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

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ClinicalTrials.gov Identifier: NCT03382834
Recruitment Status : Not yet recruiting
First Posted : December 26, 2017
Last Update Posted : April 11, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This study will evaluate 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 Early Phase 1

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 will evaluate 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 (ART), when compared to vorinostat alone.

The study will be conducted in two steps. During Step 1, the study will enroll women with HIV into two groups. Arm A will receive tamoxifen daily for 38 days, plus a single dose of vorinostat on Days 35 and 38. Arm B will have a 38-day observation period with no tamoxifen, plus a single dose of vorinostat on Days 35 and 38. All participants will continue to take the antiretroviral (ARV) drugs prescribed by their doctors. ARV drugs will not be provided by the study.

Study visits during Step 1 will occur at Days 0, 28, 35, 38, 45, and 65. Study visits may 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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
Estimated Study Start Date : May 1, 2018
Estimated Primary Completion Date : November 15, 2019
Estimated Study Completion Date : November 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

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 (ARV) drugs provided by their own doctors. ARV 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 (ARV) drugs provided by their own doctors. ARV drugs will not be provided by the study.



Primary Outcome Measures :
  1. 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

  2. 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).


Secondary Outcome Measures :
  1. Single copy HIV-1 RNA levels [ Time Frame: Measured through Day 65 ]
    All post-screening HIV-1 RNA quantification assays will be performed using Roche HIV-1 viral load assay.

  2. 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.



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

Step 1 Inclusion Criteria:

  • HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load. NOTE: The term "licensed" refers to a US Food and Drug Administration (FDA)-approved kit. World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
  • Women between 18 and 65 years of age up until the 66th birthday at the time of study entry.
  • Women who are postmenopausal at the time of study entry and have agreed not to participate in assisted reproductive technology in the future. Menopausal status will be verified by any one of the following:

    • Age greater than or equal to 40 years, amenorrhea greater than or equal to 12 months, and FSH greater than 40 mIU/mL with a negative serum or urine beta-HCG (urine test must have a sensitivity of less than or equal to 25 mIU/mL) and no oral or injectable exogenous hormone use within 12 months prior to study entry.
    • Any woman greater than or equal to 18 years of age is eligible for consideration if there is a documented history of surgical removal of both of the ovaries greater than 6 months prior to study entry and no injectable or oral exogenous hormone therapy for a period of greater than or equal to 12 months prior to study entry.
  • CD4+ cell count greater than 300 cells/uL obtained within 90 days prior to study entry at any US laboratory that has Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
  • Continuous antiretroviral therapy (ART) containing nucleoside or nucleotide reverse transcriptase inhibitors with a non-nucleoside reverse transcriptase inhibitor, a pharmacologically-boosted protease inhibitor, or an integrase inhibitor 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.

    • NOTE: Other ART regimens may be acceptable. Sites must consult the core protocol team for a case-by-case basis review of ART regimens not specified above.
    • NOTE: Regimens composed of three nucleoside reverse transcriptase inhibitors are not acceptable.
    • NOTE: Regimen changes within the 2-year period are acceptable, but candidates must have been on a stable regimen for at least 30 days prior to study entry.
  • Site investigator anticipates that a fully active alternative ART regimen could be constructed in the event of virologic failure on the current ART regimen.
  • At least one documented plasma HIV-1 RNA that is below the limit of detection of the FDA-approved assays (limit of detection: 75, 50, 40, or 20 copies/mL) between 13 and 24 months prior to the screening HIV-1 RNA in the protocol.
  • 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 by any US laboratory that has CLIA certification or its equivalent.
  • The following laboratory values obtained within 21 days prior to study entry by any US laboratory that has CLIA certification or its equivalent.

    • Absolute neutrophil count (ANC) greater than or equal to 1500 neutrophils/mm^3
    • Hemoglobin greater than or equal to 11.0 g/dL
    • Platelet count greater than or equal to 125,000 platelets/uL
    • Creatinine less than or equal to 1.3 x upper limit of normal (ULN) OR, if serum creatinine levels greater than 1.3 x ULN, calculated creatinine clearance (as estimated by the Cockcroft-Gault equation) greater than or equal to 50mL/min. NOTE: A calculator for the Cockcroft-Gault equation is available on the Data Management Center (DMC) website at www.fstrf.org.
    • Aspartate aminotransferase (AST) (SGOT) less than or equal to 1.5 x ULN
    • Alanine aminotransferase (ALT) (SGPT) less than or equal to 1.5 x ULN
    • Alkaline phosphatase less than or equal to 2.5 x ULN
    • Total bilirubin less than 1.5 x ULN, OR if the total bilirubin is elevated, direct bilirubin will be measured and the potential participant is eligible if the direct bilirubin is less than 2 x ULN. NOTE: For participants on atazanavir-based ART, if total bilirubin is greater than 1.5 x ULN and there is no transaminase elevation, enrollment is acceptable if the indirect bilirubin (calculated value of total bilirubin minus direct bilirubin) is less than 3 x ULN.
  • No history of opportunistic infections within 90 days prior to study entry.
  • Karnofsky performance score greater than or equal to 70 within 90 days prior to study entry.
  • Weight greater than or equal to 52.2 kg at time of screening. (This stipulation is because of the blood draw volumes involved with this trial.)
  • Body Mass Index (BMI) less than or equal to 40 kg/m^2 at time of screening. NOTE: A program for calculating BMI is available on the DMC website at www.fstrf.org.
  • HCV antibody negative result within 90 days prior to study entry or, for study candidates who are HCV antibody positive (based on testing performed at any time prior to study entry), a negative HCV RNA result obtained within 90 days prior to study entry.
  • Negative HBsAg result obtained within 90 days prior to study entry or a positive HBsAb result at any time prior to study entry.
  • QTc interval less than or equal to 450 milliseconds within 90 days prior to study entry. NOTE: A program for calculating QTc by Fridericia's correction is available on the DMC website at www.fstrf.org.
  • Ability and willingness of potential participant to provide written informed consent.

