Conditions: Transgender Health Gender Dysphoria Transgender Women Human Immunodeficiency Virus
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 8
Healthy volunteers: yes

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

Arms:
arm 1: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil arm 2: Single-dose estradiol and spironolactone co-administered with placebo arm 3: Single-dose oral Doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone

Interventions: intervention 1: Doravirine/Lamivudine/Tenofovir intervention 2: Spironolactone 100mg intervention 3: Estradiol 2mg intervention 4: Placebo
Intervention descriptions: intervention 1: 100mg/300mg/300mg orally for one dose, daily intervention 2: 200mg orally for two doses, twice-daily intervention 3: 4mg orally for two doses, twice-daily intervention 4: Placebo for one dose, daily

Protocol document:
Prot_SAP_000.pdf: 
Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
Protocol Version: 2.0 
Protocol Date:   27 December 2021 
JeffTrial Number: 15431 – IRB #20C.135 
 
Page 1 of 47 
 
Clinical Protocol 
 
A prospective, randomized, placebo-controlled, three-period crossover, two-way 
interaction study to evaluate the pharmacokinetics of doravirine and tenofovir disoproxil 
fumarate on the pharmacokinetics of cross-sex hormonal therapy in adult HIV-negative 
transgender women   
 
JeffTrial Protocol Number: 15431 
Merck MISP Number: 59198 
 
Principal Investigator: 
 
 
 
 
 
 
 
Walter K. Kraft, MD 
 
Department of Pharmacology & Experimental Therapeutics  
132 South 10th Street, 1170 Main Building  
Philadelphia, PA 19107 
215 -955-6086 
 
Co-Investigator:  
Edwin Lam, PharmD  
 
Department of Pharmacology & Experimental Therapeutics  
132 South 10th Street, 1170 Main Building  
Philadelphia, PA 19107 
215-955-5916 
 
Study Site:  
 
Thomas Jefferson University 
Funder: 
 
Merck & Co., Inc. 
Study Compounds: 
Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(DELSTRIGO) 
Estradiol 
Spironolactone 
 
Phase: 
 
1 
Protocol Date: 
27 December 2021 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
Protocol Version: 2.0 
Protocol Date:   27 December 2021 
JeffTrial Number: 15431 – IRB #20C.135 
 
Page 2 of 47 
 
 
PROTOCOL AMENDMENTS AND SUMMARY OF CHANGES 
 
Document 
Version Date 
Summary of Changes 
1.0 
24 JANUARY 2020 
Original IRB submission 
1.1 
14 FEBUARY 2020 
Revisions based on IRB 
review 
2.0 
           27 December 2021           
Update exclusion criteria, 
minor typographical 
corrections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
Protocol Version: 2.0 
Protocol Date:   27 December 2021 
JeffTrial Number: 15431 – IRB #20C.135 
 
Page 3 of 47 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
PROTOCOL AMENDMENTS AND SUMMARY OF CHANGES .......................................................................... 2 
TABLE OF CONTENTS ..................................................................................................................................... 3 
LIST OF TABLES .............................................................................................................................................. 6 
LIST OF FIGURES ............................................................................................................................................ 6 
LIST OF ABBREVIATIONS ............................................................................................................................... 7 
PROTOCOL SUMMARY .................................................................................................................................. 8 
SCHEDULE OF EVENTS ................................................................................................................................. 12 
1 
INTRODUCTION ................................................................................................................................... 15 
1.1 Study Background ............................................................................................................................. 15 
1.1.1 Transgender Women and Human Immunodeficiency Virus ...................................................... 15 
1.1.2 Gender Affirming Feminizing Hormone Therapy ....................................................................... 15 
1.1.3 Management of Human Immunodeficiency Virus Infection in Transgender Women............... 15 
1.1.4 Overview of Doravirine/Lamivudine/Tenofovir disoproxil fumarate (DOR/3TC/TDF) .............. 16 
1.1.5 Mechanism of Interaction .......................................................................................................... 16 
1.1.6 Overview of Gender Affirming Feminizing Hormone Therapy .................................................. 17 
1.2 Study Population and Dosing Rationale ............................................................................................ 17 
1.2.1 Rationale for Study Population .................................................................................................. 17 
1.2.2 Rationale for Dose Selection ...................................................................................................... 17 
1.3 Rationale for Endpoints .................................................................................................................... 17 
1.3.1 Pharmacokinetic/Pharmacodynamic Endpoints ........................................................................ 17 
1.3.2 Safety Endpoints ........................................................................................................................ 18 
2 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................................. 18 
2.1 Objectives.......................................................................................................................................... 18 
2.1.1 Primary Objectives ..................................................................................................................... 18 
2.1.2 Secondary Objective .................................................................................................................. 18 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
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Protocol Date:   27 December 2021 
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2.1.3 Exploratory Objective................................................................................................................. 18 
2.2 Endpoints .......................................................................................................................................... 18 
2.2.1 Primary Endpoint ....................................................................................................................... 18 
3 
STUDY DESIGN..................................................................................................................................... 19 
4 
PARTICIPANT SELECTION .................................................................................................................... 19 
4.1 Inclusion Criteria ............................................................................................................................... 19 
4.2 Exclusion Criteria ............................................................................................................................... 20 
4.3 Study Drug and Adherence ............................................................................................................... 20 
4.4 Participant Discontinuation and Withdrawal ................................................................................... 21 
4.4 Participant Replacement Strategy .................................................................................................... 21 
5 
STUDY INTERVENTIONS ...................................................................................................................... 21 
5.1 Treatment Drugs ............................................................................................................................... 21 
5.2 Treatment Allocation ........................................................................................................................ 22 
6 
STUDY PROCEDURES ........................................................................................................................... 22 
6.1 Overview ........................................................................................................................................... 22 
6.2 Informed Consent ............................................................................................................................. 22 
6.2 Participant Recruitment and Screening ............................................................................................ 22 
6.3 Study Visit Schedule .......................................................................................................................... 23 
6.3.1 Treatment A (Sequence E, Period I): Administration of DOR/3TC/TDF Alone ........................... 23 
6.3.2 Treatment A (Sequence F, Period III): Administration of DOR/3TC/TDF Alone ......................... 24 
6.3.3 Treatment B (Sequence E & F, Period II): Administration of Estradiol & Spironolactone ......... 25 
6.3.1 Treatment C (Sequence F, Period I): Administration of DOR/3TC/TDF + 
Estradiol/Spironolactone .................................................................................................................... 26 
6.3.1 Treatment C (Sequence E, Period III): Administration of DOR/3TC/TDF + 
Estradiol/Spironolactone .................................................................................................................... 28 
6.4 Domiciling ......................................................................................................................................... 29 
6.5 Clinical Procedures & Assessments ................................................................................................... 29 
6.5.1 Medical History .......................................................................................................................... 29 
6.5.2 Physical Examination.................................................................................................................. 29 
6.5.3 12-Lead Electrocardiogram ........................................................................................................ 29 
6.5.4 Vital Signs ................................................................................................................................... 29 
6.5.5 Laboratory Safety Evaluations ................................................................................................... 30 
6.5.6 Prior and Concomitant Medications Review ............................................................................. 30 


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6.6 Study Restrictions ............................................................................................................................. 30 
6.6.1 Diet and Fruit Juice Restriction .................................................................................................. 30 
6.6.2 Alcohol Restriction ..................................................................................................................... 30 
6.6.3 Smoking Restriction ................................................................................................................... 30 
6.6.4 Activity Restrictions ................................................................................................................... 30 
6.7 Participant Identification Card .......................................................................................................... 30 
6.8 Standardized Meals ........................................................................................................................... 31 
6.9 Study, Drug Dosing, and Procedure Modification Permitted ........................................................... 31 
6.10 Study Stopping Rules ...................................................................................................................... 31 
7 
POTENTIAL RISKS AND BENEFITS ........................................................................................................ 31 
7.1 Potential Risks Associated with Doravirine ....................................................................................... 31 
7.1 Potential Risks Associated with Lamivudine ..................................................................................... 32 
7.3 Potential Risks Associated with Tenofovir Disoproxil Fumarate ...................................................... 34 
10 SAFETY, ADVERSE EVENTS (AE) & SERIOUS ADVERSE EVENTS (SAE) .................................................. 35 
10.1 Definitions ....................................................................................................................................... 35 
10.1.1 Adverse Event (AE) ................................................................................................................... 35 
10.1.2 Serious Adverse Event (SAE) .................................................................................................... 36 
10.2 Assessing and Recording AEs & SAEs .............................................................................................. 36 
10.3 Data Safety Monitoring Plan ........................................................................................................... 37 
11 STATISTICAL AND PHARMACOKINETIC METHODS .............................................................................. 37 
11.1 Sample Size Estimation ................................................................................................................... 37 
11.2 Pharmacokinetic Analysis ............................................................................................................... 38 
11.3 Statistical Analysis of Pharmacokinetic Parameters ....................................................................... 38 
11.4 Safety Analysis ................................................................................................................................ 38 
12 ETHICS AND PROTECTION OF HUMAN PARTICIPANTS ....................................................................... 39 
12.1 Institutional Review Board Review ................................................................................................. 39 
12.2 Informed Consent ........................................................................................................................... 39 
12.3 Participant Confidentiality .............................................................................................................. 39 
13 SUPPORTING DOCUMENTATION ........................................................................................................ 40 
13.1 Appendix 1: Clinical Laboratory Tests ............................................................................................. 40 
13.2 Appendix 2: Adverse Events: Definitions and procedures for Recording, Evaluating, Follow-up and 
Reporting ................................................................................................................................................ 42 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
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Protocol Date:   27 December 2021 
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13.2.1 Definition of AE ........................................................................................................................ 42 
13.2.2 Definition of SAE ...................................................................................................................... 42 
13.2.3 Additional Events Reported ..................................................................................................... 43 
13.2.4 Recording AEs and SAEs ........................................................................................................... 43 
13.3 Supplemental Material ................................................................................................................... 44 
14 REFERENCES ........................................................................................................................................ 46 
 
