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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)

Tracking Information
First Submitted Date  ICMJE December 19, 2017
First Posted Date  ICMJE December 26, 2017
Results First Submitted Date  ICMJE December 2, 2019
Results First Posted Date  ICMJE December 18, 2019
Last Update Posted Date December 27, 2019
Actual Study Start Date  ICMJE April 26, 2018
Actual Primary Completion Date December 4, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 2, 2019)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 19, 2017)
  • Frequency of new Grade 3 or greater adverse events that are considered definitely, probably, or possibly related to study treatment [ Time Frame: Measured through Day 65 ]
    As judged by the core protocol team
  • Change in cell-associated HIV-1 RNA in resting CD4+ T cells from baseline [ Time Frame: Measured on Day 38 ]
    Cell-associated total HIV-1 RNA and HIV-1 DNA (total and integrated) will be measured in CD4+ T cells from peripheral blood mononuclear cells (PBMCs).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2019)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2017)
  • Single copy HIV-1 RNA levels [ Time Frame: Measured through Day 65 ]
    All post-screening HIV-1 RNA quantification assays will be performed using the Roche Taqman V2.0 assay.
  • Total HIV-1 DNA levels [ Time Frame: Measured through Day 65 ]
    Cell-associated total HIV-1 RNA and HIV-1 DNA (total and integrated) will be measured in CD4+ T cells from PBMCs.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors
Official Title  ICMJE Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors
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 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Tamoxifen
    • Drug: Vorinostat
    • Drug: Antiretroviral drugs
  • 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.
    Interventions:
    • Drug: Vorinostat
    • Drug: Antiretroviral drugs
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 2, 2019)
31
Original Estimated Enrollment  ICMJE
 (submitted: December 19, 2017)
30
Estimated Study Completion Date  ICMJE June 30, 2023
Actual Primary Completion Date December 4, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03382834
Other Study ID Numbers  ICMJE ACTG A5366
38190 ( Registry Identifier: DAIDS-ES Registry Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Rajesh Gandhi, MD Massachusetts General Hospital (MGH) CRS
Study Chair: Eileen Scully, MD, PhD Johns Hopkins University
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP