HIV Infections
Conditions
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.
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 was 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 were followed for 240 additional weeks for annual long-term safety follow-up. These visits were conducted by phone and collected information from participants on vital status and any new cancer diagnoses. Step 1 and Step 2 have been completed and this results submission pertains to both.
Interventions
DRUGTamoxifen
20 mg orally
DRUGVorinostat
400 mg orally
Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 21 |
| 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.
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. | 10 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Step 1 | Lost to Follow-up | 0 | 1 |
| Step 2 | Death | 1 | 0 |
| Step 2 | Lost to Follow-up | 2 | 2 |
| Step 2 | Site Terminated by Sponsor | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A: Tamoxifen + Vorinostat | Arm B: Vorinostat Alone | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 55 years | 57 years |
| Age, Customized Age categorized 50 - 59 years | 11 Participants | 7 Participants | 18 Participants |
| Age, Customized Age categorized < 50 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Customized Age categorized >= 60 years | 8 Participants | 2 Participants | 10 Participants |
| Baseline Cell-associated HIV-1 RNA | 1.81 log10 copies/million CD4 cells | 2.5 log10 copies/million CD4 cells | 2.17 log10 copies/million CD4 cells |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 8 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 7 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 3 Participants | 12 Participants |
| Region of Enrollment Puerto Rico | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 20 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 21 Participants | 10 Participants | 31 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 21 | 0 / 10 |
| other Total, other adverse events | 3 / 21 | 0 / 10 |
| serious Total, serious adverse events | 0 / 21 | 0 / 10 |
Outcome results
Primary
Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells
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
Population: Efficacy population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Tamoxifen + Vorinostat | Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells | 0.06 log10 copies/million CD4 cells |
| Arm B: Vorinostat Alone | Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells | 0.17 log10 copies/million CD4 cells |
p-value: 0.68t-test, 1 sided
Primary
Proportion of Participants With New Grade 3 or Greater Adverse Events
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
Population: Enrolled participants who were exposed to study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tamoxifen + Vorinostat | Proportion of Participants With New Grade 3 or Greater Adverse Events | 0 proportion of participants |
| Arm B: Vorinostat Alone | Proportion of Participants With New Grade 3 or Greater Adverse Events | 0 proportion of participants |
Secondary
Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells
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
Population: Efficacy Population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Tamoxifen + Vorinostat | Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells | 0 log10 copies/million CD4 cells |
| Arm B: Vorinostat Alone | Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells | -0.04 log10 copies/million CD4 cells |
p-value: 0.73t-test, 2 sided
Secondary
Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification
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
Population: Efficacy population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 28 SCA >=LOQ | 11 Participants |
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 38 SCA >=LOQ | 7 Participants |
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Entry SCA >=LOQ | 9 Participants |
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 45 SCA >=LOQ | 9 Participants |
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 35 SCA >=LOQ | 11 Participants |
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 65 SCA >=LOQ | 10 Participants |
| Arm A: Tamoxifen + Vorinostat | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Pre-entry SCA >= LOQ | 10 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 65 SCA >=LOQ | 5 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Pre-entry SCA >= LOQ | 6 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Entry SCA >=LOQ | 3 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 28 SCA >=LOQ | 4 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 35 SCA >=LOQ | 5 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 38 SCA >=LOQ | 5 Participants |
| Arm B: Vorinostat Alone | Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification | Day 45 SCA >=LOQ | 4 Participants |