 
 
 
 
 
 
 
LIST OF TABLES 
 
Table 1: 
Dose, frequency, route of administration, and protocol regimen under 
investigation……………………………………………………………………………………………….... 
21 
 
Table 2: 
Published within-participant standard deviations pharmacokinetic 
parameters and corresponding number of participants to reject the null 
hypothesis with 80% 
power………………………………………………………………………………………………………….... 
31 
 
Table 3: 
Protocol required laboratory assessments.……………………………...……………………….... 34 
 
LIST OF FIGURES 
Figure 1: Study flow for 12 participants..………………………................................................. 11 
 
 
 
 
 
 
 
 
 
 
 
 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
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Page 7 of 47 
 
 
 
LIST OF ABBREVIATIONS 
 
AIDS 
Acquired Immunodeficiency Syndrome 
AE 
Adverse Event  
ARV 
Antiretroviral 
AUC0-24 
Area under the plasma-concentration time curve from time 0 to 24 
hours 
AUC0-inf 
Area under the plasma-concentration time curve from time 0 
extrapolated to infinity  
AUC0-last 
Area under the plasma-concentration time curve from time 0 to 
last sampled dose 
CBC 
Complete Blood Count 
CI 
Confidence interval 
Cmax 
Maximum concentration observed  
CMP 
Complete Metabolic Panel 
CRU 
Clinical Research Unit at Thomas Jefferson University 
Ctrough 
Trough concentration 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interaction 
DOR 
Doravirine 
ECG 
Electrocardiogram 
FDA 
US Food and Drug Administration 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
IND 
Investigational New Drug  
mg 
Milligram 
NNRTI 
Non-Nucleoside Reverse Transcriptase Inhibitor  
PK 
Pharmacokinetics 
PrEP 
Pre-exposure prophylaxis  
QD 
Once Daily 
SAE 
Serious adverse event 
SS 
Steady State 
TGW 
Transgender woman 
Tmax 
Time of maximum observable plasma concentration 
UA 
Urinalysis 
 
 
 
 
 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
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Protocol Date:   27 December 2021 
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Page 8 of 47 
 
 
PROTOCOL SUMMARY 
 
Synopsis 
Transgender women (TGW) living with Human Immunodeficiency Virus (HIV) may prioritize 
gender-affirming hormonal therapy over antiretroviral (ARV) drug therapy. Hormonal therapy 
consists of oral estradiol and spironolactone, which induce drug-metabolizing enzymes after 
prolonged administration. There is limited evidence evaluating the use of hormonal therapy 
together with HIV ARVs in TGW. TGW living with HIV may prioritize their gender-affirming 
therapy over ARVs. Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) is an 
ARV approved for the treatment of HIV-1 infection. DOR is primarily metabolized by 
cytochrome P450 (CYP) 3A with 3TC and TDF having minimal CYP-mediated interactions. A 
drug interaction study is warranted in light of the 1) inductive effects of hormones on drug 
metabolizing enzymes, 2) common clearance pathway of DOR/3TC/TDF, and 3) need to 
understand this interaction in order to enhance the uptake of ARV treatment in TGW living 
with HIV. This study is designed to evaluate the bi-directional pharmacokinetic interaction 
between single-dose DOR/TDF in the presence of estradiol in TGW.  
Overview of Study Design 
Randomized, placebo-controlled, three-period crossover, two-way interaction study to 
evaluate the effect of once-daily DOR/TDF with estradiol/spironolactone in HIV-negative 
transgender women. Participants will be randomized into two sequences and undergo period 
specific treatment options. For participants randomized to sequence A, participants will 
receive DOR/3TC/TDF alone (Period I), placebo and hormone therapy (Period II), and 
DOR/3TC/TDF and hormone therapy (Period III). In sequence B, participants will receive 
DOR/3TC/TDF and hormone therapy (Period I), placebo and hormone therapy (Period II), and 
DOR/3TC/TDF alone (Period 3). There will be a 14-day washout in between periods I and II and 
II and III.   
Hypothesis 
The mean ratios for estradiol and doravirine/tenofovir disoproxil fumarate (in both 
directions) will fall below or above the no-effect boundaries defined as 80-125%, 
respectively. 
Objectives and Endpoints 
Primary Objectives 
Primary Endpoint 
 Compare the change in plasma exposure-
time profile, defined as AUC(0-last), Cmax, and 
Ctrough, following a single oral dose of 
DOR/TDF together with 
estradiol/spironolactone 
Change in pharmacokinetic parameters 
measured as AUC(0-last), Cmax, and Ctrough. 


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Protocol Date:   27 December 2021 
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 Compare the change in plasma exposure-
time profile, defined as AUC(0-last), Cmax, and 
Ctrough, following a single oral dose of 
estradiol together with DOR/TDF 
Secondary Objective 
Secondary Endpoint 
Evaluate the safety and tolerability of 
DOR/3TC/TDF when co-administered with 
estradiol and spironolactone 
Proportion of Participants with 
treatment-emergent adverse events for 
safety parameters 
 
Exploratory Objective 
Exploratory Endpoint 
Evaluate the change in baseline testosterone 
during the treatment periods 
Change in plasma testosterone following 
treatment  
Study Population (Inclusion) 
1.  Healthy self-identified transgender women (male-to-female) between 18-45 years 
old at the time of screening  
2. Have not undergone an orchiectomy  
3. Receiving oral estradiol and spironolactone for > 3 months prior to study entry with a 
self-reported adherence to prescribed doses of > 90% 
4. Abstain from alcohol consumption throughout the duration of the study  
5. Be willing to briefly interrupt hormonal therapy prior to and during the study 
6. If on pre-exposure prophylaxis (PrEP) therapy containing tenofovir alafenamide or 
disoproxil fumarate, willing to discontinue PrEP at least 2 weeks before study start 
and for the duration of the study   
7. Agree to use condoms for all sexual activity prior to the start and throughout the 
duration of the study 
8. Evidence of a personal signed and dated informed consent document indicating that 
the participant has been informed of all pertinent aspects of the study  
Study Population (Exclusion) 
1. Presence of clinically significant acute or chronic disease, that in the investigator’s 
opinion, would compromise the participant’s safety during the study  
2. Current use of any antiretroviral drug. This will not be exclusionary if participants 
reported discontinuing within 30 days of screening 
3. Creatinine clearance < 60 mL/min, as estimated by the Cockcroft-Gault equation 
4. Known anaphylactic or severe systemic reactions to any components of doravirine, 
lamivudine, or tenofovir  
5. 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 
6. Recent significant blood or plasma donation  


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Protocol Date:   27 December 2021 
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Page 10 of 47 
 
7. Concomitant use of drugs, as deemed by the investigator, to have significant drug-
drug interactions 
8. Received study drug in another study within 4 weeks or within 5 half-lives; whichever 
occurring first- before first anticipated dose of study drug in this study  
9. Unable to refrain from use of over-the-counter, prescription (unless determined 
appropriate by the investigator), herbal or natural products, vitamins or supplements, 
or grapefruit juice/grapefruit products 
10. Presents any concern by the investigator regarding safe participation in the study or 
for any other reason the investigator considers the participant inappropriate for 
participation in the study 
Compounds Under Investigation and Doses 
Doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo) 
Class: Antiretroviral  
Availability: 100 mg/300 mg/ 300 mg oral tablet  
Investigational dosing: 100 mg/300 mg/ 300 mg once-daily 
 
Estradiol (Various) 
Class: Feminizing Hormone 
Availability: Tablet 
Investigational dosing: 8 mg/day 
 
Spironolactone (Various) 
Class: Anti-androgen 
Availability: Tablet 
Investigational dosing: 400 mg/day 
 
Number of Participants 
12 
 
 
 
 
 
 
 
 
 


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Page 11 of 47 
 
Figure 1. Study flow for 12 participants. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Date: 14 February 2020          
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Page 12 of 47 
 
SCHEDULE OF EVENTS 
Treatment A (DOR/3TC/TDF) – Sequence E (Period I); Sequence F (Period III)  
 
 
Procedures 
Days 
 
Post-
Study (7-
14 days) 
Screening 
(-30) 
Pre-
study 
(-14) 
Day 
-1 
1 
2 
3 
4 
5 
Pre-
dose 
PK Sampling (Hours) 
0 
0.5 
1 
2 
6 
12 
24 
48 
72 
96 
Assessment of Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Randomization  
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Laboratory 
Complete Blood Count 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Comprehensive Metabolic 
Panel 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & Drug Screen 
X 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Procedure 
Physical Exam 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research 
Labs 
DOR/TDF PK 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Estradiol PK 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Total Testosterone 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Treatment 
DOR/3TC/TDF 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
SOC Hormone Therapy 
Interruption 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient 
 
