I-BrEATHe - Interactions Between Antiretrovirals And Transgender Hormones
Phase: PHASE4
Conditions: HIV Prevention, Transgender Health
Sponsor: University of California, San Francisco

Study of Truvada for HIV Pre Exposure Prophylaxis Using Daily Directly 
Observed Therapy to Look at Potential Interactions Between Truvada 
and Hormone Therapy 
 
NCT04050371 
 
Document Date: March 15, 2018 
 

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I-BrEATHe - Interactions BEtween Antiretrovirals And Transgender 
Hormones:
A Pharmacokinetic sub study of the TRIUMPH study
Protocol 
Number:
N/A
Version Date:
1.3 – 15-March-2018
Investigational 
Product:
N/A
IND Number:
N/A
Development 
Phase:
FDA approved
Sponsor:
Robert M. Grant, MD, MPH 
1650 Owens Street, San Francisco, CA 94158
Madeline B. Deutsch, MD, MPH
2356 Sutter St, San Francisco, CA 94143
Funding 
Organization:
University of California Office of the President, via the 
California HIV/AIDS Research Program (UCOP via CHRP)
Principal 
Investigator:
Name:
Robert M Grant 
Telephone:
415-350-8909
E-mail:
Robert.Grant@ucsf.edu 
Co -Principal 
Investigator:
Name:
Madeline B. Deutsch 
Telephone:
415-797-7136
E-mail:
Madeline.Deutsch@ucsf.edu 

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Approval:
PI/Sponsor Signature (Name and Title) 
Date

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This confidential information about the protocol is provided for the exclusive use of investigators of 
this protocol and is participant to recall at any time.  The information in this document may not be 
disclosed unless federal or state law or regulations require such disclosure.  Participant to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  

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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and 
providing Drs. Robert Grant and Madeline Deutsch with complete and timely information, 
as outlined in the protocol.  It is understood that all information pertaining to the study 
will be held strictly confidential and that this confidentiality requirement applies to all 
study staff at this site. Furthermore, on behalf of the study staff and myself, I agree to 
maintain the procedures required to carry out the study in accordance with accepted GCP 
principles and to abide by the terms of this protocol.
Protocol Number:  N/A
Protocol Title: I-BrEATHe - Interactions BEtween Antiretrovirals And Transgender 
Hormones.
Protocol Date:  22Mar2017
Investigator Signature 
Date
Print Name and Title
Site #
N/A
Site Name
San Francisco AIDS Foundation
Address
1035 Market Street
San Francisco, CA 94103
Phone Number

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TABLE OF CONTENTS
1
PROTOCOL TEAM AND SITE....................................................................................11
1.1
PROTOCOL TEAM ROSTER .............................................................................................11
1.2
RESEARCH FACILITIES...................................................................................................12
1.3
CLINICAL LABORATORIES .............................................................................................13
1.4
RESEARCH LABORATORIES............................................................................................13
1.5
INSTITUTIONAL REVIEW BOARD ...................................................................................14
2
BACKGROUND ............................................................................................................15
2.1
OVERVIEW OF NON-CLINICAL STUDIES ........................................................................16
2.2
OVERVIEW OF CLINICAL STUDIES .................................................................................16
3
STUDY RATIONALE ...................................................................................................16
3.1
RISK / BENEFIT ASSESSMENT ........................................................................................17
4
STUDY OBJECTIVES ..................................................................................................18
4.1
PRIMARY OBJECTIVE.....................................................................................................18
4.2
SECONDARY OBJECTIVES......................................................................................................18
5
STUDY DESIGN.................................................................................................................18
5.1
STUDY OVERVIEW ..............................................................................................................18
5.2
PHARMACOGENETIC TESTING ...............................................................................................19
6
CRITERIA FOR EVALUATION..................................................................................19
6.1
PRIMARY ENDPOINT ......................................................................................................19
6.2
SECONDARY ENDPOINTS ...............................................................................................19
6.3
SAFETY EVALUATIONS ..................................................................................................19
7
PARTICIPANT SELECTION.......................................................................................19
7.1
STUDY POPULATION ......................................................................................................19
7.2
INCLUSION CRITERIA:..........................................................................................................19
7.3
EXCLUSION CRITERIA....................................................................................................20
7.4
ELIGIBILITY DETERMINATION........................................................................................20
7.5
RECRUITMENT AND RETENTION.....................................................................................21
7.5.1
Study site ...................................................................................................................21
7.5.2
Recruitment ...............................................................................................................21
7.5.3
Retention ...................................................................................................................22
8
CONCURRENT MEDICATIONS.................................................................................22
8.1
ALLOWED MEDICATIONS AND TREATMENTS ...........................................................................22
8.2
PROHIBITED MEDICATIONS AND TREATMENTS ........................................................................22
9
STUDY TREATMENT..................................................................................................23
9.1
METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ................................23
9.2
FTC/TDF.......................................................................................................................23
9.2.1
FTC/TDF Formulation..............................................................................................23
9.2.2
FTC/TDF and pregnancy..........................................................................................23
9.2.3
Packaging and Labeling............................................................................................23
9.3
SUPPLY OF STUDY DRUG AT THE SITE.....................................................................................23
9.3.1
Storage ......................................................................................................................24
9.4
DISPENSATION OF STUDY DRUG AT THE SITE ...............................................................24
9.4.1
Dosage/Dosage Regimen ..........................................................................................24

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9.4.2
Dispensing.................................................................................................................24
9.4.3
Administration Instructions.......................................................................................24
9.4.4
Participant Replacement Instructions .......................................................................25
9.5
STUDY DRUG ACCOUNTABILITY ...................................................................................25
9.6
MEASURES OF TREATMENT ADHERENCE ......................................................................25
10
STUDY PROCEDURES AND GUIDELINES...............................................................25
10.1
CLINICAL ASSESSMENTS ...............................................................................................25
10.1.1
Concomitant Medications .....................................................................................25
10.1.2
Demographics.......................................................................................................26
10.1.3
Medical History ....................................................................................................26
10.1.4
Physical Examination ...........................................................................................26
10.1.5
Vital Signs.............................................................................................................26
10.1.6
HIV Rapid Test......................................................................................................26
10.1.7
Counselling around daily DOT.............................................................................26
10.1.8
Adverse Events......................................................................................................26
10.1.9
Drug and Alcohol Use assessment........................................................................27
10.1.10
Pregnancy test.......................................................................................................27
10.2
CLINICAL LABORATORY MEASUREMENTS....................................................................27
10.2.1
Blood Chemistry Profile........................................................................................27
10.2.2
Kidney function Profile.........................................................................................27
10.2.3
Hormonal Therapy Profile....................................................................................27
10.2.4
Serology testing.....................................................................................................27
10.2.5
HIV infection testing .............................................................................................27
10.2.6
Off protocol testing ...............................................................................................27
10.3
RESEARCH LABORATORY MEASUREMENTS ..................................................................28
10.3.1
Pharmacokinetic Measurements ..........................................................................28
10.3.2
Hormonal Therapy Profile.....................................................................................28
10.3.3
Genetic testing......................................................................................................28
10.4
VIDEO DOSING ASSESSMENTS .......................................................................................28
11
EVALUATIONS BY VISIT....................................................................................................29
11.1
PHONE OR REFERRING CLINIC PRE SCREENING ..............................................................29
11.2
VISIT 1 (SCREENING VISIT) ............................................................................................29
11.3
VISIT 2 (WEEK 0 OR ENROLMENT, WITHIN 28 DAYS OF SCREENING)..............................29
11.4
VISIT 3 (WEEK 1, 2 AND 3, VISIT WINDOW PLUS OR MINUS 2 DAYS)..............................30
11.5
VISIT 4 (WEEK 4 OR END OF STUDY, VISIT WINDOW PLUS OR MINUS 2 DAYS)...............30
11.6
EARLY WITHDRAWAL VISIT..........................................................................................30
12
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................31
12.1
ADVERSE EVENTS..........................................................................................................31
12.2
SERIOUS ADVERSE EXPERIENCES (SAE).......................................................................32
12.2.1
Serious Adverse Experience Reporting.................................................................33
12.2.2
Suicidal ideation ...................................................................................................33
12.3
MEDICAL MONITORING .................................................................................................33
13
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS .........................33
13.1
EARLY DISCONTINUATION OF STUDY DRUG.................................................................33
12.3
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY ..................................................................34
12.4
REPLACEMENT OF PARTICIPANTS ..........................................................................................34

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14
PROTOCOL VIOLATIONS .........................................................................................34
15
STATISTICAL METHODS AND CONSIDERATIONS ..............................................35
15.1
DATA SETS ANALYZED..................................................................................................35
15.2
DEMOGRAPHIC AND BASELINE CHARACTERISTICS.......................................................35
15.3
ANALYSIS OF PRIMARY ENDPOINT................................................................................35
15.4
SAMPLE SIZE..................................................................................................................35
16
DATA COLLECTION, RETENTION AND MONITORING.......................................36
16.1
DATA COLLECTION INSTRUMENTS................................................................................36
16.2
DATA MANAGEMENT PROCEDURES ..............................................................................36
16.3
DATA QUALITY CONTROL AND REPORTING..................................................................36
16.4
ARCHIVAL OF DATA ......................................................................................................36
16.5
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ................................37
16.6
MONITORING .................................................................................................................37
16.7
PARTICIPANT CONFIDENTIALITY...................................................................................37
17
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS...................37
17.1
PROTOCOL AMENDMENTS .............................................................................................38
17.2
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES ...............38
17.3
INFORMED CONSENT FORM...........................................................................................38
17.4
PUBLICATIONS...............................................................................................................39
17.5
INVESTIGATOR RESPONSIBILITIES .................................................................................39
18
REFERENCES ..............................................................................................................42

