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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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)

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
HIV Infections Drug: Tamoxifen Drug: Vorinostat Drug: Antiretroviral drugs 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.

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Study Type : Interventional  (Clinical Trial)
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 : April 26, 2018
Actual Primary Completion Date : December 4, 2018
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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.




Primary Outcome Measures :
  1. Proportion of Participants With New Grade 3 or Greater Adverse Events [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03382834


Locations
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United States, Alabama
Alabama CRS
Birmingham, Alabama, United States, 35294
United States, California
UCLA CARE Center CRS
Los Angeles, California, United States, 90035
Ucsf Hiv/Aids Crs
San Francisco, California, United States, 94110
Harbor-UCLA CRS
Torrance, California, United States, 90502
United States, Colorado
University of Colorado Hospital CRS
Aurora, Colorado, United States, 80045
United States, District of Columbia
Whitman-Walker Health CRS
Washington, District of Columbia, United States, 20005
United States, Georgia
The Ponce de Leon Center CRS
Atlanta, Georgia, United States, 30308-2012
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
United States, Massachusetts
Massachusetts General Hospital CRS (MGH CRS)
Boston, Massachusetts, United States, 02114
United States, New Jersey
New Jersey Medical School Clinical Research Center CRS
Newark, New Jersey, United States, 07103
United States, North Carolina
Chapel Hill CRS
Chapel Hill, North Carolina, United States, 27599
Greensboro CRS
Greensboro, North Carolina, United States, 27401
United States, Ohio
Cincinnati Clinical Research Site
Cincinnati, Ohio, United States, 45219
United States, Pennsylvania
Penn Therapeutics, CRS
Philadelphia, Pennsylvania, United States, 19104
Puerto Rico
Puerto Rico AIDS Clinical Trials Unit CRS
San Juan, Puerto Rico, 00935
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: Rajesh Gandhi, MD Massachusetts General Hospital (MGH) CRS
Study Chair: Eileen Scully, MD, PhD Johns Hopkins University
  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Statistical Analysis Plan  [PDF] September 10, 2019
Study Protocol  [PDF] December 8, 2017


Additional Information:
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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 Posted: December 26, 2017    Key Record Dates
Results First Posted: December 18, 2019
Last Update Posted: December 27, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Tamoxifen
Anti-Retroviral Agents
Vorinostat
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents