Clinical trial NCT03382834: Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors
Official title: Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2017-12-26
Enrollment: 31
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Proportion of Participants With New Grade 3 or Greater Adverse Events
timeFrame: Measured from study entry through Day 65
measure: Change From Baseline in Cell-associated HIV-1 RNA in CD4+ T Cells
timeFrame: Pre-entry, entry, and Day 38
Secondary outcomes:
measure: Number of Participants With HIV-1 RNA Levels (Measured by Single Copy Assay) Greater or Equal to the Lower Limit of Quantification
timeFrame: Pre-entry, entry, Day 28, Day 35, Day 38 (5 hours post vorinostat), Day 45, Day 65
measure: Change From Baseline in Total HIV-1 DNA Levels in CD4+ T Cells
timeFrame: Pre-entry, entry, and Day 38
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: Whitman-Walker Health CRS
state: District of Columbia
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: Massachusetts General Hospital (MGH) CRS
name: Rajesh Gandhi, MD
role: STUDY_CHAIR
affiliation: Johns Hopkins University
name: Eileen Scully, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.