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LIST OF ABBREVIATIONS
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ART
Antiretroviral Therapy
CoE-T
Center of Excellence for Transgender Health
CFR
Code of Federal Regulations
CRF
Case Report Form
DMC
Data Monitoring Committee
DOT
Directly Observed Therapy
DSMB
Data Safety Monitoring Board
FDA
Food and Drug Administration
FTC
Emtricitabine
FTC/TDF
Emtricitabine/ Tenofovir disoproxil fumarate
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
HIV
Human Immunodeficiency Virus
HT
Hormone Therapy
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
iPrEx
iniciativa Profilaxis Pre-Exposición
IRB
Institutional Review Board
MSM
Men who have Sex with Men
PI
Principal Investigator
PK
Pharmacokinetic
PrEP 
Pre-Exposure Prophylaxis
RCT
randomized controlled trial
SAE
Serious Adverse Event
TDF
Tenofovir disoproxil fumarate
TFV-DP
Tenofovir diphosphate
UCSF
University of California, San Francisco
ULN
upper limit of normal

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PROTOCOL SYNOPSIS
TITLE
I-BrEATHe - Interactions BEtween Antiretrovirals And Transgender 
Hormones.
SPONSOR
Robert M. Grant and  Madeline B. Deutsch
FUNDING 
ORGANIZATION
University of California Office of the President via the California 
HIV/AIDS Research Program
NUMBER OF SITES
1
RATIONALE
Drug concentrations after receipt of oral Truvada Pre Exposure 
Prophylaxis (or PrEP) appeared to be lower in transgender women 
compared to Men who Have Sex with Men (MSM) in the iPrEx study. 
Reasons for the lower drug concentrations may be behavioral or 
biomedical, or a combination of both. There are few to no studies 
which investigate the potential drug to drug interactions between the 
components of Truvada (emtricitabine or FTC and tenofovir disproxil 
fumarate or TDF) and feminizing hormones. In addition, no PrEP 
studies have ever included transgender men; therefore no knowledge 
exists on the potential interactions between FTC/TDF and 
masculinizing hormones. 
The pharmacokinetic study, using directly observed therapy (DOT), is 
designed to address the question whether feminizing or masculinizing 
hormones affect FTC/TDF levels in transgender women or 
transgender men respectively.
STUDY DESIGN
This is a pharmacokinetic study
PRIMARY 
OBJECTIVE
Assess pharmacokinetic drug-drug interactions between tenofovir 
disoproxil fumarate/emtricitabine (TDF/FTC) and cross-sex hormone 
therapy.
SECONDARY 
OBJECTIVES
Assess Adverse Events related to TDF/FTC in transgender men and 
women and compare to historical controls in non trangender MSM
NUMBER OF 
PARTICIPANTS
48 (24 transgender women and 24 transgender men)
PARTICIPANT 
SELECTION
CRITERIA
Inclusion Criteria: 
All subjects:
•
HIV antibody seronegative (negative HIV rapid test),
•
18 years or older,
•
Has a smart phone with access to two-way video call 
capability,
•
Willingness to be contacted for a short call every day for 4 
weeks,

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•
Adequate renal function (creatinine clearance ≥ 60 ml/min 
estimated by the Cockcroft Creatinine Clearance Formula), 
•
Provides written informed consent,
For Transgender women:
•
Assigned male sex at birth, and self-reported current gender 
identity as “woman” or “transgender women”, or other trans-
feminine spectrum identity, 
•
Current feminizing Hormone Therapy (HT) use for at least 6 
months
For Transgender men:
•
Assigned female sex at birth, and self-reported current gender 
identity as “man” or “transgender man”, or other trans-
masculine spectrum identity,
•
Current masculinizing Hormone Therapy (HT) use for at least 
6 months with testosterone.
Exclusion Criteria:
•
Expects to change or discontinue current HT use during the 4 
weeks study period,
•
Signs of symptoms of acute viral syndrome,
•
Use of FTC or TDF in the past 90 days
•
Receiving ongoing therapy with any of the following: ART, 
including nucleoside analogs, non-nucleoside reverse 
transcriptase inhibitors, protease inhibitors or investigational 
antiretroviral agents, interferon (alpha, beta, or gamma) or 
interleukin (e.g., IL-2) therapy, aminoglycoside antibiotics, 
amphotericin B, cidofovir, systemic chemotherapeutic agents, 
other agents with significant nephrotoxic potential, other 
agents that may inhibit or compete for elimination via active 
renal tubular secretion (e.g., probenecid), and/or other 
investigational agents
•
Renal insufficiency documented as Creatinine Clearance < 60 
ml/min
•
For masculine-spectrum identifying persons, positive 
pregnancy test at screening
•
At enrollment, has any other condition that, based on the 
opinion of the investigator or designee, would preclude 
provision of informed consent; make participation in the study 

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unsafe; complicate interpretation of study outcome data; or 
otherwise interfere with achieving the study objectives.
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
FDA approved Truvada (one tablet containing 200 mg of 
emtricitabine or FTC and 300 mg of tenofovir disoproxil fumarate or 
TDF) once daily taken orally with or without food. Gilead Sciences 
will dispense medication to through their FDA approved commercial 
packaging of 30 tablets per bottle with an included desiccant.
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
N/A
DURATION OF 
PARTICIPANT 
PARTICIPATION 
AND DURATION OF 
STUDY
Participants will be on study for up to 56 days
Screening:  up to 28 days
Treatment:  4 weeks or 28 days (participants come to clinic weekly 
and DOT via video calls)
Follow-up:  n/a
The total duration of the study is expected to be 7-9 months:  1-3 
months for participant recruitment and 6 for final participant follow-
up.
CONCOMMITANT 
MEDICATIONS
Allowed:
Testosterone, estradiol, spironolactone, 
Prohibited: 
ART, including nucleoside analogs, non-nucleoside reverse 
transcriptase inhibitors, protease inhibitors or investigational 
antiretroviral agents, interferon (alpha, beta, or gamma) or interleukin 
(e.g., IL-2) therapy, aminoglycoside antibiotics, amphotericin B, 
cidofovir, systemic chemotherapeutic agents, other agents with 
significant nephrotoxic potential, other agents that may inhibit or 
compete for elimination via active renal tubular secretion (e.g., 
probenecid), and/or other investigational agents
EFFICACY 
EVALUATIONS
N/A
PRIMARY ENDPOINT
Concentrations of FTC triphosphate and tenofovir diphosphate (TFV-
DP) in Dried Blood Spots (DBS)
SECONDARY 
ENDPOINTS
N/A
OTHER 
EVALUATIONS
N/A

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SAFETY 
EVALUATIONS
Incidence of adverse events (AEs will be collected as part of the 
weekly visit if participants report AEs)
PLANNED INTERIM 
ANALYSES 
N/A
STATISTICS
Primary Analysis Plan
We will compare levels of Tenofovir DiPhosphate (TFV-DP), the 
phosphorylated active tenofovir molecule in dried blood spots and 
rates of adverse events between trans men and trans women and a 
group of MSM historical controls from the iPrEx OLE study.  We will 
compare log transformed TFV-DP levels using  a linear mixed effects 
model with factors for group (trans men v. trans women v. MSM) and 
times (1, 2, 3 and 4 weeks after initiation) and their interaction with an 
unstructured covariance across visits and test for differences at 
between groups at each time point. If values appear to violate the 
normal distribution, we will obtain p-values and confidence intervals 
using the bootstrap. All p-values will be two-sided with p-value < 
0.05 considered statistically significant. Adverse events will be 
compared using the Fisher exact test.
Rationale for Number 
of Participants
A sample size of 48 (24 trans women and 24 trans men) allows 
detection of a difference of 0.52 log difference (1.68 fold difference) 
in TFV-DP from dried blood spots with 81% power on a two-sided 
0.05 level test at any time point between our trans participants and 
MSM historical controls. A difference of 0.70 log (2.0 fold difference) 
can be detected between either group (trans men or women), and 
MSM historical controls with 80% power on a two-sided 0.05 level 
test.