 
X2 
X 
------------------------------------------------------------------X 
DC 
 
 
 
 
1Subjects will be randomized prior to any dosing (for period 1) after all eligibility criteria, including  day -1 procedures are met. 
2Participants will admitted to the CRU the morning of Day -1 for period I and the afternoon for period III. 3Urine drug screen only 
 Abbreviations: DC = Discharge; DOR = Doravirine; HIV = Human Immunodeficiency Virus; PK = Pharmacokinetics; SOC = Standard of care; TDF = Tenofovir Disoproxil Fumarate; 3TC = Lamivudine 


Investigating Drug interactions between antiretrovirals and feminizing hormones (IDentify) 
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1Levels will be taken prior to the second estradiol dose. 
2Pre-dose Physical Exam may be done up to 24 hours prior to dose. 
3Participants will admitted to the CRU the afternoon of Day -1 on period II    4 Urine drug screen only 
Abbreviations: DC = Discharge; DOR = Doravirine; HIV = Human Immunodeficiency Virus; PK = Pharmacokinetics; SOC = Standard of care; TDF = Tenofovir Disoproxil Fumarate; 3TC = Lamivudine 
 
Treatment B (Hormone therapy + Placebo) – Sequence E & F (Period II) 
 
 
Procedures 
Days 
Screening   
(-30) 
Pre-
study  
(-14) 
1 
2 
3 
4 
5 
Day    
-1 
Pre-
dose 
PK Sampling (Hours) 
0 
0.5 
1 
2 
6 
12 
24 
48 
72 
96 
Assessment of Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Complete Blood 
Count 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive 
Metabolic Panel 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & Drug 
Screen 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Procedures 
Physical Exam 
X 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research 
Labs 
Estradiol PK 
X 
 
X 
X1 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Total Testosterone 
X 
 
 
X1 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Treatment 
Placebo for 
DOR/3TC/TDF 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
SOC Hormone 
Therapy Restart 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
SOC Hormone 
Therapy Interruption 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient 
 
 
X 
X3 
       ------------------------------------------------------------------X 
DC 
 
 
 


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Treatment C (DOR/3TC/TDF + Hormone Therapy) – Sequence E (Period III); Sequence F (Period I)   
 
 
Procedures 
Days 
 
Post-Study 
(7-14 days) 
Screening 
(-30) 
Pre-
study 
(-14) 
1 
2 
3 
4 
5 
 
Day -1 
Pre-
dose 
PK Sampling (Hours) 
 
0 
0.5 
1 
2 
6 
12 
24 
48 
72 
96 
 
Assessment of Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Complete Blood Count 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Comprehensive 
Metabolic Panel 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol & Drug Screen 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Procedure
Physical Exam 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Labs 
DOR/TDF PK 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Estradiol PK 
X 
 
X 
X2 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Total Testosterone 
X 
 
 
X2 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Treat
ment 
DOR/3TC/TDF 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
SOC Hormone Therapy 
Restart 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
SOC Hormone Therapy 
Interruption 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient 
 
 
X3 
X 
  ------------------------------------------------------------------X 
DC 
 
 
 
 
1Subjects will be randomized prior to any dosing (for period 1) after all eligibility criteria, including  day -1 procedures are met. only 2Levels will be taken prior to the second estradiol dose. 
3Participants will admitted to the CRU the morning of Day -1 for period I and the afternoon for period III 4 Urine drug screen. Abbreviations: DC = Discharge; DOR = Doravirine; HIV = Human 
Immunodeficiency Virus; PK = Pharmacokinetics; SOC = Standard of care; TDF = Tenofovir Disoproxil Fumarate; 3TC = Lamivudine


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1 
INTRODUCTION 
1.1 Study Background 
1.1.1 Transgender Women and Human Immunodeficiency Virus  
It is estimated that 1 million people identify as transgender (both male-to female and female-to-
male) in the United States.1 Transgender is a term for people whose gender identity differs from 
what is associated with their sex assigned at birth. A transgender woman (TGW) refers to a person 
who was assigned male at birth but identifies and lives as a woman.2 The global prevalence of 
Human Immunodeficiency Virus (HIV) infection is estimated to be 19% among TGW.3 
Transgender women represent approximately 22-28% of the 1.1 million adults living with HIV in 
the United States with a new diagnosis 3 times the national average.1 TGW are disproportionally 
affected, as they are 49 times more likely to be infected with HIV compared to the general 
population.3 Furthermore, HIV infections are more prevalent in TGW compared to transgender 
men (21% vs. 1.2%, respectively) with approximately 70% of TGW with HIV being Black or 
Hispanic.1,4,5 These national and global estimates may be underestimates as a result of stigma, 
discrimination, social rejection, healthcare provider insensitivity to transgender issues, and 
exclusion preventing adequate access to healthcare. 
1.1.2 Gender Affirming Feminizing Hormone Therapy  
Not all individuals who identify as a TGW seek gender affirming feminizing hormone therapy. For 
those who decide to undergo treatment, the Endocrine Society and the Center of Excellence for 
Transgender Health at the University of California, San Francisco have issued guidance on 
initiating and monitoring feminizing hormone therapy. Common hormone regimens in TGW 
include estrogens, antiandrogens, and progesterone. 17-estradiol is the bioidentical hormone 
produced in the ovary and is the most common estrogen used in feminizing therapy. Oral, 
transdermal, and parenteral routes of administration for 17-estradiol are available. 
Spironolactone and 5-alpha reductase inhibitors are among the common oral antiandrogens used 
to block the effects of testosterone or suppress its production, respectively. Serum estradiol and 
testosterone are used to monitor therapy with recommendations to maintain physiological levels 
between 100-200 pg/mL and <50 ng/dL, respectively.2 It is estimated that 70% of TGW use non-
injection hormones with 33% who use injectable hormone therapy in the United States.    
1.1.3 Management of Human Immunodeficiency Virus Infection in Transgender Women   
Antiretroviral (ARV) therapy is recommended to individuals infected with HIV to prevent 
progression to immunodeficiency, premature death, and transmission. Initial therapy generally 
consists of two nucleoside reverse transcriptase inhibitors (NRTI) in combination with other ARV 
classes such as integrase strand transfer inhibitor, protease inhibitors or non-nucleoside reverse 
transcriptase inhibitors (NNRTIs).6 Of the NRTIs, TGW living with HIV were reported to most 
frequently use tenofovir (79%) with 23% using abacavir.7 Twenty-eight percent reported using an 
NNRTI based regimen. NNRTIs, such as doravirine (DOR), may be an optimal choice for some TGW 
based on its low potential for drug-drug interaction (DDI), tolerability, and availability as a  


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once-daily fixed-dose regimen together with lamivudine (3TC) and TDF. The favorable metabolic 
profile of DOR makes it favored in those with dyslipidemias, especially since TGW are at a higher 
risk for cardiovascular events due to HIV infection and hormone therapy.8-10    
 
A recent cross-sectional study by Braun et al. has raised concerns over suboptimal ARV adherence 
in TGW living with HIV on feminizing hormone therapy.7 Of the half of study participants who 
were living with HIV, 57% were concerned with the DDI potential with 40% reporting not using 
ARVs, hormone therapy, or both because of this concern.     
1.1.4 Overview of Doravirine/Lamivudine/Tenofovir disoproxil fumarate (DOR/3TC/TDF) 
Doravirine is a novel NNRTI approved for use in patients with HIV-1 in combination with 3TC 
and TDF. The pharmacokinetics of doravirine is expected to be similar between healthy 
volunteers and those living with HIV-1. DOR/3TC/TDF is a complete regimen for the treatment 
of HIV-1 infection in adult patients with no prior ARV treatment or replacement of current 
stabilized ARV treatment.    
1.1.5 Mechanism of Interaction  
It is unclear what chronic hormone therapy with estradiol in TGW will do to the clearance 
mechanisms involved in ARV elimination. Evidence from in-vitro animal and human models 
have shown that chronic elevated exposures of 17-estradiol induce phase I and II drug 
metabolizing enzymes through enhancing major transcription factors that regulate the 
expression of drug metabolizing enzymes.11-13 Similarly, the metabolite 17-estradiol 
glucuronide, has been shown to regulate multidrug resistance-associate protein 2 (MDR2) 
regulation, which was associated with changes in transporter activity in in-vitro human 
intestinal cells.14 In addition, spironolactone is also implicated as an inducer for drug metabolic 
enzymes and transporters based on in-vitro and in-vivo animal studies through mechanisms 
similar to estradiol.15-17  
 
Working with the hypothesis that high-dose chronic administration of estradiol and 
spironolactone may alter ARV drug clearance through cytochrome or transporter mechanisms, 
ARV exposure may indeed be compromised in TGW. A recent PK study in TGW presented at the 
2018 International AIDS Conference may confer insight to this interaction.18 The iFACT study 
observed a 13% reduction in the TDF exposure with concurrent feminizing hormone therapy 
with no change in hormone levels. The authors concluded that there were no significant 
interactions in both directions. However, the results of this study may not be generalizable to 
TGW in the US. First, due to its fixed-sequence design, the study was unable to estimate the 
within-participant variability in drug exposure or designed to test no-effect boundaries. Second, 
the inductive effects from high dose hormone therapy may not have been truly witnessed given 
that TGW enrolled were just beginning hormone therapy or had not received hormones within 
the past 6 months.  


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1.1.6 Overview of Gender Affirming Feminizing Hormone Therapy  
1.1.6.1 17-Estradiol 
Oral 17- Estradiol (estradiol) is the most common hormone used for feminizing therapy. 
Estradiol is the bioidentical hormone to that of the human ovary. Titration upwards over 3-6 
months together with laboratory monitoring for estradiol and testosterone levels over time is 
common practice.  
1.1.6.2 Spironolactone 
Anti-androgens are used alongside estradiol to reduce masculinization and reduce testosterone 
levels. Spironolactone is the most commonly used anti-androgen in the United States. 
Suppression of testosterone production minimizes and suppresses male secondary sexual 
characteristics and lowers estradiol dosing.  
1.2 Study Population and Dosing Rationale  
1.2.1 Rationale for Study Population  
Clinical research in the TGW population is limited. There is a high burden of HIV in TGW that is 
disproportional to cisgender men and women. In the United States, the rate of new diagnosis for 
HIV infection is 3 times greater than the national average. TGW are less likely to seek access to 
healthcare for the fear of stigma, insensitivity, and discrimination. Despite the availability of pre-
exposure prophylaxis (PrEP), concerns arise when it is co-administered with hormone therapy 
reducing uptake of PrEP among TGW. Moreover, those living with HIV are less likely to take ARVs 
or maintain adequate viral load suppression as TGW may prioritize hormone therapy first for fear 
that ARVs may compromise hormone therapy. 
1.2.2 Rationale for Dose Selection  
1.2.2.1 DOR/3TC/TDF 
DOR/3TC/TDF 100 mg/300 mg/300 mg was selected based on the approved doses marketed in 
the United States.  
1.2.2.2 17-Estradiol 
A maximum dose of 8mg/day oral estradiol was selected based on the Guidelines for the 
Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People published by 
the UCSF Transgender care at the University of California.19 
1.2.2.3 Spironolactone 
A maximum dose of 400 mg/day oral spironolactone was selected based on the Guidelines for 
the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People 
published by the UCSF Transgender care at the University of California. 
   
1.3 Rationale for Endpoints  
1.3.1 Pharmacokinetic/Pharmacodynamic Endpoints 
For estradiol, plasma estradiol concentrations were selected to estimate the PK parameters for 
estradiol exposure during feminizing hormone therapy. Serial PK sampling will determine the 


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interaction potential between DOR/3TC/TDF over a period of one dosing interval for both 
drugs.  
 
For DOR/TDF, plasma DOR/TDF concentrations were selected to estimate the PK parameters for 
DOR/3TC/TDF exposure when co-administered with hormone therapy. Serial PK sampling will  
determine the interaction potential between estradiol and DOR/TDF over a period of one 
dosing interval for both drugs.  
1.3.2 Safety Endpoints  
The safety for DOR/3TC/TDF, estradiol, and spironolactone has been established. This study will 
observe the safety and tolerability following co-administration with feminizing hormone 
therapy in healthy transgender women. Given the extensive experience of these drugs, it is not 
expected that the current study will be sensitive to detect new or uncommon safety events 
associated with co-administration.  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
2.1.1 Primary Objectives 
 Evaluate the plasma concentration-time profile, defined as AUC(0-last), AUC(0-inf), and Cmax 
of estradiol when co-administered with doravirine/lamivudine/tenofovir disoproxil 
fumarate.  
 Evaluate the plasma concentration-time profile, defined as AUC(0-last), AUC(0-inf), and Cmax, 
of doravirine and tenofovir disoproxil fumarate when co-administered with estradiol 
and spironolactone. 
2.1.2 Secondary Objective 
 Evaluate the safety and tolerability of doravirine/lamivudine/tenofovir disoproxil 
fumarate when co-administered with estradiol and spironolactone in transgender 
women.  
2.1.3 Exploratory Objective  
 Evaluate the change in plasma testosterone when doravirine/lamivudine/tenofovir 
disoproxil fumarate is co-administered with estradiol. 
2.2 Endpoints 
2.2.1 Primary Endpoint 
 Change in the estradiol plasma concentration-time profile, as defined by AUC(0-last), 
AUC(0-inf), and Cmax 
 Change in the doravirine and tenofovir disoproxil fumarate plasma concentration-time 
profile, as defined by AUC(0-last), AUC(0-inf), and Cmax 
 
2.2.2 Secondary Endpoint  


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Proportion of Participants experiencing adverse event(s) characterized by type, 
frequency, severity, timing and laboratory abnormalities- and tolerability of the co-
administered drugs.  
 
2.2.1 Exploratory Endpoint  
Change in plasma testosterone following doravirine/lamivudine/tenofovir disoproxil 
fumarate administration  
3 
STUDY DESIGN 
This is a prospective, single-center, placebo-controlled, three-period, cross-over, 
pharmacokinetic study investigating the bi-directional pharmacokinetic effect between 
doravirine/lamudine/tenofovir disoproxil fumarate and cross-sex hormones.  
 
Twelve healthy HIV-negative adult participants who identify as a transgender woman will be 
enrolled.  
 
Participants will be randomized into two sequences (6 participants per sequence). Participants 
will undergo treatment specific groups for each period with a 14-day washout in between 
periods I and II and II and III. In treatment A, a single dose of DOR/3TC/TDF 100 mg/300 mg/300 
mg will be administered alone. Participants will be dosing their standard-of-care hormone 
regimens together with placebo in treatment B. Lastly, Treatment C will be co-administration of 
DOR/3TC/TDF 100 mg/300 mg/300 mg together with standard-of-care hormone therapy. Figure 
1 displays the study schematic.  
4 
PARTICIPANT SELECTION 
4.1 Inclusion Criteria  
Participant eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.  
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:  
1. Healthy self-identified transgender women (male-to-female) between 18-45 years old at 
the time of screening  
2. Have not undergone an orchiectomy  
3. Receiving oral estradiol and spironolactone for > 3 months prior to study entry with a 
self-reported adherence to prescribed doses of > 90% 
4. Abstain from alcohol consumption throughout the duration of the study  
5. Be willing to briefly interrupt hormonal therapy prior to and during the study 
6. If on pre-exposure prophylaxis (PrEP) therapy containing tenofovir alafenamide or 
disoproxil fumarate, willing to discontinue PrEP at least 2 weeks before study start and 
for the duration of the study   


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7. Agree to use condoms for all sexual activity prior to the start and throughout the 
duration of the study 
8. Evidence of a personal signed and dated informed consent document indicating that the 
participant has been informed of all pertinent aspects of the study  
 
4.2 Exclusion Criteria 
Participants with any of the following characteristics or conditions will not be included in the 
study:  
1. Presence of clinically significant acute or chronic disease, that in the investigator’s 
opinion, would compromise the participant’s safety during the study  
2. Current use of any antiretroviral drug. This will not be exclusionary if participants 
reported discontinuing within 30 days of screening 
3. Creatinine clearance < 60 mL/min, as estimated by the Cockcroft-Gault equation 
4. Known anaphylactic or severe systemic reactions to any components of doravirine, 
lamivudine, or tenofovir disoproxil fumarate 
5. 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 
6. Recent significant blood or plasma donation  
7. Concomitant use of drugs, as deemed by the investigator, to have significant drug-drug 
interactions 
8. Received study drug in another study within 4 weeks or within 5 half-lives; whichever 
occurring first- before first anticipated dose of study drug in this study  
9. Unable to refrain from use of over-the-counter, prescription (unless determined 
appropriate by the investigator), herbal or natural products, vitamins or supplements, or 
grapefruit juice/grapefruit products 
10. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for 
participation in the study 
4.3 Study Drug and Adherence  
Enrolled participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study in order to be eligible for participation:  
1. If drinks alcohol, participant should have < 3 drinks per day  
2. With the exception of marijuana, illicit drugs, should be avoided throughout the study 
duration 
3. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements, unless at the opinion of the investigator, not compromise the safety of the 
participant  


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4.4 Participant Discontinuation and Withdrawal  
Participants may withdraw consent at any time for any reason. In addition, a participant may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Participants who miss any 
treatment dose will be discontinued from the study. Any participant who suffers a serious 
safety adverse events possibly- or probably-related-to study intervention will be discontinued. 
If more than three participants are discontinued due to possibly- or probably-related-to study 
intervention, the study will be terminated. 
4.4 Participant Replacement Strategy   
If a participant discontinues from the trial, a replacement participant may be enrolled if 
deemed appropriate by the investigators. The replacement participant will undergo the same 
treatment sequence (as appropriate) as the participant being replaced beginning at period I 
through period III.   
5 
STUDY INTERVENTIONS 
5.1 Treatment Drugs 
A fixed-dose combination product, doravirine/lamivudine/tenofovir disoproxil fumarate, will be 
used in this study. Participants will be using their standard of care hormone therapy consisting 
of estradiol and spironolactone.  
 
Table 1 highlights the dose, frequency, route of administration, and protocol regimen under 
investigation. 
 
