Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors
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
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
- 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.
- 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
- 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.
- 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
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.- ACTG A5366
- 38190
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
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%
|
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) |
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%
|
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
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 |
ACTGCT.Gov@s-3.com |
- ACTG A5366
- 38190