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1
PROTOCOL TEAM AND SITE
1.1
Protocol Team Roster
University of California, San Francisco
Robert Grant, MD, MPH
Principal Investigator
Pulmonary and Critical Care, School of Medicine
University of California, San Francisco
1001 Potrero Avenue
San Francisco, CA 94110 USA
robert.grant@ucsf.edu
Phone: 415-3508909
Fax: 915-800-6055
Madeline Deutsch, MD, MPH
Co-principal investigator
Department of Family Community Medicine
School of Medicine
University of California, San Francisco
2356 Sutter St, 3rd Floor
San Francisco, CA 94143 USA
Madeline.Deutsch@ucsf.edu
Phone: 1-415-797-7136
David Glidden, PhD
Co-Investigator (Statistics)
Department of Epidemiology and Biostatistics 
School of Medicine
University of California, San Francisco
185 Berry Street, Suite 5700
San Francisco, CA 94107 USA
dave@biostat.ucsf.edu
Phone: 1-415-514-8009
Fax: 1-415-514-8150
Jae Sevelius, PhD
Co-investigator
Department of Medicine
School of Medicine
University of California, San Francisco

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San Francisco, CA 94143 USA
j.sevelius@ucsf.edu
Phone: 1- 415-476-6358
Patricia Defechereux, PhD
Pulmonary and Critical Care, School of Medicine
University of California, San Francisco
1001 Potrero Avenue
San Francisco, CA 94110 USA
pdefechereux@gladstone.ucsf.edu
Phone: 1-415-734-4811
Fax: 915-800-6055
San Francisco AIDS Foundation
Marion Pellegrini, 
1035 Market Street, 
San Francisco, California, 94103
mpellegrini@sfaf.org
Phone: 1-415-487-3000
Bringham And Women’s Hospital Research Institute
Shalender Bhasin, MD, PhD
Co-investigator
Brigham and Womens Hospital
Endocrine - RFB 2
221 Longwood Ave 
Boston MA 02115
sbhasin@partners.org
Phone: 1-617-732-5661
1.2
Research Facilities
San Francisco AIDS Foundation 
1035 Market Street, Suite 400 
San Francisco, CA 94103 USA
Phone: 1-415-487-8000
Fax: 1-415-487-8079
1.3
Clinical Laboratories
Quest Diagnostics

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Director: Salim Kabawat, MD
415 Massachusetts Ave, Cambridge, MA  02139 USA
Salim.E.Kabawat@questdiagnostics.com
Phone: 1-617-547-8900
Fax: 1-617-520-7703
Quest Diagnostics Inc.
Director: Dr. Russell L. Kerschmann
967 Mabury Rd, San Jose, CA 95133 USA
Russell.L.Kerschmann@questdiagnostics.com
Phone: 1- 408-975-1000 
Fax: 1-408-975-1030
ARI/UCSF Virology Laboratory 
Director: Robert M. Grant, MD, MPH
San Francisco General Hospital
1001 Potrero St., Building 100, Room 104
San Francisco, CA 94110 USA
robert.grant@ucsf.edu
Phone: 1-415-734-4810
Fax: 1-415-206-6016
LabCorp
13112 Evening Creek Dr. So STE 200
San Diego, CA 92128-4108
Phone: 1-800-888-1113
TBN as needed to support study site
1.4
Research Laboratories
Colorado AntiViral Pharmacology Laboratory
Director: Dr Peter Anderson, PhD
UC Denver-Skaggs School of Pharmacy and Pharmaceutical Sciences
V20-4410
12850 E Montview Blvd
Aurora, CO 80045
Peter.Anderson@ucdenver.edu
Phone: 1-303-724-6132
Fax: 1-303-724-6135
Brigham Research Assay Core
Director: Dr. Shalender Bhasin, MD PhD

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221 Longwood Avenue
RFB Room 477
Boston, MA 02115
Phone: 1-617-732-5661
sbhasin@partners.org
TBN as needed to support study site
1.5
Institutional Review Board
Committee on Human Research
Office of Research
3333 California St., Ste. 315
University of California
San Francisco, CA 94118 USA
chr@research.ucsf.edu
Campus Mailbox: 0962
General Office: 1-415-476-1814
Fax: 1-415-502-1347

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2
BACKGROUND
The TRIUMPH study, or trans Research-Informed communities United in the 
Mobilization for the Prevention of HIV, is a new study responding to a pressing need for 
culturally-relevant community-led pre-exposure prophylaxis (PrEP) programs for 
transgender communities, especially for trans women of color who are most affected by 
the HIV epidemic. The TRIUMPH study will strive to identify the most effective PrEP 
service provision strategies which take into account the particular facilitators and barriers 
that transgender communities encounter in the health care system. To date, transgender 
women included in HIV prevention studies have been lumped into the larger aggregate of 
Men who have sex with Men (MSM) without taking into account the unique sociocultural 
context of transgender women. The TRIUMPH study will also include transgender men 
and other members of various transgender communities. The TRIUMPH project’s goal is 
to identify the best methods to deliver PrEP safely and effectively to transgender 
communities while achieving the highest levels of adherence possible.
PrEP is the newest and most promising biomedical HIV prevention intervention yet 
developed and tested. The first clinical trial of PrEP (‘iPrEx’ or iniciativa Profilaxis Pre-
Exposición) included MSM and transgender women who were at higher risk for HIV 
infection, and found that daily oral Truvada PrEP reduced the risk of HIV acquisition by 
44% on an intention to treat basis [1].  However, a sub-analysis of the iPrEx data 
conducted by Deutsch et al , found zero effectiveness on an intention to treat basis among 
the small subgroup of transwomen in the study [2]. Further analyses revealed that the 
subgroup of trans women in iPrEx who were using hormones were less likely to have 
protective drug levels than those trans women not on hormones (OR 0.14, p<0.001). It is 
unclear if this difference is behavioral (less drug uptake) or biomedical (drug-drug 
interactions) in nature, or due to some combination of these factors, given the lack of 
pharmacokinetic (PK) studies testing for interactions between cross-sex hormone therapy 
(HT) and TDF/FTC, the active ingredients of Truvada. While there are studies of systemic 
drug-drug interactions between oral contraceptives and TDF, no such studies have been 
done with FTC, and no studies have been done with gender affirming HT, which differs 
from hormonal contraception in several respects. Drug-drug interactions with bioidentical 
17-beta estradiol used for gender affirming hormone therapy among transgender women 
have not been studied.
The Interactions BEtween Antiretrovirals And Transgender Hormones, or I-BrEATHe 
study, described in this protocol is a sub study of the TRIUMPH study. I-BrEATHe will 
address one of the secondary aims of the TRIUMPH study which is to assess the 
pharmacokinetic drug-drug interactions between cross-sex HT and daily oral FTC/TDF. 
Given that there are no PrEP studies to date that have specifically enrolled trans identified 
men, or have looked at the interactions between masculinizing HT and FTC/TDF, I-
BrEATHe will enroll both transgender women and men. Transgender men report sexual 
rapports without condoms both vaginally and anally (range 26-60%), exhibit patterns of 
STIs transmission and unwanted pregnancies. Transgender men also report use of sex for 
gender affirmation. Small convenience samples show that HIV prevalence is between 2- 
5% [3, 4]. To date, there are no programs or PrEP recommendations specific for 
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2.1
Overview of Non-Clinical Studies
N/A
2.2
Overview of Clinical Studies
There have been a large number of trials conducted with Truvada PrEP, including several 
demonstration projects. While there is no evidence to suggest that TDF/FTC interacts with 
commonly used feminizing or masculinizing hormone regimens, and evidence from 
studies of ARV interactions with hormonal contraceptives have been reassuring, no direct 
study of these interactions has been conducted to date. 
Our team led the only trans-specific sub analysis to date of the iPrEx randomized 
controlled trial (RCT) data as well as the open label extension (OLE) study, which 
included periodic dried blood spot (DBS) drug level monitoring [2]. In iPrEx, gender 
identity data was not collected using current best practices (“two-step” method [5]), 
making the identification of transgender participants in this multinational, multicultural 
and multilingual trial difficult. As all iPrEx participants had been assigned male sex at 
birth, a transgender subgroup of 339/2499 participants (14% of overall sample) was 
constructed comprised of the 29 (1%) who identified as women, 296 (12%) who identified 
as “trans”, and 14 (1%) who reported use of feminizing hormones. None had undergone 
gender affirming genital surgery. Compared with MSM, transgender women more 
frequently reported transactional sex, receptive anal intercourse without a condom, or 
more than 5 partners in the past 3 months.  Excluding those with a male identity who also 
used feminizing hormones, trans- and woman-identified participants were less likely to 
have TDF levels detected on random testing in the RCT (OR=0.39, 95% CI = 0.16 to 
0.96, p=0.04). While there was no effectiveness of PrEP for transgender women on an 
intention-to-treat basis, none of the transgender participants who seroconverted had 
detectible drug levels at the time of HIV diagnosis. In comparison to MSM in the OLE, 
transgender participants had less time with protective drug concentrations (17% vs 35%, 
p<0.001) and were less likely to have concentrations indicating > 3 tablets/week (OR 
0.71, 95% CI 0.49 to 1.03, p=0.07). Of the two transgender women who seroconverted 
during the OLE, both had drug levels below 350 fmol/punch in DBS, the level associated 
use of 2 tablets per week at the time of seroconversion. The lower concentrations were 
more likely if the transgender women used feminizing hormones.
Of the 7 clinical trials of Truvada PrEP for HIV prevention conducted to date, iPrEx is the 
only one with confirmed enrollment of trans women [6]. No clinical studies or 
demonstration projects were conducted with transgender men. 
For more detail regarding PrEP clinical trials, please refer to the Prescribing information 
for Truvada.
3
STUDY RATIONALE
The fact that concentrations of FTC/TDF were especially low among transgender women 
reporting use of feminizing hormones in the iPrEx study, which may reflect less PrEP use 
or a drug-drug interaction, is of high interest given that concerns about the impact of PrEP 

