A Phase I Trial for the Evaluation of the Two-way Pharmacokinetic-pharmacodynamic (PD) Interaction of Gender Affirming Exogenous Estrogen (With Testosterone Suppression) on TDF/FTC PrEP in Transgender Women (TGW)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 13
- 试验地点
- 2
- 主要终点
- Change in Tenofovir plasma concentration
研究概览
简要总结
This is a research study to determine the best way to dose Truvada®, an oral medication licensed to be taken as Pre-Exposure Prophylaxis (PrEP) to prevent HIV infection, in transgender women who are also taking feminizing hormones. The duration of the study is about 4 months, and involves a screening visit, a baseline visit with colon biopsies and kidney function testing, and several outpatient visits, including 5 intensive sampling visits that last about 9 hours and involve colon biopsies, kidney function testing and other blood specimen collections.
After the baseline visit, participants will start on PrEP, daily Truvada® pills, and will continue on the Truvada® for 5 weeks. Participants will then receive either an injection of Lupron, oral low-dose estradiol or oral high-dose estradiol, which will be taken along with the Truvada® PrEP for 1-2 weeks before returning for an intensive sampling visit.
详细描述
The PrEP-GAHT Interactions in TGW protocol is a phase 1, open label study to compare the safety, PK and PD of five sequential phases of PrEP administration in the presence or absence of testosterone-reducing therapies or dose-escalated estrogen therapy. Each participant will undergo a Screening Visit to evaluate eligibility.
Following Baseline evaluation, eligible participants will receive 300 milligrams (mg) TDF/200 mg FTC (Truvada®) once daily for seven days, using direct observation approaches, to achieve steady state drug PrEP concentrations. After one week of therapy, participants will undergo intensive PK analysis as well as collection of colorectal biopsies for PD testing (PK1). During the PK-intensive day, iohexol will be administered intravenously for the empirical determination of renal function and measured glomerular filtration rate (mGFR). While concurrently on PrEP, participants will then be intramuscularly administered depot leuprolide acetate (11.25 mg Lupron®). Two weeks post-injection, when testosterone concentrations are far below the lower limit of normal of total testosterone in men (typically < 200 ng/dL, or < 2 ng/mL), sampling for PK, PD, and renal function will be performed (PK2).
Participants will then immediately begin low-dose oral estrogen therapy (1 mg 17β-estradiol) in conjunction with PrEP for one week, at which time samples will be collected for the analyses described above (PK3). While still on PrEP, participants will then transition to high-dose estrogen therapy (6 mg 17β-estradiol) for the remainder of the study. One week post-high dose estrogen therapy in the presence of PrEP, pharmacologic and renal samples will be collected for analysis (PK4). PrEP will then be discontinued, and two weeks later, samples will be collected to assess renal function and hormonal concentrations, and evaluate the presence of any remaining PrEP in plasma, Peripheral Blood Mononuclear Cells (PBMC), or colorectal tissue (though it should be near undetectable levels for most analytes according to the investigators' prior data)(PK5).
Safety assessments, including history/physical, chemistry/hematology labs at screening and interim history will be performed at each study-intensive visit. Additionally, periodic assessments of gender dysphoria will be conducted at baseline and a convenient time during PK visits throughout the study. To ensure compliance, participants will undergo direct observation of dosing each day of the week prior to PK visits, using the aforementioned strategies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •18 years of age or older
- •Self-identifying as a transgender woman
- •Not currently taking any gender affirming hormonal therapy (GAHT) with a total testosterone concentration of ≥ 200 ng/dL, or willing to abstain from feminizing therapies (including estradiol, spironolactone, progesterone, etc.) until total total testosterone concentrations are ≥ 200 ng/dL. Note: Testosterone may be retested every 2-4 weeks during screening to determine eligibility up to 6 weeks.
- •HIV-1 uninfected at screening as documented by Combo Ag/Ab HIV-1/HIV-2 immunoassay
- •Understand and agree to local STI reporting requirements
- •Able and willing to communicate in English
- •Able and willing to provide written informed consent to take part in the study
- •Able and willing to provide adequate information for locator purposes
- •Able and willing to participate in a directly observed study, which may occur in person, using live streaming or a time stamped video?
