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

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT03382834
Collaborator
(none)
31
14
2
62.1
2.2
0

Study Details

Study Description

Brief Summary

This study evaluated the effects of tamoxifen exposure in combination with vorinostat on viral reactivation among HIV-1 infected post-menopausal women with virologic suppression on antiretroviral therapy (ART), when compared to vorinostat alone.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

The selective estrogen receptor modulator (SERM) tamoxifen may enhance the ability of the histone deacetylase inhibitor (HDACi) vorinostat to reverse HIV-1 latency. This study evaluated the safety of tamoxifen therapy combined with vorinostat and the effectiveness of this combination on latent virus reactivation in HIV-1 infected post-menopausal women with virologic suppression on antiretroviral therapy, when compared to vorinostat alone.

The study will be conducted in two steps. During Step 1, the study enrolled women with HIV into two groups. Arm A received tamoxifen daily for 38 days, plus a single dose of vorinostat on Days 35 and 38. Arm B had a 38-day observation period with no tamoxifen, plus a single dose of vorinostat on Days 35 and 38. All participants continued to take ART drugs prescribed by their doctors. ART drugs were not be provided by the study.

Study visits during Step 1 occurred at Days 0, 28, 35, 38, 45, and 65. Study visits could include physical examinations, blood collection, electrocardiograms, and adherence assessments.

During Step 2, all participants will be followed for 240 additional weeks for annual long-term safety follow-up. These visits will be conducted by phone and will collect information from participants on vital status and any new cancer diagnoses.

Step 1 has been completed and this results submission pertains to Step 1. Step 2 follow-up is ongoing.

Study Design

Study Type:
Interventional
Actual Enrollment :
31 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors
Actual Study Start Date :
Apr 26, 2018
Actual Primary Completion Date :
Dec 4, 2018
Anticipated Study Completion Date :
Jun 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A: Tamoxifen + Vorinostat

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.

Drug: Tamoxifen
20 mg orally

Drug: Vorinostat
400 mg orally

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

Active Comparator: Arm B: Vorinostat alone

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.

Drug: Vorinostat
400 mg orally

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

Outcome Measures

Primary Outcome Measures

  1. Proportion of Participants With New Grade 3 or Greater Adverse Events [Measured from study entry through Day 65]

    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.

  2. Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells [Pre-entry, entry, and Day 38]

    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.

Secondary Outcome Measures

  1. Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification [Pre-entry, entry, Day 28, Day 35, Day 38 (5 hours post vorinostat), Day 45, Day 65]

    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.

  2. Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells [Pre-entry, entry, and Day 38]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 65 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • HIV-1 infection

  • Postmenopausal at study entry with agreement not to participate in assisted reproductive technology in the future.

  • CD4+ cell count greater than 300 cells/uL obtained within 90 days prior to study entry.

  • Continuous antiretroviral therapy (ART) for at least 2 years prior to enrollment with no known interruption in therapy for greater than 7 days within 90 days prior to study entry.

  • Plasma HIV-1 RNA level of less than 20 copies/mL obtained by Roche HIV-1 viral load assay or less than 40 copies/mL obtained by the Abbott assay, within 90 days prior to study entry.

  • Ability and willingness of potential participant to provide written informed consent.

Exclusion Criteria:
  • History of venous thromboembolism.

  • History of stroke.

  • Known history of hypercoagulable state.

  • Tobacco smoking or e-cigarette use within 90 days prior to study entry.

  • History of any malignancy requiring systemic chemotherapy or systemic immunotherapy.

  • History of endometrial or breast cancer or known genetic testing with BRCA positive results indicating an increased risk for breast and ovarian cancer.

  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, or investigational therapy within 60 days prior to study entry.

  • Any systemic hormonal therapy defined as oral or injectable contraceptives, estrogen and combined estrogen-progesterone replacement therapy in the prior 12 months, or a hormone containing intrauterine device (IUD) within 6 months prior to study entry.

  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Alabama CRS Birmingham Alabama United States 35294
2 UCLA CARE Center CRS Los Angeles California United States 90035
3 Ucsf Hiv/Aids Crs San Francisco California United States 94110
4 Harbor-UCLA CRS Torrance California United States 90502
5 University of Colorado Hospital CRS Aurora Colorado United States 80045
6 Whitman-Walker Health CRS Washington District of Columbia United States 20005
7 The Ponce de Leon Center CRS Atlanta Georgia United States 30308-2012
8 Northwestern University CRS Chicago Illinois United States 60611
9 Massachusetts General Hospital CRS (MGH CRS) Boston Massachusetts United States 02114
10 New Jersey Medical School Clinical Research Center CRS Newark New Jersey United States 07103
11 Chapel Hill CRS Chapel Hill North Carolina United States 27599
12 Greensboro CRS Greensboro North Carolina United States 27401
13 Penn Therapeutics, CRS Philadelphia Pennsylvania United States 19104
14 Puerto Rico AIDS Clinical Trials Unit CRS San Juan Puerto Rico 00935