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on gender affirming hormone therapy is the main barrier for uptake of PrEP among 
transgender women [7]. While transgender men as a group have also been shown to be at 
elevated risk for HIV infection [4, 8], no information about PrEP use and drug levels is 
available for transgender men since they have never been formally included in PrEP 
research. Therefore, there are no data on the potential effects of testosterone on FTC/TDF 
drug concentrations. FTC/TDF drug concentrations have emerged as strong correlates of 
protection in PrEP trials, accounting for the majority of the variation in PrEP benefits 
across trials and across individual participants in trials. For example, while oral FTC/TDF 
PrEP had 44% efficacy on an intention to treat basis in iPrEx, the protective effect was 
more than 90% among those with detectable drug and negligible among those with no 
detectable drug in blood [1, 9].
The pharmacokinetic study of PrEP metabolites concentrations in association with 
feminizing and masculinizing hormones using directly observed therapy (DOT) will allow 
to establish whether interactions exist between these drugs. I-BrEATHe also provides an 
opportunity to include transgender men in PrEP research. Though transgender men are 
likely to be at lower risk for HIV acquisition than transgender women, the lack of 
available data regarding use of PrEP in transgender men must be remediated. I-BrEATHe 
will recruit equal numbers of transgender women who are using estradiol plus 
spironolactone (the most common HT regimen) and transgender men who are using 
testosterone. The primary aim will be to measure the intracellular active metabolites of 
TDF/FTC, tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP), 
levels in DBS collected after 1, 2, 3, and 4 weeks of video-observed Truvada for PrEP 
daily dosing, and comparing drug levels in the two groups receiving HT to previously 
acquired DBS drug levels data in MSM [9-11].
3.1
Risk / Benefit Assessment
Oral Truvada for PrEP has been FDA approved since 2012. At this time, there is plentiful 
evidence to support the use of daily oral FTC/TDF in HIV-1-uninfected heterosexual 
biological men and women, and men who have sex with men for HIV prevention [12]. 
The toxicity and tolerability of daily oral FTC/TDF in HIV-uninfected individuals have 
been established. Side effects that may arise in the first weeks of PrEP use -- nausea, 
abdominal cramping, vomiting, dizziness, headache, and fatigue usually go away without 
treatment interruption (see Truvada Prescribing information for more details). Known 
potential risks can be effectively managed by experienced PrEP providers. Participants 
enrolled in this study will be provided Truvada for PrEP within the confines of an 
established PrEP clinic, and will benefit from the expertise of trained staff.  Individuals 
who may be susceptible to the possible nephrotoxic effect of FTC/TDF as determined by 
the measure of creatinine clearance (see exclusion criteria) will not be enrolled in the 
study. Long term effect of Truvada use (such as bone density loss or kidney dysfunction) 
are unlikely to occur over the course of this short study in otherwise healthy participants 
[13-15].  Participants will be seen weekly by a clinician, and any adverse event 
immediately addressed, in addition participants will be interacting daily with study staff 
via phone, providing an opportunity to address any questions or concerns. Moreover, the 
daily interactions with study staff will provide support for adherence. Concerns about 
risks of combining gender-affirming hormone therapy and PrEP will be alleviated by 
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therapy. Guidelines for these matters will be provided by the UCSF Center of Excellence 
for Transgender Health (CoE-T).
4
STUDY OBJECTIVES
4.1
Primary Objective
To assess pharmacokinetics for daily oral FTC/TDF in transgender women and 
transgender men, and to determine if FTC/TDF drug concentrations are lower among 
transgender women who are using hormone therapy and in transgender men who use 
testosterone compared to historical controls in non-transgender MSM.
4.2
Secondary Objectives
To determine if daily oral FTC/TDF is associated with comparable rates of adverse events 
(AEs) in transgender women and in transgender men compared to historical controls in 
non-transgender MSM.
5
STUDY DESIGN
5.1
Study Overview
This is a single center pharmacokinetic study of daily oral Truvada at the following FDA 
approved dose of one tablet containing 200 mg of emtricitabine (FTC) and 300 mg of 
tenofovir disoproxil fumarate (TDF) for PrEP using daily directly observed therapy 
(DOT). 
The study will include 48 participants will be divided into two groups: one group will 
include 24 participants who currently describe their gender identity as “woman” or 
“transgender women”, or other transfeminine spectrum identity, and the second group will 
enroll 24 participants who identify as “man” or “transgender man”, or other 
transmasculine spectrum identity. 
Each participant will be taking a single daily dose of study drug in DOT performed either 
via video calling, or at study visit, for a total study duration of 28 to 30 days (4 weeks).
Laboratory evaluations for HT (including testosterone, or estradiol) drug levels will be 
performed at enrolment, and after 4 weeks on study drug. Study drug levels will be 
monitored weekly in DBS while participants are on study.
Screening data will be reviewed to determine participant eligibility.  Participants who 
meet all inclusion criteria and none of the exclusion criteria will be entered into the study. 
The treatment regimen that will be used:
•
Truvada at the following FDA approved dose of one tablet containing 200 mg of 
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Total duration of participant participation will be up to 4 weeks, plus the 28 days of 
screening window period between screening visit and on study daily observed therapy.  
Total duration of the study is expected to be 9 -10 months.
5.2
Pharmacogenetic testing
Pharmacogenetics (PGx) studies the variability in drug response due to hereditary factors 
in populations. There is increasing evidence that individual’s genetic background may 
impact the pharmacokinetics (absorption, distribution, metabolism and elimination) of 
drugs. The goal of the PGx analyses is to investigate a relationship between genetic 
factors and PK measures in I-BrEATHe, for example if there is potential unexpected or 
unexplained variation in drug levels. Blood samples collected for drug levels on DBS may 
be used for DNA extraction and PGx assessments. Participants will be specifically asked 
if they wish to participate in the genetic testing in the informed consent form.
6
CRITERIA FOR EVALUATION
6.1
Primary Endpoint
The primary endpoints for this study are the pharmacokinetics measures. These PK 
analyses are dependent on adherence and will be assessed at the end of study completion.
6.2
Secondary Endpoints
N/A
6.3
Safety Evaluations
AEs: Grade 1 and above as reported side effects on a structured instrument
7
PARTICIPANT SELECTION
7.1
Study Population
I-BrEATHe is a sub study of the TRIUMPH study with an anticipated overall cohort of 
188 transgender participants. Volunteers who are participants in the larger TRIUMPH 
project may be recruited to participate in this sub study, however the I-BrEATHe sub 
study may also enroll volunteers outside of the TRIUMH study.  
Up to 48 volunteers who meet the inclusion and exclusion criteria will be eligible for 
participation.  
7.2
Inclusion Criteria:
All subjects:
•
HIV antibody seronegative (negative HIV rapid test),
•
18 years or older,
•
Has a smart phone with access to two-way video call capability,
•
Willingness to be contacted for a short call every day for 4 weeks,
•
Adequate renal function (creatinine clearance ≥ 60 ml/min estimated by the 
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•
Provides written informed consent,
For Transgender women:
•
Male assigned sex at birth, and self-reported current gender identity as “woman” 
or “transgender women”, or other trans-feminine spectrum identity, 
•
Current feminizing Hormone Therapy (HT) use for at least 6 months,
For Transgender men:
•
Female assigned sex at birth, and self-reported current gender identity as “man” or 
“transgender man”, or other trans-masculine spectrum identity,
•
Current masculinizing Hormone Therapy (HT) use for at least 6 months with 
testosterone 
7.3
Exclusion Criteria
•
Expects to change or discontinue current HT use during the 4 weeks study period,
•
Signs of symptoms of acute viral syndrome,
•
Use of FTC or TDF in the past 90 days
•
Receiving ongoing therapy with any of the following:
ART, including nucleoside analogs, non-nucleoside reverse transcriptase 
inhibitors, protease inhibitors or investigational antiretroviral agents interferon 
(alpha, beta, or gamma) or interleukin (e.g., IL-2) therapy, aminoglycoside 
antibiotics, amphotericin B, cidofovir, systemic chemotherapeutic agents, other 
agents with significant nephrotoxic potential, other agents that may inhibit or 
compete for elimination via active renal tubular secretion (e.g., probenecid), 
and/or other investigational agents
•
Renal insufficiency documented as Creatinine Clearance < 60 ml/min
•
For masculine-spectrum identifying persons, positive pregnancy test at screening
•
At enrollment, has any other condition or factor that, based on the opinion of the 
investigator or designee, would preclude provision of informed consent; make 
participation in the study unsafe; complicate interpretation of study outcome data; 
or otherwise interfere with achieving the study objectives.
7.4
Eligibility determination
Eligibility criteria must be carefully assessed at the screening visit and confirmed at the 
enrolment visit prior to drug dispensation. Eligibility for recruitment will be determined 
by the study team based on the data collected at the screening visit. Eligibility assessment 
will happen between the screen and enrolment visits, and will include reviewing medical 
record with medical exam, medical history and ongoing medications, reviewing testing 
results for HIV and chemistries. All clinical and laboratory assessments of eligibility must 
be performed and reviewed within 28 days of initiating the screening process and all 
screen results available prior to enrolment. If all inclusion criteria are met, and participant 