Table 1: Dose, frequency, route of administration, and protocol regimen under investigation 
Drug 
Maximum 
Dose 
during 
the study 
Dosage 
Form 
Dosing 
Frequency 
Route of 
Administration 
Protocol Regimen 
Doravirine/ 
Lamivudine/ 
Tenofovir 
disoproxil 
fumarate 
100 mg/      
300 mg/      
300 mg 
Tablet 
Once-daily 
for one 
dose 
Oral 
One time dose for  
treatment groups 
A & C 
Estradiol 
8 mg 
Tablet 
4 mg twice-
daily for 
two doses 
Oral 
One time dose for 
treatment group B 
& C 
Spironolactone 400 mg 
Tablet 
200 mg 
twice-daily 
for two 
doses 
Oral 
One time dose for 
treatment group B 
& C 


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Placebo 
NA 
Tablet 
Once-daily 
for one 
dose 
Oral 
One time dose for 
treatment group B 
 
5.2 Treatment Allocation 
Participants will be screened using a screening number (SN) consisting of an alpha-numeric 
code starting with SN 1001. Allocation numbers will begin with 201. Replacement Participants 
will begin with allocation 301.  
6 
STUDY PROCEDURES 
6.1 Overview 
Procedures to be performed at each visit are summarized on the table of scheduled events. It 
may be necessary to perform study procedures at unscheduled time points if deemed clinically 
necessary by the investigator. Additional evaluations/testing may be deemed necessary by the 
investigator and or sponsor for reasons related to Participant safety. 
Trial procedures should be completed as close to the prescribed/scheduled time as possible.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
6.2 Informed Consent  
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion. A copy of the signed 
and dated consent form will be given to the participant before participation in the trial. The 
participant will be informed in a timely manner if new information becomes available that may 
be relevant to the participant’s willingness to continue participation in the trial.  The informed 
consent will adhere to institutional review board (IRB) requirements, applicable laws and 
regulations. 
6.2 Participant Recruitment and Screening  
Participants will be recruited through Jefferson Marketing Media advertisement.. Within 
approximately 4 weeks prior to randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements. Informed consent will be obtained from 
participants who elect to participate in the study. Consent form must be signed before any 
study related procedures are done. Participants will be asked to fast from food and drink, 
except water, for at least 8 hours prior to the screening visit labs being drawn. The following 
procedures/assessments will be performed during the screening visit:  
 Medical history 
 Vital signs 
 Physical examination  
 Electrocardiogram (ECG) 
 Concomitant medication review  


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 Laboratory safety tests including: 
o Complete blood count with differential and complete metabolic panel  
 Hepatitis B surface antigen, Hepatitis C antibody and HIV tests 
 Estradiol and testosterone level 
 Urine drug screen 
 Urinalysis 
 Estradiol/testosterone level 
6.3 Study Visit Schedule 
In addition to the procedures and assessments detailed below- adverse events and concomitant 
medication will be assessed. Any nonscheduled procedures required for urgent evaluation of safety 
concerns take precedence over all routine scheduled procedures.  
6.3.1 Treatment A (Sequence E, Period I): Administration of DOR/3TC/TDF Alone  
 
Study Day -14 
Participants will be scheduled to discontinue their hormone therapy -14 days before the initial 
study start date. Participants will be randomized 1:1 to either sequence E or F. 
 
 
Study Day -1  
Participants will report to the CRU in the morning. The following procedures/assessments will be 
performed: 
- 
Urine drug screen 
- 
Lab Safeties 
- 
Urinalysis 
- 
Physical exam  
- 
Vital signs 
- 
Estradiol PK  
 
 
Study Day 1 
Assessments: Vital signs, adverse events, and concomitant medication review prior to dosing 
Pre-Dose PK: A PK will be drawn prior to dosing of DOR/3TC/TDF (time 0 = pre-dose),  Physical 
exam (may be done up to 24 hours prior to dose) 
Pre-Dose Research Labs: Total testosterone will be drawn prior to dosing DOR/3TC/TDF (time 0 
= pre-dose) 
Dosing: Participants will be given only DOR/3TC/TDF (100mg/300mg/300mg) with 8 ounces of 
water in the morning following an 8-hour overnight fast.  
Post-Dose PK: PK will be drawn 0.5, 1, 2, 6, and 12 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn following DOR/3TC/TDF dose at 0.5, 
1, 2 and 6 hours post study day 1 dose 
 
 
Study Day 2 
Assessments: Adverse events and concomitant medication review  
Post-Dose PK: PK will be drawn 24 hours post study day 1 dose 
Post-Dose Research Labs: Total testosterone will be drawn 24 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and 24 hour post-dose PK 
 


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 
Study Day 3 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 48 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 48 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 4 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 72 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 72 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 5 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 96 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 96 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to not use hormone therapy for a washout period of 14 days  
 
6.3.2 Treatment A (Sequence F, Period III): Administration of DOR/3TC/TDF Alone  
 
Study Day -14 
Participants will have a 14 day washout from Period II prior to entry into period III 
 
 
Study Day -1  
Participants will report to the CRU in the evening. The following procedures/assessments will be 
performed: 
- 
Urine drug screen 
- 
Urinalysis 
- 
Physical exam  
- 
Vital signs 
- 
Estradiol PK  
 
 
Study Day 1 
Assessments: Vital signs, adverse events, and concomitant medication review prior to dosing 
Pre-Dose PK: A PK will be drawn prior to dosing of DOR/3TC/TDF (time 0 = pre-dose)  
Pre-Dose Research Labs: Total testosterone will be drawn prior to dosing DOR/3TC/TDF (time 0 
= pre-dose) 
Dosing: Participants will be given only DOR/3TC/TDF (100mg/300mg/300mg) with 8 ounces of 
water in the morning following an 8-hour overnight fast.  
Post-Dose PK: PK will be drawn 0.5, 1, 2, 6, and 12 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn following DOR/3TC/TDF dose at 0.5, 
1, 2 and 6 hours post study day 1 dose 
 


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 
Study Day 2 
Assessments: Adverse events and concomitant medication review  
Post-Dose PK: PK will be drawn 24 hours post study day 1 dose 
Post-Dose Research Labs: Total testosterone will be drawn 24 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and 24 hour post-dose PK 
 
 
Study Day 3 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 48 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 48 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 4 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 72 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 72 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to restart hormone therapy 
 
 
Study Day 5 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 96 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 96 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to restart hormone therapy 
 
6.3.3 Treatment B (Sequence E & F, Period II): Administration of Estradiol & Spironolactone  
 
Study Day -14 
Participants will have a 14 day washout from Period I prior to entry of period II 
 
 
Study Day -1  
Participants will report to the CRU in the evening. The following procedures/assessments will be 
performed prior to dosing: 
- 
Urine drug screen 
- 
Urinalysis 
- 
Physical exam  
- 
Vital signs 
- 
Estradiol PK  
Dosing: Participants will be given oral estradiol 4 mg and spironolactone 200 mg with 8 ounces 
of water in the evening following performed procedure/assessments  
 
 
Study Day 1 
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Pre-Dose PK: A PK will be drawn prior to dosing of estradiol and spironolactone (time 0 = pre-
dose)  
Pre-Dose Research Labs: Total testosterone and estradiol will be drawn prior to dosing estradiol 
and spironolactone (time 0 = pre-dose) 
Dosing: Participants will be given placebo + estradiol 4 mcg and spironolactone 200 mg with 8 
ounces of water  
Post-Dose PK: PK will be drawn at 2, 6, and 12 hours post study day 1 dose 
Post-Dose Research Labs: Total testosterone will be drawn following estradiol and 
spironolactone dosing at 0.5, 1, 2, and 6 hours post study day 1 dose  
 
 
Study Day 2 
Assessments: Adverse events and concomitant medication review  
Post-Dose PK: PK will be drawn 24 hours post study day 1 dose 
Post-dose Research Labs: Total testosterone will be drawn 24 hours post study day 1 dose  
Participants will be discharged from the CRU following assessments and 24 hour post-dose PK  
 
 
Study Day 3 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 48 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 48 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 4 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 72 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 72 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 5 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK: PK will be drawn 96 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 96 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to not use hormone therapy for a washout period of 14 days 
 
6.3.1 Treatment C (Sequence F, Period I): Administration of DOR/3TC/TDF + 
Estradiol/Spironolactone  
 
Study Day -14 
Participants will be scheduled to discontinue their hormone therapy -14 days before the initial 
study start date. Participants will be randomized 1:1 to either sequence E or F. 
 
