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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Tamoxifen; Drug: Vorinostat; Drug: Antiretroviral drugs

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: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Puerto Rico AIDS Clinical Trials Unit CRS
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama CRS
  • California
    • Los Angeles, California, United States, 90035
      • UCLA CARE Center CRS
    • San Francisco, California, United States, 94110
      • Ucsf Hiv/Aids Crs
    • Torrance, California, United States, 90502
      • Harbor-UCLA CRS
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS
  • District of Columbia
    • Washington, District of Columbia, United States, 20005
      • Whitman-Walker Health CRS
  • Georgia
    • Atlanta, Georgia, United States, 30308-2012
      • The Ponce de Leon Center CRS
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital CRS (MGH CRS)
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School Clinical Research Center CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Chapel Hill CRS
    • Greensboro, North Carolina, United States, 27401
      • Greensboro CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Cincinnati Clinical Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Therapeutics, CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• Scully EP, Aga E, Tsibris A, Archin N, Starr K, Ma Q, Morse GD, Squires KE, Howell BJ, Wu G, Hosey L, Sieg SF, Ehui L, Giguel F, Coxen K, Dobrowolski C, Gandhi M, Deeks S, Chomont N, Connick E, Godfrey C, Karn J, Kuritzkes DR, Bosch RJ, Gandhi RT. Impact of Tamoxifen on Vorinostat-Induced Human Immunodeficiency Virus Expression in Women on Antiretroviral Therapy: AIDS Clinical Trials Group A5366, The MOXIE Trial. Clin Infect Dis. 2022 Oct 12;75(8):1389-1396. doi: 10.1093/cid/ciac136.

Helpful Links

• Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2018
• Primary Completion (Actual): December 4, 2018
• Study Completion (Actual): July 27, 2023

Study Registration Dates

• First Submitted: December 19, 2017
• First Submitted That Met QC Criteria: December 19, 2017
• First Posted (Actual): December 26, 2017

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Histone Deacetylase Inhibitors; Tamoxifen; Vorinostat; Anti-Retroviral Agents
• Other Study ID Numbers: ACTG A5366; 38190 (Registry Identifier: DAIDS-ES Registry Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by the NIH.

IPD Sharing Access Criteria

With whom?

Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.

For what types of analyses?

To achieve aims in the proposal approved by the AIDS Clinical Trials Group. By what mechanism will data be made available?

Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://submit.mis.s-3.net/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data."

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No