Sponsors and Collaborators

  • National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

  • Study Chair: Rajesh Gandhi, MD, Massachusetts General Hospital (MGH) CRS
  • Study Chair: Eileen Scully, MD, PhD, Johns Hopkins University

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT03382834
Other Study ID Numbers:
  • ACTG A5366
  • 38190
First Posted:
Dec 26, 2017
Last Update Posted:
Jan 18, 2022
Last Verified:
Jan 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
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 20 9
NOT COMPLETED 1 1

Baseline Characteristics

Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone Total
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 Participants 21 10 31
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]
57
55
57
Age, Customized (Count of Participants)
< 50 years
2
9.5%
1
10%
3
9.7%
50 - 59 years
11
52.4%
7
70%
18
58.1%
>= 60 years
8
38.1%
2
20%
10
32.3%
Sex: Female, Male (Count of Participants)
Female
21
100%
10
100%
31
100%
Male
0
0%
0
0%
0
0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
4
19%
2
20%
6
19.4%
Not Hispanic or Latino
17
81%
8
80%
25
80.6%
Unknown or Not Reported
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
1
4.8%
0
0%
1
3.2%
Asian
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
11
52.4%
7
70%
18
58.1%
White
9
42.9%
3
30%
12
38.7%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%
Region of Enrollment (participants) [Number]
Puerto Rico
1
4.8%
0
0%
1
3.2%
United States
20
95.2%
10
100%
30
96.8%
Baseline Cell-associated HIV-1 RNA (log10 copies/million CD4 cells) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/million CD4 cells]
1.81
2.5
2.17

Outcome Measures

1. Primary Outcome
Title Proportion of Participants With New Grade 3 or Greater Adverse Events
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

Outcome Measure Data

Analysis Population Description
Enrolled participants who were exposed to study treatment
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
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.
Measure Participants 21 9
Number (95% Confidence Interval) [proportion of participants]
0
0%
0
0%
2. Primary Outcome
Title Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells
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

Outcome Measure Data

Analysis Population Description
Efficacy population
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
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.
Measure Participants 19 8
Mean (95% Confidence Interval) [log10 copies/million CD4 cells]
0.06
0.17
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Tamoxifen + Vorinostat, Arm B: Vorinostat Alone
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.68
Comments
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
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

Outcome Measure Data

Analysis Population Description
Efficacy population
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
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.
Measure Participants 19 8
Pre-entry SCA >= LOQ
10
47.6%
6
60%
Entry SCA >=LOQ
9
42.9%
3
30%
Day 28 SCA >=LOQ
11
52.4%
4
40%
Day 35 SCA >=LOQ
11
52.4%
5
50%
Day 38 SCA >=LOQ
7
33.3%
5
50%
Day 45 SCA >=LOQ
9
42.9%
4
40%
Day 65 SCA >=LOQ
10
47.6%
5
50%
4. Secondary Outcome
Title Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells
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

Outcome Measure Data

Analysis Population Description
Efficacy Population
Arm/Group Title Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
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.
Measure Participants 19 8
Mean (95% Confidence Interval) [log10 copies/million CD4 cells]
0
-0.04
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Tamoxifen + Vorinostat, Arm B: Vorinostat Alone
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.73
Comments
Method t-test, 2 sided
Comments

Adverse Events

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
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 (%) # Events Affected / at Risk (%) # Events
Total 0/21 (0%) 0/10 (0%)
Serious Adverse Events
Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/21 (0%) 0/10 (0%)
Other (Not Including Serious) Adverse Events
Arm A: Tamoxifen + Vorinostat Arm B: Vorinostat Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/21 (9.5%) 0/10 (0%)
General disorders
Thirst 1/21 (4.8%) 0/10 (0%)
Metabolism and nutrition disorders
Hyperglycaemia 1/21 (4.8%) 0/10 (0%)
Nervous system disorders
Dysgeusia 1/21 (4.8%) 0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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

Name/Title ACTG Clinicaltrials.gov Coordinator
Organization ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone 3016283313
Email ACTGCT.Gov@s-3.com
Responsible Party:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT03382834
Other Study ID Numbers:
  • ACTG A5366
  • 38190
First Posted:
Dec 26, 2017
Last Update Posted:
Jan 18, 2022
Last Verified:
Jan 1, 2022