Clinical trial NCT06005610: Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy
Official title: Giving Standardized Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: HIV I Infection
Keywords: HIV
Transgender women
Estradiol
ART
Drug interactions
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2023-08-22
Enrollment: 93
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Transgender women (TW) are a key population and priority for HIV treatment. More research is needed to develop evidence-based clinical guidance when it comes to choosing antiretroviral treatment (ART) regimens for TW on feminizing hormonal therapy (FHT). Concerns about ART interacting with FHT and decreasing its effectiveness can lead to decreased ART adherence and increased viral loads.

The GET IT RiGHT trial aims to address concerns about drug-drug interactions (DDIs) between ART and FHT while providing access to hormonal therapy to TW living with HIV. Data suggest that access to FHT improves adherence to HIV treatment and decreases treatment interruptions.

This is an open-label, non-randomized, 3-group trial of adult TW and other individuals identifying as female or transfeminine but with male sex assigned at birth living with HIV. Participants will be on ART at entry and receive study-supplied 17-β estradiol for FHT for 48 weeks.

The primary objectives of the study are to 1) assess whether TW continue to achieve therapeutic concentrations of ART while receiving FHT for 48 weeks and 2) assess whether serum estradiol concentrations on FHT (across a range of estradiol doses) vary between boosted and un-boosted ART regimens.

Detailed description: A5403 is a phase IIb, 48-week, open-label, non-randomized, 3-group trial, of 90 adult (≥18 years) transgender women and other individuals identifying as female or transfeminine but with male sex assigned at birth (TW) living with HIV on suppressive antiretroviral therapy (ART) and not currently on FHT. The trial will target at least 50% enrollment of participants identifying as non-white or Latine.

The trial consists of three groups, a BIC-treated group (BIC/TAF/FTC; n=30) (Group 1), a DTG-treated group (DTG/TDF/FTC or 3TC; n=30) (Group 2), and a boosted DRV-treated group (DRV/c; n=30) (Group 3), for a total of 90 participants.

All participants will continue on ART (not provided by the trial) and receive study-supplied 17-β estradiol for weeks 0-48. At entry, participants will be assigned to one of the three analysis groups based on their current ART regimen. Participants on other ART regimens at screening who are willing to switch to one of the regimens above, may also be enrolled.

All participants will receive study supplied 17-β estradiol for weeks 0-48. Oral 17-β estradiol 2 mg once daily will be initiated at study entry. At weeks 4, 12, 24, and 36, study clinicians may titrate 17-β estradiol in 2 mg increments as described in the protocol.

Intensive PK subgroup (n=15 per ART group): At entry (week 0), an 8-hour intensive PK sampling will assess ART exposure prior to FHT initiation. At week 24, intensive sampling will be repeated to assess 17-β estradiol and ART exposure. A final intensive PK visit will occur at week 48 to assess 17-β estradiol and ART exposure at the maximal FHT dosing achieved during the study period.

Sparse PK sampling: all participants not participating in an intensive PK sampling visit on the same day will have timed, sparse PK sampling collected at each visit to characterize the trough plasma (BIC, DTG, and DRV) and intracellular ART (TFV-DP, FTC-TP, 3TC-TP) concentrations to evaluate the relationship of ART PK exposure across a range of 17-β estradiol doses.

FHT satisfaction and acceptability:

To measure acceptability, participants will be asked to self-report the degree to which they find the intervention appropriate and useful using Likert-type agreement scales at three study time points: entry, 24 weeks, and 48 weeks. To measure satisfaction, the 12-question Transgender Congruence Scale (TCS) will be used, which will assess associations between gender-affirming treatments, perceived gender congruence, and satisfaction at three study time points: entry, 24 weeks, and 48 weeks. In addition, brief, 20-minute, semi-structured interviews will be conducted with 30 purposively sampled participants across English- or Spanish-speaking sites to provide an opportunity for more in-depth (open-ended) feedback on intervention satisfaction and acceptability at three time points: entry, 24 weeks, and 48 weeks.

Other assessments throughout the study include: anthropometric measurements (including weight, height, minimum waist circumference, and maximum hip circumference), routine chemistry and hematology labs, HIV-1 RNA, CD4+ and CD8+ T cell counts and percentages, lipids, glucose and insulin, non-estradiol hormone concentrations, stored PBMC, plasma, and serum, and ART and FHT adherence assessments.

Eligibility criteria: Inclusion Criteria:

1. Age greater than or equal to 18 years.
2. Documentation of HIV-1 status.
3. Assigned male sex at birth and identifies as a TW, female or transfeminine person.
4. On ART for at least 24 weeks prior to study entry. Regimen changes within the 24 weeks prior to study entry are acceptable, but candidates must have been on a stable regimen for at least 28 days prior to study entry.
5. On BIC/FTC/TAF, DTG/TDF/FTC or 3TC, or DRV/c-containing ART for at least 28 days prior to study entry (single tablet regimen not required), and with no plans to change ART regimen over the study duration of 48 weeks.
6. Desire to initiate or restart FHT, regardless of orchiectomy status.
7. HIV-1 RNA \<200 copies/mL at screening.
8. HIV-1 RNA \<400 copies/mL available through routine clinical care between 24 and 96 weeks prior to study entry and while on ART. The HIV-1 RNA must be the most recent value obtained between 24 and 96 weeks prior to study entry.
9. The following laboratory values obtained within 60 days prior to study entry

   * Hemoglobin ≥9.0 g/dL
   * Platelet count ≥75,000/mm3
   * Estimated Glomerular Filtration Rate (eGFR) ≥30 mL/min/1.73m2 if on or switching to TAF, ≥50 mL/min/1.73m2 if on or switching to TDF without cobicistat, or ≥70 mL/min/1.73m2 if on or switching to TDF in combination with cobicistat, calculated using the CKD-Epi equation
   * Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and alkaline phosphatase are within normal range per local laboratory range
   * Prolactin \<25 ng/dL
10. Serum estradiol level \<75 pg/mL within 60 days prior to study entry.
11. Willingness to avoid the use of prescribed, non-study provided FHT and non-prescribed FHT during the study period, and no planned use of prescribed or non-prescribed anti-androgens for the first 24 weeks of the study.
12. Ability and willingness of participant to provide informed consent and ability and willingness of participant to undergo study procedures.