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is deemed likely to adhere to the daily observed therapy regimen, participants will be 
confirmed for their pre-scheduled enrolment visit.
At the enrolment visit, an HIV rapid test will be repeated. If the rapid HIV test results are 
negative, and no other exclusion criteria are identified, participant will be enrolled into the 
study, and study medication will be dispensed.
7.5
Recruitment and retention
7.5.1
Study site
The study site will have the capacity to comply with the protocol, study-specific 
procedures, and all applicable regulations.  The site will have a reception area or a waiting 
area, a physical examination room, and/or counseling room, a study storage area or 
pharmacy, a data management area with locked cabinets or equivalent, computer access, 
laboratory facilities, and/or a phlebotomy area.
7.5.2
Recruitment
The current recruitment aim for this study is 48 participants, as described in sections 5.1 
and 7.1.  To reach the target enrolment number, up to 80 potential participants may be 
screened.
The recruitment strategies may include one or several of the following: 
•
Sending a “Dear Doctor” letter to healthcare providers who have a large number of 
transgender patients and asking for provider referral, 
•
Advertising the I-BrEATHe study on social media plate-forms, 
•
Using principal investigators’ database of participants who were enrolled in 
studies previously conducted at the UCSF CoE-T. Volunteers in this CoE-T 
database have given consent to be contacted for future research, 
•
Asking participants who have enrolled in the main TRIUMPH study,
•
Inviting USCF CoE-T staff who may be good candidates,
•
Using word of mouth,
•
Posting flyers in targeted areas, agencies, clinics, Community Based 
Organizations, or Triumph community mobilization activities
These approaches, along with input from our community advisory boards and our current 
programs that serve transgender communities, will be used in recruitment efforts. 
Volunteers interested in I-BrEATHe will be able to contact a special phone number 
created especially for the study. Callers to this number will be routed to the study team. If 
a study staff member is unable to answer the phone, there will be an outgoing message 
which will allow leaving a voicemail for a call back, as well as information on clinic drop-
in hours for those with unreliable phone service. Study team members may also be 
available at community mobilization activities to recruit. Efforts will be made to pre-
screen inquiries by phone, at events, or at the referring clinics for eligibility based on 
inclusion criteria. Participants will then be referred to the study site for screening.

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7.5.3
Retention
Given to the lack of evidence to guide trans-specific recruitment and retention strategies 
or trans-inclusive implementation practices, we will use the expertise of the CoE-T to 
engage with our transgender identified participants. The lack of attention to the 
sociocultural context of trans women’s lives especially and adaptations from other 
populations (i.e. MSM) have proven insufficient and unacceptable by the trans 
communities, evidenced by low recruitment and retention in clinical trials. Our study team 
has an understanding of the pervasive role of trauma in transgender people’s lives, 
specifically trauma that is often enacted in medical settings and can lead to the avoidance 
of medical care, including HIV testing and prevention. For transgender people, feeling 
safe and being able to trust one’s provider is a pre-requisite to successful engagement and 
retention in healthcare. Trust must be established within and throughout the community, 
as transgender social networks are tightly knit. 
Therefore, the I-BrEATHe study staff will be selected based on heightened sensitivity to 
transgender issues, appropriate training in transgender competency, and will possibly be 
members of the transgender communities themselves. Staff will be in close contact with 
the participants. Staff will remind participants by e-mail and/or telephone of their 
upcoming appointments. The participants will be interacting daily via video calls which 
can help create a relationship of trust. Participants will receive monetary incentive at their 
visit to the study site to encourage the video calls participations during the previous week. 
These incentives will be reviewed by the UCSF IRB to ensure that they are not excessive 
and coercive. At the end of the study, the participants may be invited to an appreciation 
event.
8
CONCURRENT MEDICATIONS
All participants should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.
8.1
Allowed Medications and Treatments
Standard therapy is allowed except for treatments noted in the exclusion criteria described 
above and as noted in the prohibited medications section below.  
8.2
Prohibited Medications and Treatments
The following medications are prohibited during the study and administration will be 
considered a protocol violation:
ART, including nucleoside analogs, non-nucleoside reverse transcriptase inhibitors, 
protease inhibitors or investigational antiretroviral agents, interferon (alpha, beta, or 
gamma) or interleukin (e.g., IL-2) therapy, aminoglycoside antibiotics, amphotericin B, 
cidofovir, systemic chemotherapeutic agents, other agents with significant nephrotoxic 
potential, other agents that may inhibit or compete for elimination via active renal tubular 
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9
STUDY TREATMENT
9.1
Method of Assigning Participants to Treatment Groups
Participants will be separated into two groups based on their gender identity, and all 
participants will undergo the same study procedures, to the exception of a pregnancy test 
for female assigned at birth transmasculine people, when appropriate (see study 
procedures below).
9.2
FTC/TDF
9.2.1
FTC/TDF Formulation
FTC/TDF is a fixed-dose co-formulation of FTC and TDF disproxil fumarate (TDF). Each 
FTC/TDF tablet contains of 200 mg of FTC and 300 mg of TDF (equivalent to 245 mg of 
tenofovir disoproxil). Please refer to the full prescribing information for FTC/TDF for 
more information regarding drug information, side effects, and storage conditions. The 
Truvada pill is a blue oblong pill to be swallowed with some liquid. 
9.2.2
FTC/TDF and pregnancy
FTC/TDF is categorized as pregnancy category B by the FDA.  For the study population 
assigned male at birth, the risks to pregnancy will be limited. For the population assigned 
female at birth, risks associated with pregnancy will be shared, and a positive pregnancy 
test at enrolment will be an exclusion criterion.  Study participants will be counselled that 
study drug should not be shared with any individual.  
9.2.3
Packaging and Labeling
Gilead Sciences will dispense medication to the study team through their FDA approved 
commercial packaging of 30 tablets per bottle with a child-resistant screw cap.  In addition 
to the tablets, each bottle contains a silica gel desiccant to protect the product from 
humidity and polyester packing material that cushions it during handling and shipping.  
Gilead will prepare bottles of study agent that are each labeled with the active agents, the 
expiry date and instructions for use as well as for storage. Each bottle will be assigned the 
participant’s individual identification number or PID at the site for tracking purposes.
9.3
Supply of Study Drug at the Site
Gilead will ship Study Drug to the investigational site at study start up.  The initial study 
drug shipment will be shipped after site activation (i.e., all required regulatory 
documentation has been received and approved by the UCSF IRB, and the study is ready 
to begin). Subsequent study drug shipments will be made after site request for resupply. 
Replacement study drug will be shipped at the investigator’s request.

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9.3.1
Storage
The study drug will be stored in accordance with the drug manufacturer’s 
recommendations. Storage area will be locked by a secure door.  The study area and 
storage facility will have climate-controlled environments, with temperature to remain 
within limits allowed by the manufacturer for drug storage. The drug will be stored at 
room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at 
temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Drug will 
be stored away from heat, moisture, and light. If the temperature of study drug storage in the 
clinic/pharmacy exceeds or falls below this range, this should be reported to the investigators 
and captured as a deviation. Participants will be instructed to store the medication in original 
packaging (bottle and protected from light) at room temperature according to the instructions 
outlined on the drug packaged insert.
9.4
Dispensation of Study Drug at the Site
9.4.1
Dosage/Dosage Regimen
The treatment is FTC/TDF orally once daily via DOT, with or without food for a duration 
of 28 days. Optimal timing between doses is 24 hours. 
9.4.2
Dispensing
Study clinicians (PrEP clinician, or Research Nurse Practitioner, or physician) or nurses 
will be responsible for dispensing study medication to participants. Only participants who 
meet enrolment criteria will be dispensed study medication. Upon study drug dispensation, 
the study staff will document dispensation and date of dispensation in a Drug Dispensation 
Log. 
9.4.3
Administration Instructions 
Participants who enroll in the study will schedule a face to face video calls plan with the 
study clinician. Calls will occur daily at a time that is convenient for the participant.  Calls 
will last 60 seconds in duration and will be focused on watching the FTC/TDF tablet be 
placed into the mouth, swallowed, and the mouth opened to verify the table is no longer 
present. Before the table is ingested, the participant will be asked a question about food 
ingestion in the prior hour or intent to eat in the next hour.
Participant are encouraged not to take the study drug outside of the video call setting. 
However, if participant cannot perform a video call for the DOT (no Wi-Fi, cell phone 
dies…), the pill taking can happen over an audio phone call, or back up documentation of 
the pill taking such as filming oneself taking the pill may be done. The time stamped 
video will be shared with study team at the next visit. In last resort, if none of these 
options are possible, a simple text such as “Hi study clinician’s name, dosing at hh.mm on 
dd-mmm, Thanks” could be sent to the team. If the daily DOT call is not documented, it 
will be considered a missed dose.