 
Study Day -1  


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Participants will report to the CRU in the evening. The following procedures/assessments will be 
performed: 
- 
Urine drug screen 
- 
Urinalysis 
- 
Physical exam  
- 
Vital signs 
- 
Estradiol PK  
Dosing: Participants will be given oral estradiol 4 mg and spironolactone 200 mg with 8 ounces 
of water in the evening following performed procedure/assessments 
 
 
Study Day 1 
Assessments: Vital signs, adverse events, and concomitant medication review prior to dosing 
Pre-Dose PK: A PK will be drawn prior to dosing of DOR/3TC/TDF + estradiol and spironolactone 
(time 0 = pre-dose)  
Pre-Dose Research Labs: Total testosterone will be drawn prior to dosing DOR/3TC/TDF (time 0 
= pre-dose) 
Dosing: Participants will be given only DOR/3TC/TDF (100mg/300mg/300mg) + estradiol 4 mg 
and spironolactone 200 mg with 8 ounces of water in the morning following an 8-hour overnight 
fast.  
Post-Dose PK (Estradiol): PK will be drawn 0.5, 1, 2, and 12 hours post study day 1 dose  
Post-Dose PK (DOR/TDF): PK will be drawn 0.5, 1, 2, 6, and 12 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn following DOR/3TC/TDF dose at 0.5, 
1, 2 and 6 hours post study day 1 dose 
 
 
Study Day 2 
Assessments: Adverse events and concomitant medication review  
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 24 hours post study day 1 dose 
Post-Dose Research Labs: Total testosterone will be drawn 24 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and 24 hour post-dose PK 
 
 
Study Day 3 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 48 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 48 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 4 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 72 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 72 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to not use hormone therapy for a washout period of 14 days  
 
 
Study Day 5 


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Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 96 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 96 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to not use hormone therapy for a washout period of 14 days  
 
6.3.1 Treatment C (Sequence E, Period III): Administration of DOR/3TC/TDF + 
Estradiol/Spironolactone  
 
Study Day -14 
Participants will have a 14 day washout from Period I prior to entry of period II 
 
 
Study Day -1  
Participants will report to the CRU in the evening. The following procedures/assessments will be 
performed: 
- 
Urine drug screen 
- 
Urinalysis 
- 
Physical exam  
- 
Vital signs 
- 
Estradiol PK  
Dosing: Participants will be given oral estradiol 4 mg and spironolactone 200 mg with 8 ounces 
of water in the evening following performed procedure/assessments 
 
 
Study Day 1 
Assessments: Vital signs, adverse events, and concomitant medication review prior to dosing 
Pre-Dose PK: A PK will be drawn prior to dosing of DOR/3TC/TDF + estradiol and spironolactone 
(time 0 = pre-dose)  
Pre-Dose Research Labs: Total testosterone will be drawn prior to dosing DOR/3TC/TDF (time 0 
= pre-dose) 
Dosing: Participants will be given only DOR/3TC/TDF (100mg/300mg/300mg) + estradiol 4 mg 
and spironolactone 200 mg with 8 ounces of water in the morning following an 8-hour overnight 
fast.  
Post-Dose PK (Estradiol): PK will be drawn 0.5, 1, 2, and 12 hours post study day 1 dose  
Post-Dose PK (DOR/TDF): PK will be drawn 0.5, 1, 2, 6, and 12 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn following DOR/3TC/TDF dose at 0.5, 
1, 2 and 6 hours post study day 1 dose 
 
 
Study Day 2 
Assessments: Adverse events and concomitant medication review  
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 24 hours post study day 1 dose 
Post-Dose Research Labs: Total testosterone will be drawn 24 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and 24 hour post-dose PK 
 
 
Study Day 3 
Participants will arrive in the morning to the CRU 


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Assessments: Adverse events and concomitant medication review 
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 48 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 48 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures  
 
 
Study Day 4 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 72 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 72 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to restart hormone therapy  
 
 
Study Day 5 
Participants will arrive in the morning to the CRU 
Assessments: Adverse events and concomitant medication review 
Post-Dose PK (DOR/TDF + estradiol): PK will be drawn 96 hours post study day 1 dose  
Post-Dose Research Labs: Total testosterone will be drawn 96 hours post study day 1 dose 
Participants will be discharged from the CRU following assessments and procedures and advised 
to restart hormone therapy 
6.4 Domiciling 
Participants will be admitted to the CRU as outlined in the schedule of events.  
6.5 Clinical Procedures & Assessments  
6.5.1 Medical History  
Medical history of Participants participating in the study will be obtained by the investigator or 
co-investigator(s). 
6.5.2 Physical Examination  
The full physical examination includes evaluation of the head, eye, ear, nose and throat; the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological 
systems. The screening examination will also include height and weight for BMI calculation. 
6.5.3 12-Lead Electrocardiogram 
Participants will receive an ECG measurement for which they should remain supine for at least 
2 minutes. 
6.5.4 Vital Signs 
Participants should remain supine for at least 2 minutes prior to measurement of vital signs. 
Measurements include heart rate, blood pressure and respiratory rate. Oral or tympanic 
temperature will be checked during the screening visit and if needed by the discretion of the 
physician-investigator, during and after the study. 


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6.5.5 Laboratory Safety Evaluations 
Refer to Appendix 1 for the list of clinical laboratory tests. Laboratory tests will be performed at 
screening, during and after the study.  
 The investigator or medically qualified designee will review the laboratory report, 
document this review, and record any clinically relevant changes occurring during the 
study that meet the reporting requirements in the AE section of the CRF. The laboratory 
reports must be filled with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the participant’s 
condition.   
 For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after a protocol-specified procedure, every 
attempt should be made to perform repeat assessments until the values return to 
normal or baseline or if a new baseline is established as determined by the investigator. 
6.5.6 Prior and Concomitant Medications Review 
The investigator or designated personnel will review prior medication, vitamins or supplement 
use and record prior medication taken by the Participant within 4 weeks before starting the 
study. All medications, vitamins or supplements, if any, taken from screening visit until the after 
the study will be recorded.  
6.6 Study Restrictions 
6.6.1 Diet and Fruit Juice Restriction  
Participants must fast from food and drinks with the exception of water for 8 hours prior to the 
screening visit.  
6.6.2 Alcohol Restriction 
Alcohol consumption should be avoided during the study. However, if the participant drink 
alcohol, the participant should have < 3 drinks/day.   
6.6.3 Smoking Restriction 
Participants must continue to avoid smoking throughout the study up until the post-study visit.  
6.6.4 Activity Restrictions 
Participants will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the screening visit, throughout the trial until the post-trial visit. Participants 
may participate in light recreational activities during studies (eg, watching television, reading). 
6.7 Participant Identification Card 
All participants will be given a Participant Identification Card identifying them as participants in 
a research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 


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will provide the participant with a Participant Identification Card after their written informed 
consent. 
6.8 Standardized Meals 
Meals (Breakfast, lunch, dinner and snacks) will be provided to participants during the 
admission days. Participants will be fasting for at least 8 hours prior to all lab safety and prior to 
all dosing. Participants will fast 8 hours prior to dosing and 1 hour post dose for all study drugs.  
6.9 Study, Drug Dosing, and Procedure Modification Permitted 
Modifications to the dose, dosing regimen and clinical or laboratory procedures may be 
required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the study Participants.  As such, some alterations from the currently 
outlined schedule may be necessary. Additional laboratory safety tests may be drawn or added 
to blood samples previously drawn to obtain additional safety information (e.g., creatinine 
kinase to evaluate elevated AST/ALT). These changes may or may not increase the number of 
study procedures for a given participant during his/her participation in the entire study.   
6.10 Study Stopping Rules 
If one or more study participants are discontinued due to a serious safety adverse event, 
possibly- or probably- related to the study intervention, the study will be halted for review by 
the investigator along with the medical monitor and in consultation with the Global 
Pharmacovigilance group at Merck. An independent study physician will be assigned to the 
study. 
7 
POTENTIAL RISKS AND BENEFITS 
7.1 Potential Risks Associated with Doravirine 
The following most common adverse events (for All Grades) have been reported (> 5%) with the 
chronic use of doravirine in patients with HIV infection. The reported adverse event rates 
reflect chronic daily use together with other ARVs and are derived from large clinical trials in 
patients with HIV. Although these adverse event rates have been reported in patients, it may be 
possible that healthy volunteers may also experience these side effects under this protocol.   
 Central nervous system: 
o Altered sensorium (Doravirine + 3TC + TDF: 4%) 
 Defined as: altered state of consciousness, lethargy, somnolence, 
syncope  
o Sleep disorders and disturbances (Doravirine + 3TC + TDF: 12%)  
 Defined as: abnormal dreams, hyposomnia, initial insomnia, insomnia, 
nightmare, sleep disorder, somnambulism  
o Dizziness (Doravirine + 3TC + TDF: 9%)  
o Fatigue (4-6%) 
o Headache (4-6%)   
 Gastrointestinal:   


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o Nausea (5-7%) 
o Diarrhea (3-5%) 
 Laboratory abnormalities 
o Total bilirubin 1.1- < 1.6 x ULN (4-5%)  
Less commonly reported (< 2%) with chronic use of doravirine in patients with HIV on 
concomitant ARVs include: 
 Dermatologic 
o Rash (2%) 
 Laboratory abnormalities  
o Total bilirubin  
 1.6 - <2.6 x ULN (2%) 
 > 2.6 x ULN (<1%) 
o Creatinine (mg/dL) 
 >1.3- 1.8 x ULN or increase of >0.3 mg/dL above baseline (2-3%) 
 >1.8 x ULN or increase of 1.5 x above baseline (2%)  
o Aspartate aminotransferase (IU/L) 
 2.5 - <5.0 x ULN (2-4%) 
 > 5 x ULN (<1%) 
o Alanine aminotransferase (IU/L)  
 2.5 - <5.0 x ULN (3%) 
 > 5 x ULN (<1-1%) 
o Alkaline phosphatase (IU/L) 
 2.5 - <5.0 x ULN (<1%) 
o Lipase 
 1.5 - <3.0 x ULN (4-5%) 
 > 3 x ULN (1-3%) 
o Creatine Kinase (IU/L) 
 6 - <10 x ULN 2%) 
 >10 x ULN (2-3%) 
o Cholesterol, fasted (mg/dL) 
 >300 mg/dL (<1%) 
o LDL Cholesterol, fasted (mg/dL) 
 >190 mg/dL (<1%) 
o Triglycerides, fasted (mg/dL) 
 >500 mg/dL (<1%) 
7.1 Potential Risks Associated with Lamivudine  
The following most common adverse events (for All Grades) have been reported (> 5%) with the 
chronic use of lamivudine in patients with HIV infection. The reported adverse event rates 


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reflect chronic daily use together with other ARVs and are derived from large clinical trials in 
patients with HIV. Although these adverse event rates have been reported in patients, it may be 
possible that healthy volunteers may also experience these side effects under this protocol.   
 
