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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A | Experimental | Single-dose oral Doravirine/lamivudine/tenofovir disoproxil |
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| Treatment B | Experimental | Single-dose estradiol and spironolactone co-administered with placebo |
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| Treatment C | Experimental | Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Doravirine/Lamivudine/Tenofovir | Drug | 100mg/300mg/300mg orally for one dose, daily |
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| Measure | Description | Time Frame |
|---|---|---|
| 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 | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
| Doravirine Maximum Concentration (Cmax) | Doravirine maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
| Doravirine Trough Concentration (C24) | Doravirine observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms | 24 hours post-dose for all participants |
| 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 | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
| Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax) | Tenofovir maximum observed concentration during the dosing interval | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
| Tenofovir Disoproxil Fumarate Trough Concentration (C24) | Tenofovir observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms |
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Inclusion Criteria:
Exclusion Criteria:
Transgender Female
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| Name | Affiliation | Role |
|---|---|---|
| Walter K Kraft, MD | Thomas Jefferson University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Research Unit at Thomas Jefferson University | Philadelphia | Pennsylvania | 19107 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38421210 | Result | Lam K, Kraft WK, Zhan T, Lam E. Bidirectional pharmacokinetics of doravirine, tenofovir, and feminizing hormones in transgender women (IDentify): A randomized crossover trial. Clin Transl Sci. 2024 Mar;17(3):e13721. doi: 10.1111/cts.13721. |
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Pharmacokinetic data will be updated in study outcome and results.
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8 enrolled participants were randomized 1:1 to either Sequence E of F.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 27, 2021 |
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Three period crossover
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| Spironolactone 100mg | Drug | 200mg orally for two doses, twice-daily |
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| Estradiol 2mg | Drug | 4mg orally for two doses, twice-daily |
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| Placebo | Other | Placebo for one dose, daily |
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| 24 hours post-dose for all participants |
| 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 | Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
| Estradiol Maximum Concentration (Cmax) | Estradiol maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms | Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
| Estradiol Trough Concentration (C12) | Estradiol observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms | 12 hours post-dose for all participants |
| FG001 | 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 |
| COMPLETED |
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| NOT COMPLETED |
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8 participants were enrolled in the study and randomized 1:1 to either Sequence E or F.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Median | Full Range | years |
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| Sex/Gender, Customized | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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 | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | hr*ng/mL | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
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| Primary | Doravirine Maximum Concentration (Cmax) | Doravirine maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
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| Primary | Doravirine Trough Concentration (C24) | Doravirine observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 24 hours post-dose for all participants |
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| 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 | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | hr*ng/mL | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
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| Primary | Tenofovir Disoproxil Fumarate Maximum Concentration (Cmax) | Tenofovir maximum observed concentration during the dosing interval | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
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| Primary | Tenofovir Disoproxil Fumarate Trough Concentration (C24) | Tenofovir observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 24 hours post-dose for all participants |
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| 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 | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | hr*pg/mL | Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
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| Primary | Estradiol Maximum Concentration (Cmax) | Estradiol maximum observed concentration during the dosing interval with geometric mean ratio compared between treatment arms | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Pre-dose, 0.5, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants |
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| Primary | Estradiol Trough Concentration (C12) | Estradiol observed trough concentration during the dosing interval with geometric mean ratio compared between treatment arms | 6 participants completed the study and were included in the pharmacokinetic analysis. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | 12 hours post-dose for all participants |
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9 weeks, up to 30 days after last dose of drug administered
Adverse events were collected throughout the duration of the study, up to 30 days after last dose of drug administered. All subjects received all treatments, and as such the comparisons are between sequences. Adverse events were not separated out by treatment, but only by Sequence. Adverse Events were monitored without regard to the specific intervention or period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sequence E | All subjects received all treatments, and as such the comparisons are between sequences. Adverse events were not separated out by treatment, but only by Sequence 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 | 0 | 4 | 0 | 4 | 4 | 4 |
| EG001 | Sequence F | All subjects received all treatments, and as such the comparisons are between sequences. Adverse events were not separated out by treatment, but only by Sequence 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 | 0 | 4 | 0 | 4 | 4 | 4 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea/vomiting | Gastrointestinal disorders | MedDRA 26.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 26.0 | Systematic Assessment |
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| Application site erythema | General disorders | MedDRA 26.0 | Systematic Assessment | Tegaderm redness |
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| Catheter site redness | General disorders | MedDRA 26.0 | Systematic Assessment |
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| Catheter site pruritus | General disorders | MedDRA 26.0 | Systematic Assessment |
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| Folliculitis | Infections and infestations | MedDRA 26.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 26.0 | Systematic Assessment |
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| Blood glucose increased | Investigations | MedDRA 26.0 | Systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 26.0 | Systematic Assessment | Muscle cramps |
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| Brain fog | Nervous system disorders | MedDRA 26.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 26.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 26.0 | Systematic Assessment |
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| Migraine | Nervous system disorders | MedDRA 26.0 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Distractibility | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Dysphoria | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Irritability | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Gender dysphoria | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Libido increased | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Mood swings | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Acne | Skin and subcutaneous tissue disorders | MedDRA 26.0 | Systematic Assessment |
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| Hair growth abnormal | Skin and subcutaneous tissue disorders | MedDRA 26.0 | Systematic Assessment |
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| Seborrhoea | Psychiatric disorders | MedDRA 26.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Walter K. Kraft | Thomas Jefferson University | (215) 955-9077 | Walter.Kraft@jefferson.edu |
| Jul 7, 2023 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D000068116 | Gender Dysphoria |
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D020018 | Sexual Dysfunctions, Psychological |
| D001523 | Mental Disorders |
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| C000592662 | doravirine |
| D002191 | Canrenoic Acid |
| D013148 | Spironolactone |
| D004958 | Estradiol |
| ID | Term |
|---|---|
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011283 | Pregnenes |
| D004963 | Estrenes |
| D004962 | Estranes |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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| >=65 years |
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| Transgender male (female-to-male) |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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Ratio represents Treatment C (Single-dose oral doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone) over Treatment A (Single-dose oral doravirine/lamivudine/tenofovir disoproxil fumarate alone) |
| Equivalence |
The no-effect (bioequivalence) boundaries of 80%-125% were used. |
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