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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tamoxifen
* Drug: Vorinostat
* Drug: Antiretroviral drugs


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Tamoxifen + Vorinostat<br>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<br>* 20 mg orally<br>Drug: Vorinostat<br>* 400 mg orally<br>Drug: Antiretroviral drugs<br>* Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.<br>|
| Active Comparator: Arm B: Vorinostat alone<br>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<br>* 400 mg orally<br>Drug: Antiretroviral drugs<br>* Participants will receive antiretroviral drugs provided by their own doctors. Antiretroviral drugs will not be provided by the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Measured from study entry through Day 65 | 
| 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. | Pre-entry, entry, and Day 38 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Pre-entry, entry, Day 28, Day 35, Day 38 (5 hours post vorinostat), Day 45, Day 65 | 
| 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. | Pre-entry, entry, and Day 38 |