 21 10
Completed [1] 20 9
Not Completed 1 1
Reason Not Completed
Lost to Follow-up             1             0
Withdrawal by Subject             0             1
[1]
Completed Step 1 of the study.
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone Total
Hide Arm/Group Description

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Total of all reporting groups
Overall Number of Baseline Participants 21 10 31
Hide Baseline Analysis Population Description
All enrolled participants
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 21 participants 10 participants 31 participants
57
(54 to 61)
55
(51 to 59)
57
(53 to 60)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age categorized Number Analyzed 21 participants 10 participants 31 participants
< 50 years
2
   9.5%
1
  10.0%
3
   9.7%
50 - 59 years
11
  52.4%
7
  70.0%
18
  58.1%
>= 60 years
8
  38.1%
2
  20.0%
10
  32.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 10 participants 31 participants
Female
21
 100.0%
10
 100.0%
31
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 10 participants 31 participants
Hispanic or Latino
4
  19.0%
2
  20.0%
6
  19.4%
Not Hispanic or Latino
17
  81.0%
8
  80.0%
25
  80.6%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 10 participants 31 participants
American Indian or Alaska Native
1
   4.8%
0
   0.0%
1
   3.2%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
11
  52.4%
7
  70.0%
18
  58.1%
White
9
  42.9%
3
  30.0%
12
  38.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Puerto Rico Number Analyzed 21 participants 10 participants 31 participants
1 0 1
United States Number Analyzed 21 participants 10 participants 31 participants
20 10 30
Baseline Cell-associated HIV-1 RNA   [1] [2] 
Median (Inter-Quartile Range)
Unit of measure:  Log10 copies/million CD4 cells
Number Analyzed 19 participants 8 participants 27 participants
1.81
(1.38 to 2.49)
2.5
(2.01 to 3.15)
2.17
(1.56 to 2.69)
[1]
Measure Description: Baseline cell-associated HIV-1 RNA levels (CA-RNA) (log10 copies/mL) were measured in CD4 T-cells. Baseline CA-RNA was calculated as the average of the pre-entry and entry CA-RNA results.
[2]
Measure Analysis Population Description: CA-RNA analyses were performed on the efficacy population, defined as the subset of enrolled participants who received full study treatment and did not have ART interruption or confirmed viral load (VL) >= 200 copies/mL. The definition was expanded by team to exclude 2 participants; one with high pre-entry VL and one with wrong timing of samples.
1.Primary Outcome
Title Proportion of Participants With New Grade 3 or Greater Adverse Events
Hide Description Proportion of participants with new Grade 3 or greater adverse events that are considered definitely, probably, or possibly related to study treatment (as judged by the core protocol team). The DAIDS AE Grading Table (corrected Version 2.1, July 2017) was used.
Time Frame Measured from study entry through Day 65
Hide Outcome Measure Data
Hide Analysis Population Description
Enrolled participants who were exposed to study treatment
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Hide Arm/Group Description:

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Overall Number of Participants Analyzed 21 9
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0
(0 to 0.13)
0
(0 to 0.28)
2.Primary Outcome
Title Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells
Hide Description Baseline is defined as the average of the pre-entry and entry values. Change was calculated as the value of Cell-associated HIV-1 RNA on Day 38 (5 hours post vorinostat) minus the value at baseline.
Time Frame Pre-entry, entry, and Day 38
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy population
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Hide Arm/Group Description:

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Overall Number of Participants Analyzed 19 8
Mean (95% Confidence Interval)
Unit of Measure: log10 copies/million CD4 cells
0.06
(-0.24 to 0.36)
0.17
(-0.15 to 0.50)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Tamoxifen + Vorinostat, Arm B: Vorinostat Alone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.68
Comments [Not Specified]
Method t-test, 1 sided
Comments The hypothesis was that tamoxifen would enhance the HIV transcription effect of vorinostat (i.e., log10 change would be greater in Arm A than Arm B)
3.Secondary Outcome
Title Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification
Hide Description Number of participants with HIV-1 RNA levels measured by single copy assay (SCA) greater or equal to the lower limit of quantification (LOQ). The lower limit of quantification for this study was 0.47 copies/mL.
Time Frame Pre-entry, entry, Day 28, Day 35, Day 38 (5 hours post vorinostat), Day 45, Day 65
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy population
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Hide Arm/Group Description:

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Overall Number of Participants Analyzed 19 8
Measure Type: Count of Participants
Unit of Measure: Participants
Pre-entry SCA >= LOQ
10
  52.6%
6
  75.0%
Entry SCA >=LOQ
9
  47.4%
3
  37.5%
Day 28 SCA >=LOQ
11
  57.9%
4
  50.0%
Day 35 SCA >=LOQ
11
  57.9%
5
  62.5%
Day 38 SCA >=LOQ
7
  36.8%
5
  62.5%
Day 45 SCA >=LOQ
9
  47.4%
4
  50.0%
Day 65 SCA >=LOQ
10
  52.6%
5
  62.5%
4.Secondary Outcome
Title Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells
Hide Description Baseline is defined as the average of the pre-entry and entry values. Change was calculated as the value of Total HIV-1 DNA on Day 38 (5 hours post vorinostat) minus the value at baseline.
Time Frame Pre-entry, entry, and Day 38
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Population
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Hide Arm/Group Description:

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Overall Number of Participants Analyzed 19 8
Mean (95% Confidence Interval)
Unit of Measure: log10 copies/million CD4 cells
0
(-0.12 to 0.13)
-0.04
(-0.33 to 0.25)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Tamoxifen + Vorinostat, Arm B: Vorinostat Alone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.73
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Time Frame From study entry to study day 65
Adverse Event Reporting Description The protocol required reporting of all diagnoses, and all signs/symptoms/laboratory values Grade ≥ 3, and all diagnoses and signs/symptoms/laboratory values that led to treatment change or met SAE or EAE reporting requirements. For grading, sites referred to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables.
 
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Hide Arm/Group Description

From Day 0 to Day 38, participants will receive tamoxifen orally once a day. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Tamoxifen: 20 mg orally

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

Day 0 to Day 38 will be an observation period with no tamoxifen. On Days 35 and 38, participants will receive a single dose of vorinostat orally.

Vorinostat: 400 mg orally

Antiretroviral drugs: Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.

All-Cause Mortality
Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Affected / at Risk (%) Affected / at Risk (%)
Total   0/21 (0.00%)   0/10 (0.00%) 
Hide Serious Adverse Events
Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Affected / at Risk (%) Affected / at Risk (%)
Total   0/21 (0.00%)   0/10 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Affected / at Risk (%) Affected / at Risk (%)
Total   2/21 (9.52%)   0/10 (0.00%) 
General disorders     
Thirst  1  1/21 (4.76%)  0/10 (0.00%) 
Metabolism and nutrition disorders     
Hyperglycaemia  1  1/21 (4.76%)  0/10 (0.00%) 
Nervous system disorders     
Dysgeusia  1  1/21 (4.76%)  0/10 (0.00%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: ACTG Clinicaltrials.gov Coordinator
Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone: 3016283313
EMail: ACTGCT.Gov@s-3.com
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03382834    
Other Study ID Numbers: ACTG A5366
38190 ( Registry Identifier: DAIDS-ES Registry Number )
First Submitted: December 19, 2017
First Posted: December 26, 2017
Results First Submitted: December 2, 2019
Results First Posted: December 18, 2019
Last Update Posted: December 27, 2019