Body as a Whole 
o Headache (35%) 
o Malaise & fatigue (27%) 
o Fever or chills (10%) 
 
Digestive 
o Nausea (33%) 
o Diarrhea (18%) 
o Nausea & vomiting (13%) 
o Anorexia and/or decreased appetite (10%) 
o Abdominal pain (9%) 
o Abdominal cramps (6%) 
o Dyspepsia (4%) 
o Flatulence (4%) 
 
Nervous System 
o Peripheral neuropathy (5%) 
o Insomnia (4%) 
o Dizziness (3%) 
o Depressive disorders (8%) 
 
Respiratory  
o Pneumonia (3%) 
 
Skin  
o rashes (9%) 
 
Musculoskeletal  
o Musculoskeletal pain (12%) 
o Myalgia (8%) 
o Arthralgia (5%) 
 
Laboratory abnormalities  
o Absolute neutrophil count (<750/mm3) (15%) 
Less commonly reported (< 2%) with chronic use of lamivudine in patients with HIV on 
concomitant ARVs include: 
 
Laboratory abnormalities  
o Hemoglobin (<8 g/L) (2.2%) 
o Platelets (<50,000/mm3) (2.8%) 
o ALT (>5.0 x ULN) (3.8%) 
o AST (>5.0 x ULN) (4.0%) 
o Bilirubin (>2.5 x ULN) (0.8%) 
o Amylase (>2.0 x ULN) (2.2%) 


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7.3 Potential Risks Associated with Tenofovir Disoproxil Fumarate  
The following most common adverse events (for All Grades) have been reported (> 3%) with the 
chronic use of tenofovir disoproxil fumarate in patients with HIV infection. The reported 
adverse event rates reflect chronic daily use together with other ARVs and are derived from 
large clinical trials in patients with HIV. Although these adverse event rates have been reported 
in patients, it may be possible that healthy volunteers may also experience these side effects 
under this protocol.   
 
Body as a Whole 
o Headache (8%) 
o Abdominal pain (7%) 
o Back pain (4%) 
o Chest pain (3%) 
o Fever (4%) 
 
Digestive 
o Nausea (11%) 
o Diarrhea (16%) 
o Vomiting (7%) 
o Dyspepsia (5) 
 
Nervous System 
o Neuropathy (12%) 
o Insomnia & other sleep disorders (11%) 
o Dizziness (10%) 
o Depressive disorders (9%) 
 
Respiratory  
o Nasal signs & symptoms (20%) 
o Cough (18%) 
 
Skin  
o Rash (7%) 
o Sweating (3%) 
 
Musculoskeletal  
o Myalgia (4%) 
 
Metabolic 
o Weight loss (4%) 
 
Laboratory abnormalities 
o Triglycerides (>750 mg/dL) (11%) 
o Creatine kinase (M: >990 U/L; F: >845 U/L) (12%) 
o Serum amylase (>175 U/L) (7%) 
o Glycosuria (>3+) (3%) 
o AST (M: >180 U/L; F: >170 U/L) (4%) 
o ALT (M: >215 U/L; F: >170 U/L) (4%) 
o Serum glucose (>250 U/L) (3%) 


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Less commonly reported (< 2%) with chronic use of tenofovir disoproxil fumarate in patients 
with HIV on concomitant ARVs include: 
 
Laboratory abnormalities  
o Neutrophils (<750/mm3) (2%) 
10 
SAFETY, ADVERSE EVENTS (AE) & SERIOUS ADVERSE EVENTS (SAE) 
10.1 Definitions  
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing 
causality of AE and SAE and the procedures for completing and transmitting AE, SAE, and other 
reportable safety event reports can be found in Appendix 2. Adverse events, SAEs, and other 
reportable safety events will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety events 
for outcome.  
The investigator, who is a qualified physician, will assess events that meet the definition of an 
AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality. 
10.1.1 Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a Participant administered 
an investigational product that occurs during the conduct of a clinical trial and does not 
necessarily have a causal relationship with the study drug(s). This can be any unfavorable and 
unintended physical sign, symptom, laboratory parameter or disease entity that develops or 
worsens in severity during the course of the trial whether considered related to study drug or 
not. Adverse events can include any of the following:  
 
 All suspected adverse medication reactions. This includes events possibly related to any 
concomitant medication use 
 Physical Injuries or accidents. If a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) will be reported as two separate adverse events. 
 Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test). 
 Drug interactions 
 Onset or worsening of preexisting clinical illness 
 Laboratory or diagnostic test abnormality that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 


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with an already reported clinical event. A clinical laboratory abnormality should be 
documented as an adverse event if any one of the following conditions is met:  
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a degree that requires active management; e.g. more 
frequent follow-up assessments, further diagnostic investigation, etc.  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed will be reported if it meets the definition of an adverse event. 
 
All adverse events will be assessed and recorded from the time Participant is enrolled into the 
study until the post-trial visit. At each contact with the Participant, the investigator or study 
personnel must seek information on adverse events by specific questioning and, as appropriate, 
by examination. Information on all adverse events, including degree of severity and relationship 
to study agent, should be recorded immediately in the source document. 
10.1.2 Serious Adverse Event (SAE) 
An SAE is an event that is not an AE per definition above, resulting in death, is life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, is a congenital anomaly or any other important 
medial events.  SAEs must be reported using the Serious Adverse Event Form. All events that 
meet the definition of a serious adverse event will be reported as serious adverse events, 
regardless of whether they are protocol-specific assessments. 
10.2 Assessing and Recording AEs & SAEs 
All adverse events, whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained until completion of the participant's last study-related procedure, which 
may include contact for follow-up of safety.  
 
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g. cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection").  
 
Investigators must record in the CRF their opinion concerning the relationship of the adverse 
event to study therapy. All measures required for adverse event management must be 
recorded in the source document and reported. 
During the outpatient phase the Participant will be provided with a "wallet (study) card" and 
instructed to carry this card with them for the duration of the study indicating the following:  


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 Study number 
 Statement that the Participant is participating in a clinical study 
 Investigator's name and 24-hour contact telephone number 
 Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
10.3 Data Safety Monitoring Plan  
The investigators will oversee the safety of the study. This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above. Independent medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
A Medical Monitor will be assigned to this study. This will be a physician who is not directly 
involved in the study and is not currently a principal investigator on any other sponsored Merck 
trial. The role of the Medical Monitor is to review all reportable AEs/SAEs including grading, 
toxicity assignments, non-reportable AEs, protocol violations/deviations, as well as all other 
safety data and activity data. The Medical Monitor may recommend reporting of adverse 
events and relevant safety data, and may also recommend suspension or termination of the 
study to the investigators and IRB. 
11 
STATISTICAL AND PHARMACOKINETIC METHODS 
11.1 Sample Size Estimation 
Sample size was determined from the published within-Participant variability in the 
pharmacokinetic parameters, AUC and Cmax, for estradiol, doravirine, and tenofovir disoproxil 
fumarate (Table 2). A sample size of 10 (G*Power version 3.1.9.2, University of Kiel, Germany) 
was determined to provide 80% power to reject the null hypothesis that the mean ratios for 
estradiol and doravirine/tenofovir disoproxil fumarate (in both directions) will fall below or 
above the no-effect boundaries defined as 80-125%, respectively. The calculation assumes a 
mean ratio of 1 (no-effect) for the bi-directional interacting drugs with a two-sided significance 
level of 0.05.   
 
No-effect boundaries were chosen based on the US Food and Drug Administration Guidance on 
Clinical Drug Interaction Studies. The standard deviation of the paired difference was calculated 
assuming independence between reference drug (estradiol or doravirine/tenofovir disoproxil 
fumarate) and co-administered drug. For calculation of standard deviations, a standard normal 
distribution was assumed for studies with n>60. A t-distribution was used for studies with n<60. 
 
Table 2. Published within-Participant standard deviations pharmacokinetic parameters and 
corresponding number of Participants to reject the null hypothesis with 80% power.   
 
 
Drug 
Within-Participant standard deviation 
 
Number of 
Participants 
 
 
Reference 
Cmax 
AUC 
Doravrine 
0.18 
0.17 
10 
20 
Tenofovir disoproxil 
fumarate 
0.11 
0.09 
5 
21 


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Estradiol 
0.26 
0.24 
10 
22 
 
11.2 Pharmacokinetic Analysis  
Plasma concentrations of DOR and TDF will be used to calculate the PK parameters for each 
Participant in the presence or absence of estradiol and spironolactone. Similarly, plasma 
concentrations of estradiol will be used to calculate the PK parameters for each Participant in 
the presence or absence of DOR/3TC/TDF.  
 