Exclusion Criteria:

1. Known clotting disorders, active deep vein thrombosis (DVT), pulmonary embolism (PE), or history of these conditions, active arterial thromboembolic disease (e.g., stroke, myocardial infarction), or history of these conditions.
2. Known liver impairment or disease.
3. History of chronic hepatitis B virus (HBV) infection or active HBV infection.
4. History of current active hepatitis C virus (HCV) infection.
5. Prohibited medication use (including drugs with known or expected DDIs with FHT or ART) at time of study entry.
6. Receipt of any estrogen therapy within 14 days prior to study entry for persons on oral FHT, or within 30 days prior to entry for persons on injectable FHT.
7. Known HIV-1 resistance mutations that would preclude remaining on current ART or a switch to a study regimen, in the opinion of the site investigator.
8. Personal history of breast cancer. or known personal history of breast cancer (BRCA) gene.
9. Known or a history of testicular cancer.
10. Known or a history of gall bladder disease.
11. Known or suspected pituitary adenoma.
12. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
13. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
14. Suicidal ideation in the past 30 days or suicide attempt in the past 90 days, as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS).
15. Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry. Stable (in the opinion of the site investigator) treatments for chronic comorbidities are allowed.
16. Presence of any other medical condition that would preclude FHT administration for safety reasons, in the opinion of the site investigator.

Primary outcomes:
measure: Geometric Mean Ratio of ART Analytes BIC, DTG, and DRV trough concentrations (Ctrough) in plasma at each received dose of oral 17-β estradiol
timeFrame: Study Entry and Weeks 4, 12, 24, 36, and 48
measure: Percentage of Participants with ART Analyte trough concentration (Ctrough) above drug-specific threshold
timeFrame: Study Entry and Weeks 4, 12, 24, 36, and 48
measure: Trough serum total estradiol assessed at each received dose of oral 17-β estradiol as quantified via batch testing at central lab.
timeFrame: Study Entry and Weeks 4, 12, 24, 36, and 48
Secondary outcomes:
measure: Trough concentrations of TFV-DP, FTC-TP, and 3TC-TP in non-viable PBMCs at each received dose of oral 17-β estradiol
timeFrame: Study Entry and Weeks 4, 12, 24, 36 and 48
measure: Percentage of Participants with TFV-DP, FTC-TP, and 3TC-TP trough concentration above drug-specific threshold
timeFrame: Study Entry and Weeks 4, 12, 24, 36 and 48
measure: Percentage of participants with an occurrence of any reportable adverse event related to 17-β estradiol
timeFrame: Study entry to Week 48
measure: Percentage of participants with an occurrence of SAEs as defined by International Conference on Harmonization (ICH) and new events of CAD/CVD, cancer, DM/pre-DM, and vascular event
timeFrame: Study entry to Week 48
measure: Percentage of participants with serum total testosterone < 50 ng/dL at each received dose of oral 17-β estradiol
timeFrame: Study entry and Weeks 4, 12, 24, 36, 48
measure: Percentage of participants with virologic suppression of HIV
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Absolute changes in overall transgender congruence score
timeFrame: Study entry and weeks 24, and 48
measure: Area under the curve over 8 hours (AUC 0-8h) of 17-β estradiol
timeFrame: Study entry and Weeks 24, and 48
measure: Percent change in weight
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Percent change in BMI
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Absolute change in minimum waist circumference
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Absolute change in maximum hip circumference
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Absolute change in waist-hip ratio measured
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Absolute changes in fasting lipids
timeFrame: Study entry and weeks 12, 24, and 48
measure: Absolute changes in glucose sensitivity
timeFrame: Study entry and weeks 12, 24, 36, and 48
measure: Absolute changes in insulin sensitivity
timeFrame: Study entry and weeks 12, 24, 36, and 48
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS (701)
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco HIV/AIDS CRS (801)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Washington
country: United States
facility: Whitman-Walker Institute, Inc. CRS (31791)
state: District of Columbia
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (Site #2701)
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University CRS (201)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS) (101)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS (2101)
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS (31786)
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Chelsea CRS (7804)
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS (site 7803)
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS (3201)
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS (3203)
state: North Carolina
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS (2301)
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: Seattle
country: United States
facility: University of Washington Positive Research CRS (1401)
state: Washington
city: Gaborone
country: Botswana
facility: Gaborone CRS (12701)
city: Mexico City
country: Mexico
facility: Nutrición-Mexico CRS (32078)
state: Tlalpan
city: Lima
country: Peru
facility: Barranco CRS (11301)
city: Johannesburg
country: South Africa
facility: Soweto ACTG CRS (12301)
city: Bangkok
country: Thailand
facility: Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (31802)
state: Patumwan
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (31784)
Study officials:
affiliation: Houston AIDS Research Team CRS
name: Jordan E. Lake, MD, MSc
role: STUDY_CHAIR
affiliation: University of Nebraska
name: Kimberly K. Scarsi, PharmD, MS, FCCP
role: STUDY_CHAIR
affiliation: Barranco CRS
name: Jorge A. Gallardo-Cartagena, MD
role: STUDY_CHAIR
References: