Gender Dysphoria, Human Immunodeficiency Virus, Transgender Health, Transgender Women
Conditions
Brief summary
Transgender women living with Human Immunodeficiency Virus (HIV) may prioritize gender-affirming hormonal therapy over antiretroviral drug therapy. Hormonal therapy typically consists of oral estradiol and spironolactone, which induce drug-metabolizing enzymes after prolonged administration. This study evaluates the bi-directional potential drug interaction between the antiretroviral drug, doravirine, when co-administered with estradiol and spironolactone.
Detailed description
This study will consist of healthy transgender women volunteers randomized to a 1:1 sequence (E or F) There are three periods and in each period there are one of three treatments Treatment A: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate alone Treatment B: Single-dose estradiol and spironolactone co-administered with placebo Treatment C: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone The primary outcome measures are the drug concentrations The primary comparisons are geometric mean ratios of drugs with potential perpetrators of drug interactions using a crossover method
Interventions
100mg/300mg/300mg orally for one dose, daily
200mg orally for two doses, twice-daily
DRUGEstradiol 2mg
4mg orally for two doses, twice-daily
OTHERPlacebo
Placebo for one dose, daily
Sponsors
Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Three period crossover
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy self-identified transgender women (male-to-female) between 18-45 years old at the time of screening * Have not undergone an orchiectomy * Receiving oral estradiol and spironolactone for \>/= 3 months prior to study entry with a self-reported adherence to prescribed doses of \>/= 90% * Agree to abstain from alcohol consumption throughout the duration of the study * Be willing to briefly interrupt hormonal therapy prior to and during the study * If on pre-exposure prophylaxis (PrEP) therapy containing tenofovir alafenamide or tenofovir disoproxil fumarate, willing to discontinue PrEP at least 2 weeks before study start and for the duration of the study * Agree to use condoms for all sexual activity prior to the start and throughout the duration of the study * Evidence of a personal signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study
Exclusion criteria
* Presence of clinically significant acute or chronic disease, that in the investigator's opinion, would compromise the participant's safety during the study * Use of injectable or transdermal estradiol * Use of any other hormonal replacement therapy, wit h the exception of oral estradiol and spironolactone * Current use of any antiretroviral drug. This will not be exclusionary if participants reported discontinuing within 30 days of screening * Creatinine clearance \</= 60 mL/min, as estimated by the Cockcroft-Gault equation * Known anaphylactic or severe systemic reactions to any components of doravirine, lamivudine, or tenofovir disoproxil fumarate * Positive HIV, hepatitis B or Hepatitis C virus at screening. Evidence of prior hepatitis B infection and immunity is not exclusionary. Positive hepatitis C antibody with negative viral load or documented antiviral hepatitis C treatment with one post treatment non-detectable hepatitis C viral load is not exclusionary * Recent significant blood or plasma donation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants | Doravirine AUC derived from plasma sampling with geometric mean ratio compared between treatment arms |
| Doravirine Maximum Concentration (Cmax) | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants | Doravirine maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms |
| Doravirine Trough Concentration (C24) | 24 hours post-dose for all participants | Doravirine observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms |
| Tenofovir Disoproxil Fumarate Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants | Tenofovir AUC derived from plasma sampling with geometric mean ratio compared between treatment arms |
| Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax) | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants | Tenofovir maximum observed concentration during the dosing interval |
| Tenofovir Disoproxil Fumarate Trough Concentration (C24) | 24 hours post-dose for all participants | Tenofovir observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms |
| Estradiol Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants | Estradiol area under the plasma concentration versus time curve from 0 hours to infinity (AUC) derived from plasma sampling |
| Estradiol Maximum Concentration (Cmax) | Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants | Estradiol maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms |
| Estradiol Trough Concentration (C12) | 12 hours post-dose for all participants | Estradiol observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through social media outreach and by interaction with advocacy groups. They were enrolled in the study between January 4, 2022 and September 21, 2022 at the Clinical Research Unit at Thomas Jefferson University.
Pre-assignment details
8 enrolled participants were randomized 1:1 to either Sequence E of F.
Participants by arm
| Arm | Count |
|---|---|
| Sequence E 4 of 8 enrolled participants were assigned to receive Sequence E, which consisted of Treatment A, B, and C administered during period I, II, and III, respectively.
Treatment A: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate alone Treatment B: Single-dose estradiol and spironolactone co-administered with placebo Treatment C: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone Doravirine/Lamivudine/Tenofovir: 100mg/300mg/300mg orally for one dose, daily Spironolactone 100mg: 200mg orally for two doses, twice-daily Estradiol 2mg: 4mg orally for two doses, twice-daily Placebo: Placebo for one dose, daily | 4 |
| Sequence F 4 of 8 enrolled participants were assigned to receive Sequence F, which consisted of Treatment C, B, and A administered during period I, II, and III, respectively.
Treatment A: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate alone Treatment B: Single-dose estradiol and spironolactone co-administered with placebo Treatment C: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone Doravirine/Lamivudine/Tenofovir: 100mg/300mg/300mg orally for one dose, daily Spironolactone 100mg: 200mg orally for two doses, twice-daily Estradiol 2mg: 4mg orally for two doses, twice-daily Placebo: Placebo for one dose, daily | 4 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Sequence E | Sequence F | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 25.5 years | 27 years | 25.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 4 Participants | 4 Participants | 8 Participants |
| Sex/Gender, Customized Gender Identity Transgender female (male-to-female) | 4 Participants | 4 Participants | 8 Participants |
| Sex/Gender, Customized Gender Identity Transgender male (female-to-male) | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)
Doravirine AUC derived from plasma sampling with geometric mean ratio compared between treatment arms
Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | 17798.14 hr*ng/mL | Geometric Coefficient of Variation 21.7 |
| Treatment A | Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | 18413.21 hr*ng/mL | Geometric Coefficient of Variation 41.75 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for doravirine AUC falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.76, 1.24]
Primary
Doravirine Maximum Concentration (Cmax)
Doravirine maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms
Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Doravirine Maximum Concentration (Cmax) | 745.46 ng/mL | Geometric Coefficient of Variation 21.43 |
| Treatment A | Doravirine Maximum Concentration (Cmax) | 799.67 ng/mL | Geometric Coefficient of Variation 26.01 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for doravirine Cmax falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.66, 1.32]
Primary
Doravirine Trough Concentration (C24)
Doravirine observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms
Time frame: 24 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Doravirine Trough Concentration (C24) | 283.74 ng/mL | Geometric Coefficient of Variation 25.42 |
| Treatment A | Doravirine Trough Concentration (C24) | 292.89 ng/mL | Geometric Coefficient of Variation 49.3 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for doravirine C24 falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.76, 1.24]
Primary
Estradiol Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)
Estradiol area under the plasma concentration versus time curve from 0 hours to infinity (AUC) derived from plasma sampling
Time frame: Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Estradiol Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | 9370.25 hr*pg/mL | Geometric Coefficient of Variation 14.36 |
| Treatment A | Estradiol Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | 9677.31 hr*pg/mL | Geometric Coefficient of Variation 43.29 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for estradiol AUC falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.7, 1.35]
Primary
Estradiol Maximum Concentration (Cmax)
Estradiol maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms
Time frame: Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Estradiol Maximum Concentration (Cmax) | 118.08 pg/mL | Geometric Coefficient of Variation 20.5 |
| Treatment A | Estradiol Maximum Concentration (Cmax) | 105.14 pg/mL | Geometric Coefficient of Variation 21.26 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratios for estradiol Cmax falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.92, 1.36]
Primary
Estradiol Trough Concentration (C12)
Estradiol observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms
Time frame: 12 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Estradiol Trough Concentration (C12) | 100.26 pg/mL | Geometric Coefficient of Variation 26.56 |
| Treatment A | Estradiol Trough Concentration (C12) | 92.01 pg/mL | Geometric Coefficient of Variation 36.94 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratios for estradiol C12 falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.88, 1.35]
Primary
Tenofovir Disoproxil Fumarate Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞)
Tenofovir AUC derived from plasma sampling with geometric mean ratio compared between treatment arms
Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Tenofovir Disoproxil Fumarate Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | 2370.6 hr*ng/mL | Geometric Coefficient of Variation 23.42 |
| Treatment A | Tenofovir Disoproxil Fumarate Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) | 2031.84 hr*ng/mL | Geometric Coefficient of Variation 35.25 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for tenofovir AUC falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.91, 1.5]
Primary
Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax)
Tenofovir maximum observed concentration during the dosing interval
Time frame: Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax) | 178.84 ng/mL | Geometric Coefficient of Variation 58.4 |
| Treatment A | Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax) | 129.95 ng/mL | Geometric Coefficient of Variation 99.92 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for tenofovir Cmax falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.73, 2.6]
Primary
Tenofovir Disoproxil Fumarate Trough Concentration (C24)
Tenofovir observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms
Time frame: 24 hours post-dose for all participants
Population: 6 participants completed the study and were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment C | Tenofovir Disoproxil Fumarate Trough Concentration (C24) | 29.59 ng/mL | Geometric Coefficient of Variation 24.23 |
| Treatment A | Tenofovir Disoproxil Fumarate Trough Concentration (C24) | 26 ng/mL | Geometric Coefficient of Variation 35.77 |
Comparison: 6 participants completed the study and were included in the pharmacokinetic analysis. As all participants received the same treatment groups but not necessarily in the same order, calculations were done between arms (Sequence E and F). 10 subjects was determined to achieve 80% power to reject the null hypothesis (geometric mean ratio for tenofovir C24 falls outside of the no-effect boundaries) with two-sided significance level of 0.05 assuming a mean ratio of 1 for no effect.90% CI: [0.93, 1.4]