- •Availability to return for all study visits, barring unforeseen circumstances
- •Willing to abstain from insertion of anything (drug, enema, penis, or sex toy) in rectum for 72 hours before and 72 hours after each flexible sigmoidoscopy
- •Willing to refrain from aspirin and NSAID use for one week before and after each study biopsy visit
- •Willing and able to use condoms for all Receptive Anal Intercourse (RAI) for the duration of participation
- •Willing and able to participate in a directly observed study, which may occur in person, using live streaming or a time stamped video
- •Has an identified healthcare provider for transgender health management
- •Agree not to participate in other research studies involving drugs and/or medical devices for the duration of the study
排除标准
- •Not currently on any PrEP regimen (e.g., Truvada®, tenofovir alafenamide/ emtricitabine)
- •History of chronic Hepatitis B infection, as documented by positive HBsAg at screening
- •≥ Grade 2 laboratory abnormality at baseline as defined by Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 - July 2017, and Addendum 3 (Rectal Grading Tables for Use in Microbicide Studies)
- •Significant colorectal symptom(s) as determined by medical history or by participant self- report (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, history of inflammatory bowel disease, presence of symptomatic hemorrhoids, and presence of any painful anorectal conditions that would be tender to manipulation)
- •At screening or within the past 2 months: participant-reported symptoms and/or clinical or laboratory diagnosis of active rectal infection requiring treatment per current Centers for Disease Control (CDC) guidelines or symptomatic urinary tract infection (UTI). Infections requiring treatment include Chlamydia (CT), gonorrhea (GC), syphilis, active herpes simplex virus (HSV) lesions, chancroid, genital sores or ulcers, and, if clinically indicated, genital warts. Note that HSV seropositivity with no active genital lesions is not an exclusion criterion. (Note: if an Sexually Transmitted Infection (STI) apart from HIV is detected, the participant will be referred for treatment and can be retested in 30 days and rescreened once.)
- •History of an underlying clinically significant cardiac arrhythmia or renal disease (including creatinine clearance < 60 mL/min using Cockcroft-Gault equation)
- •Serum phosphate < 2.3 mg/dL
- •History of severe or recent cardiac or pulmonary event
- •History of significant gastrointestinal bleeding
- •Current use of warfarin or heparin or other anticoagulant medications associated with increased risk for bleeding following mucosal biopsy (e.g., daily high dose aspirin [>81 mg], Non-steroidal anti-inflammatory drug [NSAIDs], or Pradaxa®)
- •Use of systemic or anorectal immunomodulatory medications within 4 weeks of enrollment or planned use at any time during study participation
研究组 & 干预措施
PrEP plus High Dose Estrogen
Truvada one tablet by mouth daily Estradiol 6 milligrams (mg) by mouth daily x 2 weeks
干预措施: Truvada plus Estradiol 6 mg (Drug)
High Dose Estrogen
Estradiol 6 mg by mouth daily x 2 weeks
干预措施: Estradiol 6 mg alone (Drug)
PrEP plus Gonadotropin Releasing Hormone (GnRH) Agonist
Truvada one tablet by mouth daily Leuprolide 11.25 milligrams (mg) intramuscular (im) injection once
干预措施: Truvada plus Leuprolide 11.25mg intramuscular injection (Drug)
Pre-Exposure Prophylaxis (PrEP) only
Truvada one tablet by mouth daily
干预措施: Truvada alone (Drug)
PrEP plus Low Dose Estrogen
Truvada one tablet by mouth daily Estradiol 1 milligram by mouth daily x 2 weeks
干预措施: Truvada plus Estradiol 1 mg (Drug)
结局指标
主要结局
Change in Tenofovir plasma concentration
时间窗: Days 7-8, Days 21-22, Days 28-29, Days 35-36, Days 49-50
Change in Tenofovir plasma concentration measured in nanograms (ng) per milliliter (mL)
Change in Tenofovir-Diphosphate PBMC concentration
时间窗: Days 7-8, Days 21-22, Days 28-29, Days 35-36, Days 49-50
Change in tenofovir-diphosphate (TFV-DP) PBMC concentration reported in femtomoles per million cells (fmol/million)
Change in TFV-DP colon tissue concentration
时间窗: Days 7-8, Days 21-22, Days 28-29, Days 35-36, Days 49-50
Change in TFV-DP colon tissue concentration reported in fmol/million
Change in Calculated Plasma TFV Area Under the Concentration-Time Curve (AUC0-24h)
时间窗: Days 7-8 for Pre-Exposure Prophylaxis (PrEP) Only, Days 21-22 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Days 28-29 for PrEP Plus Lose-Dose Estrogen, Days 35-36 for PrEP Plus High-Dose Estrogen, and Days 49-50 for High-Dose Estrogen.
The reported AUC is the area under the curve of the concentration-time curve calculated using trapezoidal rule (sum of trapezoids) over a 24h period (AUC0-24h). Median AUCs and IQRs were determined. Changes in AUC0-24h from baseline were based on comparisons between the reported AUC during each dosing period. Differences in the TFV AUC0-24h were determined for each participant, and each dosing period was compared to the PrEP Only Dosing Period. The median intra-individual difference in the TFV AUC0-24h, with IQRs, was calculated.
Change in PBMC TFV-DP C24 Concentration
时间窗: Day 8 for Pre-Exposure Prophylaxis (PrEP) Only, Day 22 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 29 for PrEP Plus Lose-Dose Estrogen, Day 36 for PrEP Plus High-Dose Estrogen, and Day 50 for High-Dose Estrogen.
The PBMC TFV-DP (fmol/10\^6 cells) concentration was measured at 24 hours following a directly observed F/TDF or high-dose estrogen dose. Median PBMC TFV-DP concentrations, normalized to millions of cells analyzed, were measured. Differences in the PBMC TFV-DP concentrations were determined for each participant, and each dosing period was compared to the PrEP Only Dosing Period. The median intra-individual difference in the PBMC TFV-DP Concentrations, with IQRs, was calculated.
Change in TFV-DP Colon Tissue Concentration
时间窗: Day 8 for Pre-Exposure Prophylaxis (PrEP) Only, Day 22 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 29 for PrEP Plus Lose-Dose Estrogen, Day 36 for PrEP Plus High-Dose Estrogen, and Day 50 for High-Dose Estrogen
The estimated colon TFV-DP was measured from colon biopsies 24 hours following a directly observed F/TDF or high-dose estrogen dose. Median colon tissue TFV-DP concentrations (with IQRs), normalized to weight of tissue biopsy analyzed, were measured. Differences in the colonic tissue TFV-DP concentrations were determined for each participant, and each dosing period was compared to the PrEP Only Dosing Period. The median intra-individual difference in the colonic tissue TFV-DP concentrations, with IQRs, was calculated.
Change in Maximum Tenofovir Plasma (Cmax) Concentration
时间窗: Days 7-8 for Pre-Exposure Prophylaxis (PrEP) Only, Days 21-22 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Days 28-29 for PrEP Plus Lose-Dose Estrogen, Days 35-36 for PrEP Plus High-Dose Estrogen, and Days 49-50 for High-Dose Estrogen.
Plasma TFV Cmax was defined as the highest observed concentration during the 24 hour (h) dosing interval and determined via non-compartmental analyses. Median maximum concentrations with interquartile ranges (IQR) were determined. Differences in TFV Cmax concentrations were determined for each participant, and each dosing period was compared to the PrEP Only Dosing Period. The median intra-individual difference in TFV Cmax, with IQRs, was calculated.
次要结局
- Change in serum free testosterone concentration(Days 7, 21, 28, 35, 49)
- Change in Serum luteinizing hormone (LH) concentration(Days 7, 21, 28, 35, 49)
- Change in serum follicular stimulating hormone (FSH)(Days 7, 21, 28, 35, 49)
- Change in serum estradiol concentration(Days 7, 21, 28, 35, 49)
- Change in serum total testosterone concentration(Days 7, 21, 28, 35, 49)
- Change in Serum Estradiol Concentration(Day 7 for Pre-Exposure Prophylaxis (PrEP) Only, Day 21 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 28 for PrEP Plus Lose-Dose Estrogen, Day 35 for PrEP Plus High-Dose Estrogen, and Day 49 for High-Dose Estrogen)
- Change in Serum Free Testosterone(Day 7 for Pre-Exposure Prophylaxis (PrEP) Only, Day 21 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 28 for PrEP Plus Lose-Dose Estrogen, Day 35 for PrEP Plus High-Dose Estrogen, and Day 49 for High-Dose Estrogen)
- Change in Serum Total Testosterone Concentration(Day 7 for Pre-Exposure Prophylaxis (PrEP) Only, Day 21 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 28 for PrEP Plus Lose-Dose Estrogen, Day 35 for PrEP Plus High-Dose Estrogen, and Day 49 for High-Dose Estrogen)
- Change in Serum Luteinizing Hormone (LH) Concentration(Day 7 for Pre-Exposure Prophylaxis (PrEP) Only, Day 21 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 28 for PrEP Plus Lose-Dose Estrogen, Day 35 for PrEP Plus High-Dose Estrogen, and Day 49 for High-Dose Estrogen)
- Change in Serum Follicle Stimulating Hormone (FSH) Concentration(Day 7 for Pre-Exposure Prophylaxis (PrEP) Only, Day 21 For PrEP Plus Gonadotropin Releasing Hormone (GnRH) Agonist, Day 28 for PrEP Plus Lose-Dose Estrogen, Day 35 for PrEP Plus High-Dose Estrogen, and Day 49 for High-Dose Estrogen)