Analysis will be conducted via a non-compartmental analysis. Parameters of interest include the 
area under the concentration-time point from time zero extrapolated to infinity (AUC0-inf), AUC0-
last, maximum concentration (Cmax), minimum concentration at 24 hours (surrogate for efficacy), 
time to maximum concentration (Tmax), apparent oral clearance (CL/F) and the apparent half-
life (t1/2) for each participant. The AUC0-last will be computed using the linear-up, log-down 
trapezoidal integration method. A log-linear regression using the least-squares method will be 
employed to estimate other parameters of interest including the terminal half-life generated 
from the plasma concentration time-curve.  
The primary endpoint will be pharmacokinetic and therefore be measured as the exposure 
parameters AUC0-last, Cmax and Ctrough 
11.3 Statistical Analysis of Pharmacokinetic Parameters  
Estradiol pharmacokinetic parameter estimates computed before and after DOR/3TC/TDF 
dosing will be compared using a paired student’s t-test. Statistical significance will be defined as 
a p-value <0.05. Geometric mean ratio (GMRs) will be estimated for estradiol. An analysis of 
variance model will be performed with 90% confidence intervals around the GMRs between 
reference (estradiol alone) and test (estradiol + DOR/3TC/TDF) will be constructed and 
compared to the no-effect boundaries (0.8, 1.25). 
 
DOR/TDF pharmacokinetic parameter estimates computed before and after estradiol dosing 
will be compared using a paired student’s t-test. Statistical significance will be defined as a p-
value <0.05. Geometric mean ratio (GMRs) will be estimated for DOR/TDF. An analysis of 
variance model will be performed with 90% confidence intervals around the GMRs between 
reference (DOR/TDF alone) and test (DOR/3TC/TDF + estradiol) will be constructed and 
compared to the no-effect boundaries (0.8, 1.25).  
11.4 Safety Analysis  
Safety and tolerability assessments will be clinically reviewed for any adverse events and 
include safety lab, vital signs, and physical exam beyond the pre-defined limit of change. 
Assessment will be performed for all participants enrolled into this study.  
Safety results will be summarized and tabulated using descriptive statistics. Results will be 
reported as the proportion of Participants experiencing an adverse event.  


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12 
ETHICS AND PROTECTION OF HUMAN PARTICIPANTS 
12.1 Institutional Review Board Review 
The principal investigator must provide the IRB with all appropriate materials, including a copy 
of the patient informed consent form. The study will not be initiated until the principal 
investigator obtains written approval of the protocol and the patient ICF from the IRB. 
Appropriate reports on the progress of this study will be made by the principal investigator to 
the IRB and medical monitor in accordance with government regulations.   
12.2 Informed Consent  
The ICH Tripartite Guideline for Good Clinical Practice establishes the general requirements for 
informed consent. Each participant will be provided with oral and written information in a 
language they can understand that describes the nature and duration of the study. Before 
undergoing screening, each Participant must consent in writing to study participation. The 
Participant will sign and personally date the patient ICF. The person rendering consent will also 
sign and personally date the ICF as the person who obtained the consent of the Participant. Each 
Participant will receive a copy of his or her signed ICF. 
12.3 Participant Confidentiality 
All records will be kept in a locked filing cabinet located in the offices of the Department of 
Pharmacology and Experimental Therapeutics in 1170 Main Building. All computer entry and 
networking programs will be performed with coded numbers only; no PHI will be entered into 
the eCRF. Clinical information will not be released without written permission of the patient, 
except as necessary for monitoring by the medical monitor, IRB, or the FDA, or other medical 
practitioner to ensure the safety and appropriate medical management of the patient in the 
event of a AE/SAE.    
 
 


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13 
SUPPORTING DOCUMENTATION   
13.1 Appendix 1: Time Windows for Serial Assessments and Dosing  
 
Sampling Window  
Sampling Timepoint (Hours) 
Sampling Window (Minutes) 
Pre-dose (DOR/3TC/TDF, estradiol, and 
spironolactone) 
-30 minutes to 0 hour 
 
 
> 0 hour – 4 hours 
-10 minutes to +10 minutes 
> 4 hours – 24 hours 
-15 minutes to +15 minutes 
> 24 hours – 96 hours 
-30 minutes to +30 minutes 
 
Dosing Window 
Dosing Timepoint  
Dosing Window (Minutes) 
DOR/3TC/TDF (Treatment A and Treatment C) 
0 hour 
Estradiol and Spironolactone (first dose) 
0 hour 
Estradiol and Spironolactone (second dose) 
+ 30 minutes from actual 0 hour time. Take this 
within 5 minutes of DOR/3TC/TDF for TX C. 
 
Pre-Dose Assessment Window 
Assessment 
Assessment Window (Minutes) 
Physical Exam 
-24hours 
Vital Signs 
-60 minutes to 0 hour 
CBC/Chemistry 
-24 hours 
Estradiol/Total testosterone( day 1 pre-dose) 
-30 minutes to 0 hour 
Estradiol/Total testosterone( day 1 post-dose) 
Same as DOR/3TC/TDF sampling windows 
 
13.2 Appendix 2: Clinical Laboratory Tests   
 Tests detailed in table 3 will be performed by Thomas Jefferson University Hospital – 
Clinical Chemistry Laboratories  
 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.  
Table 3: Protocol required laboratory assessments 
Laboratory 
Assessment 
Parameter  
Hematology 
 Platelet count 
 Hemoglobin 
 Hematocrit  
 WBC with differential  
 Partial thromboplastin time  
 Prothrombin time  
Chemistry 
 Albumin 


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 Calcium 
 Chloride 
 Bicarbonate 
 Phosphorus 
 Potassium  
 Sodium 
 Creatinine  
 Total Bilirubin 
 Direct bilirubin (If total bilirubin is elevated above the upper limit of 
normal) 
 Total protein  
 Blood urea nitrogen 
 Glucose  
 Aspartate Aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Alkaline phosphatase  
Urinalysis 
 Specific gravity  
 Microscopic examination (if blood or protein is abnormal)  
 Blood 
 Glucose 
 Specific gravity  
Other Laboratory 
Tests  
 Serology (Hepatitis B surface antigen [HBsAg] and hepatitis C virus 
antibody). Hepatitis C viral load may additionally be assessed as 
confirmation for participants with a positive antibody test 
 Human immunodeficiency virus screen 
 Urine drug screen to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines 
 Blood alcohol level  
 Testosterone level 
 Estradiol level 
 
 
 


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13.3 Appendix 3: Adverse Events: Definitions and procedures for Recording, Evaluating, 
Follow-up and Reporting 
13.3.1 Definition of AE  
 An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the procedural study intervention, whether or not considered related to 
the procedural study intervention  
 An AE can therefore any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the procedural study intervention 
Events meeting the AE definition  
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, vital signs, or measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator 
 New conditions detected or diagnosed after conduct of the procedural study 
intervention even though it may have been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of a concomitant 
medication 
 For all reports of overdose (whether accidental or intentional) with an associated AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported 
using the terminology “accidental or intentional overdose without adverse effect.” 
Events NOT meeting the AE definition 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
13.3.2 Definition of SAE  
 If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
 An SAE is defined as any untoward medical occurrence that: 
o Results in death  
o Is life threatening  
 The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant was at risk of death at the time of the 


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event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe 
o Requires inpatient hospitalization or prolongation of existing hospitalization 
 Hospitalization is defined as an inpatient admission, regardless of length 
of stay, even if the hospitalization is a precautionary measure for 
continued observation. (Note: Hospitalization for an elective procedure 
to treat a pre-existing condition that has not worsened is not an SAE. A 
pre-existing condition is a clinical condition that is diagnosed prior to 
study intervention and is documented in the participant’s medical 
history. 
o Results in persistent or significant disability/incapacity  
13.3.3 Additional Events Reported 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious 
per ICH definition, are reportable: 
 Is a cancer 
 Is associated with an overdose of medication  
13.3.4 Recording AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g. hospital progress notes, laboratory and diagnostic reports) related to the event. The 
investigator will record all relevant AE/SAE information on the AE CRFs at each examination. 
The investigator will attempt to establish a diagnosis of the vent based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.  
Assessment of intensity/toxicity  
 An event is definied as “serious” when it meets at least 1 of the pre-defined outcomes 
as described in the definition of an SAE, not when it is rated as severe  
 The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:  
o Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities  
o Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities  
o Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
 


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Assessment of causality  
The determination of the likelihood that the study intervention caused the AE will be provided 
by an investigator who is a qualified physician. The investigator’s signed/dated initials on the 
source document that supports the causality noted on the AE form, ensures that medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the study 
intervention and the AE based upon the available information.  
The following components are to be used to assess the relationship between the study 
intervention and the AE:  
 Time Course: Did the AE follow in a reasonable temporal sequence from the study 
intervention? 
 Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors. 
 Consistency with study intervention: Is the clinical/pathological presentation of the AE 
consistent with previous knowledge regarding the procedural study intervention? 
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. Use the following scale of criteria as guidance (not all 
criteria must be present to be indicative of a procedural study intervention relationship). 
 Yes, there is a reasonable possibility of study intervention relationship: 
o The temporal sequence of the AE onset relative to the study intervention is 
reasonable. The AE is more likely explained by the study intervention than by 
another cause 
 No, there is not a reasonable possibility of procedural study intervention relationship: 
o Temporal sequence of the AE onset relative to study intervention is not 
reasonable OR the AE is more likely explained by another cause than the study 
Follow up of an AE or SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
13.4 Supplemental Material 
Lab manual of bio-specimen handling  
Bio-specimen sample chain of custody shipment and manifest 
Case Report Forms 


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Source Documents 
Data Management and Clinical Monitoring Plan 
Pharmacy Repackaging Manual    
 
 


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14 
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