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9.4.4
Participant Replacement Instructions 
Participants who withdraw from the study prior to completion or who fail to adhere to the 
DOT regimen may be replaced.
9.5
Study Drug Accountability
An accurate and current accounting of study drug for each participant will be maintained 
on an ongoing basis via the DOT video calls and the on-site visits, by a member of the study 
site staff.  The number of study drug dispensed and returned by the participant will be 
recorded on the Drug Dispensation and DOT Log.  The study staff will verify these 
documents throughout the course of the study. If participant misplace the study medication, 
replacement will be allowed once.
9.6
Measures of Treatment Adherence
Daily adherence will be directly observed by participants taking part in real time DOT 
video calls, or witnessed by study staff at the study visit if the drug is taken at the clinic.  
Study staff will monitor the FTC/TDF tablet be placed into the mouth, swallowed, and the 
mouth opened to verify the table is no longer present.  Alternate documentations of pill 
taking as described in 9.4.1 may be used as back up measures if access to video capacity is 
impossible for participant. DOT will be recorded daily by the study team to document on 
the Drug Dispensation, Hormones and DOT log. Repeated failure to adhere to the DOT 
regimen will lead to discontinuation from study participation.
If participant fails to connect with study staff for the call, study staff will make every 
possible attempt to connect with participant. If participant misses the call and does not 
provide back up evidence of pill taking, it will be considered a missed dose. 
If participant misses two or more study drug doses, the participant will be excluded from 
study participation. 
DOT calls will capture hormone therapy adherence as well, which may be either directly 
observed if feasible, or verbal self-report. Hormone adherence will be captured on the 
Drug Dispensation, Hormones and DOT log.
10 STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization will be signed and 
dated by the participant or participant’s legal representative.
10.1 Clinical Assessments
10.1.1 Concomitant Medications
All concomitant medication and concurrent therapies will be documented at Screening, 
Enrolment, weeks 1, 2, 3 and 4, and at early termination when applicable.  Dose, route, 

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unit frequency of administration, and indication for administration and dates of 
medication will be captured in a Concomitant Medications Log.
10.1.2 Demographics 
Demographic information (i.e. age, birth assigned sex, gender identity, race, ethnicity, 
education, employment…) will be recorded at screening.
10.1.3 Medical History 
Relevant medical history, including history of current disease, other pertinent history, and 
information regarding underlying diseases will be recorded at Screening.
10.1.4 Physical Examination
Qualified clinician (Research Nurse Practitioner, or physician) or nurse will complete a 
brief targeted physical exam at enrolment, including weight and height.  Abnormal 
physical exam findings must be documented and will be followed by a physician or other 
qualified staff at the next scheduled visit. Special attention will be given to signs of 
symptoms of acute viral infection.
10.1.5 Vital Signs
Body temperature, blood pressure, pulse will be performed after resting for 5 minutes at 
screening and enrolment. In addition, weight and height will be collected at enrolment and 
exit.
10.1.6 HIV Rapid Test
At the screening, enrolment and end of study visits, an FDA approved HIV rapid test will 
be performed and results provided back to the participant. Rapid HIV test will only be 
performed once. Participants with positive results will be referred to the PHAST (SFDPH 
HIV Surveillance Unit phone #: 415/554-9050) or other equivalent program for 
participants outside of SF. Cases must be reported within 7 days to the Health Officer or 
other equivalent program for community resources provision and to initiate HIV care. 
Study team will ensure that participant is linked to care.  
10.1.7 Counselling around daily DOT
At screening, at enrolment, when initial study drug is dispensed, and at every weekly visit 
when the blood is drawn for DBS, participants will meet briefly with their study clinician 
or nurse, to remind participant to the importance of participating in the daily DOT for the 
success of the pharmacokinetic study
10.1.8 Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to study 
drug will be recorded via interviewer administered symptoms and side effects 
questionnaires and on an AE log, as appropriate. Study participants can also prompt study 
team during daily video calls to potential concerns, and these concerns may be addressed 
on a return phone call or at next visit by a clinician or a nurse.

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10.1.9 Drug and Alcohol Use assessment
Information regarding the use of drug and alcohol will be captured at the screening visit 
using the AUDIT 10-items questionnaire for screening alcohol use disorders and the 
DAST-10, a 10-items for screening drug use. Each takes approximately 5 minutes to 
complete. In addition, participants will be asked weekly if, and what type, substances were 
used in the past week.
10.1.10 Pregnancy test
Participants who were assigned female at birth will have a urine pregnancy test at 
enrolment, unless they affidavit that they are engaging in NO sexual activity with anyone 
with a penis, and/or have no ovaries and/or uterus.
10.2 Clinical Laboratory Measurements 
10.2.1 Blood Chemistry Profile
Blood will be obtained for determination of creatinine, and creatinine clearance estimated 
by the Cockcroft Creatinine Clearance Formula, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and total bilirubine. 
10.2.2 Kidney function Profile
Urine and blood will be obtained for kidney function biomarkers measurements, 
including, but not limited to, uromoduline and cystatin C, at enrolment and every on-study 
visit week.
10.2.3 Hormonal Therapy Profile
At screening, hormone levels may be extracted from participant’s existing health records, 
from referring clinic or physician. 
10.2.4 Serology testing
Hepatitis B immunity status will be either documented from other reliable sources proving 
previous testing (health records, referring provider) or blood may be used for Hepatitis B 
Surface Antigen testing as part of the PrEP delivery standard of care at the study site. This 
testing will be done as an off protocol testing, see 10.2.4. 
10.2.5 HIV infection testing
The I-BrEATHe protocol may conduct a series of testing related to HIV seroconversion 
(viral load, genotype, western blot …) if a participant is suspected of HIV acquisition.
10.2.6 Off protocol testing
If the need occurs to answer specific questions critical to study participant’s well-being in 
the I-BrEATHe study, at the discretion of the clinician, participant may have additional 
tests performed at the study site clinic or be referred to his or her physician for further 
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10.3 Research Laboratory Measurements 
10.3.1 Pharmacokinetic Measurements
Blood will be drawn for DBS at weeks 0, 1, 2, 3 and 4. DBS are readily accessible, require 
minimal processing, are easy to store and ship, and have been demonstrated to be suitable 
for monitoring active drug metabolites concentrations among PrEP users in iPrEx OLE. 
Analysis of the active phosphorylated moieties of tenofovir has a large dynamic range, 
capable of detecting as little as 2 tablets per month. DBS will be processed in accordance 
with procedures developed for the iPrEx OLE study [9]. 
10.3.2 Hormonal Therapy Profile
Blood will be drawn at enrolment and at study exit for quantification of estradiol, and total 
and free testosterone levels, as well as sex hormone binding globulin (SHBG) and 
dihydrotestosterone (DHT) using Liquid Chromatography-Tandem Mass Spectrometry 
(LC/MS/MS) and/or equilibrium dialysis. These measures will be used for the outcome 
analyses. 
10.3.3 Genetic testing
In accordance with UCSF IRB approval, study participants will be asked if they wish to 
provide written informed consent for genetic testing. If participant consent, DBS may be 
used for DNA extraction and pharmacogenetic studies.
10.4 Video dosing Assessments
The participant will be witnessed by study personnel to take the study drug dose by mouth 
every single day. Study personnel will ensure the tablet was swallowed by asking the 
participant to show that their mouth is empty. This will be accomplished in person at visits 
at the study site, as allowed and if feasible for participant, and by visual video-call on 
other days, including holidays, and weekends. However, if participant cannot perform a 
video call for the DOT, the pill taking can happen over an audio phone call, or back up 
documentation of the pill taking such as filming oneself taking the pill may be done. The 
time stamped video will be shared at the next visit. In last resort, if none of these options 
are possible, a simple text such as “Hi study clinician’s name, dosing at hh.mm on dd-
mmm, Thanks” could be sent. Study personnel will use the Drug Dispensation, Hormones 
and DOT (DDHD) Log to document directly observed doses. Participants will be given a 
detailed calendar that shows scheduled dosing days. This schedule will also be reinforced 
when study personnel interact with participants. The video assessments will last 
approximately 1 minute and study personnel will not discuss study details for privacy 
reasons. General study questions will be discussed, such as, “how do you feel”, “do you 
have any concerns”, etc. In this way, adverse events may be monitored on all dose 
witnessing days.  During the video assessment, staff will confirm with study participant 
uptake of HT, which may or may not be directly observed.

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11 EVALUATIONS BY VISIT
11.1 Phone or referring clinic pre screening
A number of questions will be asked from potential participants over the phone, at 
recruiting events or at the referring provider’s clinic, to prescreen volunteers. These 
questions include capability to do two-ways daily video call, ability to go to the study site 
weekly for blood draws, gender identity, and current trans hormone therapy.
11.2 Visit 1 (Screening visit)
1.
Review the study with the participant (or participant’s legal representative) and 
obtain written informed consent and HIPAA authorization, if applicable.
2.
Assign the participant a unique screening number. The screen number will be the 
Participant ID or PID for the duration of the study if enrolled.
3.
Record demographics data.
4.
Record brief targeted medical history, including a history of diseases, diagnosis 
date, and prior treatments.
5.
Record concomitant medications.
6.
Perform and record vital signs.
7.
Conduct the drug and alcohol use scales 
8.
Collect blood for clinical laboratory tests (chemistry and serology, as applicable). If 
hormone levels and/or serology are available from participant’s regular health 
management, collect from existing records.
9.
Collect blood for HIV rapid test, perform test and provide results.
10.
If HIV rapid test is negative, and inclusion criteria are met, tentatively schedule 
participant for Visit 2 (week 0).
11.
Provide visit reimbursement.
11.3 Visit 2 (week 0 or enrolment, within 28 days of screening)
1.
Review results from screening visit tests with participant 
2.
Concomitant medications review.
3.
Perform and record vital signs, including weight and height.
4.
Perform brief targeted physical exam, which includes an assessment of signs and 
symptoms of an acute viral syndrome, including fever, pharyngitis, rash, myalgias, 
arthralgias, diarrhea, or headache.  
5.
Perform and record blood HIV rapid testing
6.
If female assigned at birth, perform pregnancy test as indicated
7.
Confirm eligibility
8.
Draw blood for hormone levels, DBS, kidney function
9.
Collect urine for kidney function markers