Step 1 Exclusion Criteria:

  • History of venous thromboembolism.
  • History of stroke.
  • Known history of hypercoagulable state including Factor V Leiden mutation, Protein C and S deficiency, or decompensated cirrhosis.
  • Tobacco smoking or e-cigarette use within 90 days prior to study entry. NOTE: If recent cessation of smoking, must have been without cigarettes and e-cigarettes for greater than or equal to 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. NOTE: If additional genetic testing for breast or ovarian cancer exists, study sites should contact the core protocol team for review.
  • History of cardiac arrhythmia requiring surgical or ablative therapy.
  • History of myocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) class III or IV heart failure at any time prior to study entry, or personal or family history of prolonged QTc syndrome.
  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, or investigational therapy within 60 days prior to study entry. NOTE: Study candidates receiving stable physiologic glucocorticoid doses, defined as the equivalent of prednisone 10 mg/day or less, will not be excluded. Study candidates receiving inhaled or topical corticosteroids will not be excluded.
  • 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. NOTE: Hormonal therapy also includes aromatase inhibitors and suppressors of ovarian function including gonadotropin releasing hormone (GnRH) agonists and luteinizing-hormone releasing hormone (LH-RH) agonists. Topical estrogen cream use in the prior 12 months is acceptable, but should not be used during the study period.
  • Use of any study-prohibited medications that carry the risk of torsades de pointes within 60 days prior to study entry. NOTE: A list of prohibited medications is available on the protocol-specific web page (PSWP).
  • Use of any study-prohibited medication in the HDACi class or use of any study-prohibited medication with HDACi-like activity within 60 days prior to study entry. NOTE: A list of prohibited medications is available on the PSWP.
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations.
  • Active drug or alcohol use or dependence or psychiatric illness that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Acute or serious illness requiring systemic treatment, antibiotics, and/or hospitalization within 90 days prior to study entry.

Step 2 Inclusion Criteria:

  • Received at least one dose of tamoxifen or at least one dose of vorinostat.

Step 2 Exclusion Criteria:

  • There are no exclusion criteria for Step 2.

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
United States, Alabama
Alabama CRS Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Pam Cunningham, R.N., B.S.N., M.P.H.    205-975-2841    pamelacunningham@uabmc.edu   
United States, California
Harbor-UCLA CRS Not yet recruiting
Torrance, California, United States, 90502
Contact: Mario Guerrero    424-201-3000 ext 7318    mguerrero@labiomed.org   
United States, Colorado
University of Colorado Hospital CRS Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Suzanne Fiorillo, M.S.P.H.    303-724-5931    suzanne.fiorillo@ucdenver.edu   
United States, Massachusetts
Massachusetts General Hospital CRS (MGH CRS) Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Theresa Flynn, R.N., M.S.N., A.N.P., B.S.N.    617-724-0072    tflynn@partners.org   
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Cheryl E. Keenan, R.N.    617-732-5635    ckeenan2@partners.org   
United States, New Jersey
New Jersey Medical School Clinical Research Center CRS Not yet recruiting
Newark, New Jersey, United States, 07103
Contact: Baljinder Singh    973-972-3811    singhba@njms.rutgers.edu   
United States, New York
Weill Cornell Chelsea CRS Not yet recruiting
New York, New York, United States, 10010
Contact: Todd Stroberg, R.N., B.S.N.    212-746-7198    tstrober@med.cornell.edu   
Weill Cornell Uptown CRS Not yet recruiting
New York, New York, United States, 10065
Contact: Louise Walshe    212-746-7864    ljw2001@med.cornell.edu   
United States, North Carolina
Chapel Hill CRS Not yet recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Susan Pedersen    919-966-6713    spederse@med.unc.edu   
United States, Ohio
Ohio State University CRS Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Kathy Watson, B.S.N., R.N.    614-293-5856    kathy.watson@osumc.edu   
United States, Pennsylvania
Penn Therapeutics, CRS Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eileen B. Donaghy, C.R.N.P.    215-349-8092    eileen.donaghy2@uphs.upenn.edu   
United States, Tennessee
Vanderbilt Therapeutics (VT) CRS Not yet recruiting
Nashville, Tennessee, United States, 37204
Contact: Beverly O. Woodward, M.S.N., R.N.    615-936-8516    beverly.o.woodward@vanderbilt.edu   
United States, Texas
Houston AIDS Research Team CRS Not yet recruiting
Houston, Texas, United States, 77030
Contact: Maria L. Martinez    713-500-6718    Maria.L.Martinez@uth.tmc.edu   
Puerto Rico
Puerto Rico AIDS Clinical Trials Unit CRS Not yet recruiting
San Juan, Puerto Rico, 00935
Contact: Sylvia I. Davila Nieves, M.Sc.    787-767-9192    sylvia.davila1@upr.edu   
Sponsors and Collaborators
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

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03382834     History of Changes
Other Study ID Numbers: ACTG A5366
38190 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: April 11, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Estrogens
Tamoxifen
Selective Estrogen Receptor Modulators
Vorinostat
Estrogen Receptor Modulators
Histone Deacetylase Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Estrogen Antagonists
Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Bone Density Conservation Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action