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10.
Provide symptoms and side effect questionnaires and ask about potential substance 
use
11.
Dispense study medication and instruct participant to take daily
12.
Record study medication bottle number on the Drug Dispensation Log
13.
Review importance of study procedures (DOT/weekly visit), using client centered 
counselling for adherence
14.
Coordinate video calling schedule with participant and provide calendar of calls
15.
Provide visit reimbursement.
11.4 Visit 3 (Week 1, 2 and 3, visit window plus or minus 2 days)
1.
Record any Adverse Experiences, using PrEP and a hormones specific symptoms 
and side effects questionnaires, and the AE log
2.
Assessment for acute viral infection
3.
Review participant daily observed therapy log, discuss adherence challenges if any, 
provide support if necessary for DOT. 
4.
Ask about potential substance use
5.
Record changes to concomitant medications
6.
Draw blood for DBS and kidney function markers
7.
Collect urine for kidney function markers
8.
Provide visit reimbursement
11.5 Visit 4 (Week 4 or end of study, visit window plus or minus 2 days)
1.
Record any Adverse Experiences (including the symptoms and side effects 
questionnaires) and review participant daily observed therapy log
2.
Ask about potential substance use
3.
Record changes to concomitant medications.
4.
Perform vital signs, including height and weight
5.
Asses for symptoms of acute viral infection
6.
Collect blood for chemistries, HIV rapid testing, hormone levels, and kidney 
function markers as well as for DBS
7.
Collect urine for kidney function biomarkers
8.
Collect all unused study drug.
9.
Provide visit reimbursement
10.
Thanks participant for participation
11.
Referral to a clinical PrEP service if the participant chooses to continue PrEP

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11.6 Early Withdrawal Visit
1.
Record any Adverse Experiences and review participant DOT log. Discuss 
adherence challenges if any.
2.
Administer symptoms and side effects questionnaires
3.
Ask about potential substance use
4.
Capture reasons why participant is dropping out of the study
5.
Record changes to concomitant medications.
6.
Collect all unused study drug
7.
Perform vital signs, including height and weight
8.
Collect blood for chemistries, HIV rapid testing, hormone levels, kidney function 
and for DBS
9.
Collect urine for kidney function biomarkers
10.
Provide visit reimbursement
11.
Thanks participant for participation 
12.
Referral to a clinical PrEP service if the participant chooses to continue PrEP.
12 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
12.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure.
The Investigator will probe, via discussion with the participant, for the occurrence of AEs 
during each participant visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient chart, in an AE log and/or CRF.  Adverse 
events will be described by duration (start and stop dates and times), severity, outcome, 
treatment and relation to study drug, or if unrelated, the cause.
A side effect structured questionnaire will be used to track AE.
AE Severity
The U.S. Department of Health and Human Services, National Institutes of Health, 
National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.0. [November 2014] should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant.  The guidelines shown in 

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Table 1 below should be used to grade severity.  It should be pointed out that the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious.
Table 1.  AE Severity Grading
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Clinical adverse
event  NOT 
identified 
elsewhere in the
grading table
Mild symptoms
causing no or 
minimal interference 
with usual social &
functional activities 
with intervention not 
indicated
Moderate symptoms
causing greater than 
minimal interference 
with usual social &
functional activities 
with intervention 
indicated
Severe symptoms
causing inability to 
perform usual social & 
functional activities with
intervention or 
hospitalization indicated
Potentially life-threatening
symptoms causing inability to 
perform basic self-care 
functions with intervention
indicated to prevent 
permanent impairment, 
persistent disability, or death
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2.
Table 2.  AE Relationship to Study Drug
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the participant’s clinical state or by other 
interventions.
Possibly
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the study 
drug.
12.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:
•
death
•
a life-threatening adverse experience
•
inpatient hospitalization or prolongation of existing hospitalization
•
a persistent or significant disability/incapacity

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•
a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the participant or require intervention to 
prevent one of the outcomes listed. 
12.2.1 Serious Adverse Experience Reporting
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed.
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB), the site investigator will report SAEs to the IRB.  
12.2.2 Suicidal ideation
Suicidal ideation-related events will be reported to the IRB as indicated by the DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. 
[November 2014] described above. In addition, participants will be offered support and 
access to mental health services available at the study site. Study staff will ensure study 
participants are linked to care.
12.3 Medical Monitoring
Dr. Robert Grant should be contacted directly at these numbers to report medical concerns 
or questions regarding safety.
Phone: 415-350-8909 
13 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS
13.1 Early Discontinuation of Study Drug 
A participant may be discontinued from study treatment at any time if the participant, or 
the investigator, feels that it is not in the participant’s best interest to continue.  The 
following is a non-exclusive list of possible reasons for study treatment discontinuation: 
•
Participant withdrawal of consent
•
Participant is not adhering with study procedures
•
Adverse event that in the opinion of the investigator would be in the best interest of 
the participant to discontinue study treatment
•
Protocol violation requiring discontinuation of study treatment; including change or 
interruption of the HT regimen
•
Lost to follow-up
•
Sponsor request for early termination of study
•
Positive pregnancy test (performed outside of the study settings)

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If a participant is withdrawn from treatment due to an adverse event, the participant will 
be referred to care.
All participants who discontinue study treatment will be withdrawn from the study and 
every effort will be made to welcome participant for an early withdrawal visit as soon as 
possible at which the procedures listed in section 10.5 should be performed.  At this visit, 
reasons for stopping the study will be documented, if participant is willing to share.
All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for participant 
withdrawals.  The reason for the participant’s withdrawal from the study will be specified 
in the participant’s source documents Refer to Section 10.5 for early termination 
procedures.
12.3
Withdrawal of Participants from the Study
A participant may be withdrawn from the study at any time if the participant, or the 
investigator feels that it is not in the participant’s best interest to continue.  
All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for participant 
withdrawals.  The reason for the participant’s withdrawal from the study will be specified 
in the participant’s source documents.  As noted above, participants who discontinue 
study treatment early (i.e., they withdraw prior to week 4) should have an early 
withdrawal visit. Refer to Section 10.5 for early termination procedures.  Participants who 
withdraw after week 0 but prior to week 1 should be encouraged to come in for a 
withdrawal visit.  
12.4
Replacement of Participants
Participants who withdraw from the study treatment may be replaced.  
14 PROTOCOL VIOLATIONS
A protocol violation occurs when the participant, or investigator fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, participant safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following:
•
Failure to meet inclusion/exclusion criteria
•
Use of a prohibited concomitant medication
•
Failure to adhere to study drug regimen
•
Failure to participate in the daily directly observed therapy (2 or more failed calls with 
no back up documentation of pill taking)
•
Change or interruption of HT regimen 

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•
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor, in this case the principal investigators, will determine 
if a protocol violation will result in withdrawal of a participant.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated and submitted to the IRB. A copy 
of the form will be filed in the site’s regulatory binder.
15 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.  
15.1 Data Sets Analyzed
All eligible and dosed participants who are enrolled into the study and receive all doses of 
the study drug will be included in the pharmacokinetic analysis.
15.2 Demographic and Baseline Characteristics
The following demographic variables at screening will be summarized: race, ethnicity, 
age, gender identity, birth sex. 
15.3 Analysis of Primary Endpoint
We will compare levels of TFV-DP in dried blood spots and rates of adverse events 
between trans men and trans women and a group of MSM historical controls from the 
iPrEx OLE study.  We will compare log transformed TFV-DP levels using a linear mixed 
effects model with factors for group (trans men v. trans women v. MSM) and times (1, 2, 
3 and 4 weeks after initiation) and their interaction with an unstructured covariance across 
visits and test for differences at between groups at each time point. If values appear to 
violate the normal distribution, we will obtain p-values and confidence intervals using the 
bootstrap. All p-values will be two-sided with p-value < 0.05 considered statistically 
significant. Adverse events will be compared using the Fisher exact test.
Adverse event rates will be coded by body system and MedDra classification 
term.  Adverse events will be tabulated and will include the number of patients for whom 
the event occurred, the rate of occurrence, and the severity and relationship to study drug.  
15.4 Sample Size 
A sample size of 48 (24 trans women and 24 trans men) allows detection of a difference of 
0.52 log difference (1.68 fold difference) in TFV-DP from dried blood spots with 81% 
power on a two-sided 0.05 level test at any time point between our trans participants and 
MSM historical controls. A difference of 0.70 log (2.0 fold difference) can be detected 
between either group (trans men or women) and MSM historical controls with 80% power 
on a two-sided 0.05 level test. This is sufficient to determine if the differences in drug 

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concentrations observed in iPrEx OLE between MSM and trans women were due to 
interactions with feminizing hormone drug-drug interactions.
16 DATA COLLECTION, RETENTION AND MONITORING
16.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each participant treated with 
the study drug.  
Study personnel at study site will enter data from source documents corresponding to a 
participant’s visit into the protocol-specific database when the information corresponding 
to that visit is available.  Participants will not be identified by name in the study database 
or on any study documents to be collected by the investigators, but will be identified by a 
site number, participant identification number (PID).
For paper source documents:  If a correction is made on a CRF, the study staff member 
will line through the incorrect data, write in the correct data and initial and date the 
change.
The Investigator is responsible for all information collected on participants enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator or his representative.  A copy of the CRF 
and/or source documents will remain at the Investigator’s site at the completion of the 
study for a period of 2 years after final data analysis.
16.2 Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good 
computing practices.
16.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of data validation checks 
will be implemented and applied to the database on a regular basis. For example, query 
reports pertaining to data omissions and discrepancies may be forwarded to the study site 
for resolution, as applicable. The study database will be updated in accordance with the 
resolved queries.  All changes to the study database will be documented.
16.4 Archival of Data
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.  

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At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures.
16.5 Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized 
representatives of funding agencies, IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request. For each participant, the signed Informed Consent, HIPAA 
Authorization and copies of all source documentation related to that participant will be 
maintained. Data will be kept separate from documents containing personal identifiers.  
The Investigator must ensure the reliability and availability of source documents from 
which the information in the database was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, source logs and check lists, etc.) must be kept secured for a period of 2 
years following study results analysis is done.
16.6 Monitoring
Monitoring visits at the study site may be conducted by representatives of the 
investigators according to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH 
Guidelines for GCP (E6).  By signing this protocol, the investigators grant permission to 
the appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation.
16.7 Participant Confidentiality
In order to maintain participant confidentiality, only a PID (personal identifying number) 
will identify all study participants on CRFs and other documentation, specimens send for 
testing on site or at remote laboratories and with the data sent to data management team 
for analyses. Some information may be extracted from existing medical charts, in the case 
of hormonal therapy for referred participants, for example; in this case, data will be 
transferred to the I-BrEATHe study document and participant’s chart, associated with his 
or her PID and no personal identifiers. For the video calling, every effort will be made to 
protect the privacy or participants. Video conference platforms that encrypt data, 
password protection and study specific phone will be used. Privacy for video-dosing will 
be stressed by study personnel, and all meetings will occur in a mutually agreed upon 
location. Study details will not be discussed by study personnel during these sessions, 
unless at participant’s specific request. These procedures and risks will be described in the 
informed consent document.
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, CRFs, logs, reports and other source 
records, as well as the results database will be identified by a coded PID only.  All study 

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records will be kept in a locked file cabinet and informed consent forms linking a patient’s 
name to a patient identification number will be stored separately in another locked file 
cabinet.  Clinical information will not be released without documented permission of the 
participant, except as necessary for monitoring by the FDA.  The Investigator must also 
comply with all applicable privacy regulations (e.g., Health Insurance Portability and 
Accountability Act of 1996, EU Data Protection Directive 95/46/EC).
17.1 Protocol Amendments
Any amendment to the protocol will be written by the investigators, who are the sponsors 
for this study.  Protocol amendments cannot be implemented without prior written 
IRB/IEC approval except as necessary to eliminate immediate safety hazards to patients.  
A protocol amendment intended to eliminate an apparent immediate hazard to patients 
may be implemented immediately, provided the IRBs are notified within five working 
days.
17.2 Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of the 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to 
the IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol and the 
informed consent form will be in the possession of the Investigator before the study is 
initiated.  The IRB/IECs unconditional approval statement will be transmitted by the 
Investigator to study drug supplier prior to the shipment of study supplies to the site.  This 
approval must refer to the study by exact protocol title and number and should identify the 
documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.  
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed.

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17.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Participants (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
The Investigator will prepare the informed consent form, and research HIPAA 
authorization form. Investigators will provide the documents to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to and be 
approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will 
also comply with local regulations. The Investigator will keep an IRB/IEC-approved copy 
of the Informed Consent Form for the study file.
A properly executed, written, informed consent will be obtained from each participant 
prior to entering the participant into the study.  Information should be given in both oral 
and written form and participants (or their legal representatives) must be given ample 
opportunity to inquire about details of the study.  If a participant is unable to sign the 
informed consent form (ICF) and the HIPAA authorization, a legal representative may 
sign for the participant.   A copy of the signed consent form will be given to the 
participant or legal representative of the participant and the original will be maintained 
with the participant’s records.
17.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996. 
17.5
Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after 
notifying the IRB, except when to protect the safety, rights or welfare of participants.
2.
Personally conduct or supervise the study.
3.
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report any AEs that occur in the course of the study, in accordance with §21 CFR 
312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee).

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7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
8.
Promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to participants or others (to include amendments and IND 
safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/participants.
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.

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Page 43 of 45
APPENDIX 1.  SCHEDULE OF STUDY VISITS
VISIT 1
(Screen)
VISIT 2
(Week 0/enrollment) a
VISIT 3
(Week 1, 2, 3)b
VISIT 4
(Week 4)b
VISIT 5
(Early withdrawal)
Informed Consent
X
Demographics
X
Medical History
X
X
Abbreviated Physical Exam
X
Height 
X
X
X
Weight 
X
X
X
Vital Signs 
X
X
X
X
HIV Rapid test
X
X
X
X
Symptoms of acute viral infection
X
X
X
X
Pharmacokinetics (DBS)
X
X
X
X
Chemistryc
X
X
X
Kidney biomarkers (blood/urine)
X
X
X
X
Hormone Therapy levels
X
X
X
Pregnancy Test (Urine) 
Xd
AUDIT and DAST scale
X
Dispensing of Study Drug
X
Counting of Returned Study Drug
X
X
Schedule DOT 
X
Review DOT log
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
Questions (PrEP, HT, drug use)
X
X
X
X
Condom distribution (optional)
X
X
X
X
Refer to PrEP program (optional)
X
X
a within 28 days
b ±2 days
c Creatinine and creatinine clearance, AST, ALT, total bilirubine. Blood may be used for Hepatitis B surface antigen testing if data not available from medical chart.
d Only when indicated, see section 10.1.11 pge 27

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Version Date: 15-Mar-2018
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Protocol Template © CFFT TDN   Effective: 12 SEP 2007
18 REFERENCES
1.
Grant, R.M., et al., Preexposure Chemoprophylaxis for HIV Prevention in Men Who 
Have Sex with Men. New England Journal of Medicine, 2010. 363(27): p. 2587-
2599.
2.
Deutsch, M.B., et al., HIV pre-exposure prophylaxis in transgender women: a 
subgroup analysis of the iPrEx trial. Lancet HIV, 2015. 2(12): p. e512-9.
3.
Sevelius, J., "There's no pamphlet for the kind of sex I have": HIV-related risk 
factors and protective behaviors among transgender men who have sex with 
nontransgender men. J Assoc Nurses AIDS Care, 2009. 20(5): p. 398-410.
4.
Reisner, S.L., et al., Syndemics and gender affirmation: HIV sexual risk in female-
to-male trans masculine adults reporting sexual contact with cisgender males. Int J 
STD AIDS, 2015.
5.
Deutsch, M.B., et al., Electronic medical records and the transgender patient: 
recommendations from the World Professional Association for Transgender Health 
EMR Working Group. J Am Med Inform Assoc, 2013. 20(4): p. 700-3.
6.
Escudero, D.J., et al., Inclusion of trans women in pre-exposure prophylaxis trials: 
a review. AIDS Care, 2015. 27(5): p. 637-41.
7.
Sevelius, J.M., et al., Barriers and facilitators to engagement and retention in care 
among transgender women living with human immunodeficiency virus. Ann Behav 
Med, 2014. 47(1): p. 5-16.
8.
Reisner, S.L., et al., Laboratory-confirmed HIV and sexually transmitted infection 
seropositivity and risk behavior among sexually active transgender patients at an 
adolescent and young adult urban community health center. AIDS Care, 2015. 
27(8): p. 1031-6.
9.
Anderson, P.L., et al., Emtricitabine-tenofovir concentrations and pre-exposure 
prophylaxis efficacy in men who have sex with men. Sci Transl Med, 2012. 4(151): 
p. 151ra125.
10.
Hendrix, C.W., et al., Dose Frequency Ranging Pharmacokinetic Study of 
Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to 
Establish Adherence Benchmarks (HPTN 066). AIDS Res Hum Retroviruses, 2016. 
32(1): p. 32-43.
11.
Zheng, J.H., et al., Application of an intracellular assay for determination of 
tenofovir-diphosphate and emtricitabine-triphosphate from erythrocytes using dried 
blood spots. J Pharm Biomed Anal, 2016. 122: p. 16-20.
12.
WHO Guidelines Approved by the Guidelines Review Committee, in Guideline on 
When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. 
2015, World Health Organization. Copyright (c) World Health Organization 2015.: 
Geneva.
13.
Liu, A.Y., et al., Bone Mineral Density in HIV-Negative Men Participating in a 
Tenofovir Pre-Exposure Prophylaxis Randomized Clinical Trial in San Francisco. 
PLoS ONE, 2011. 6(8): p. e23688.

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Version #: 1.3
Version Date: 15-Mar-2018
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Protocol Template © CFFT TDN   Effective: 12 SEP 2007
14.
Mulligan, K., et al., Effects of emtricitabine/tenofovir on bone mineral density in 
seronegative men from 4 continents: DEXA results of the global iPrEx study. 18th 
CROI, 2011.
15.
Mulligan, K., et al., Low Bone Mass in Behaviorally HIV-Infected Young Men on 
Antiretroviral Therapy: Adolescent Trials Network (ATN) Study 021B. Clin Infect 
Dis, 2012.