Giving Standardized Estradiol Therapy In Transgender Women to Research Interactions With HIV Therapy
Phase: PHASE2
Conditions: HIV I Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
A5403 
 
 
Giving Standardized Estradiol Therapy In Transgender Women to Research 
Interactions with HIV Therapy: the GET IT RIgHT Study 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
 
 
Sponsored by: 
National Institute of Allergy 
and Infectious Diseases 
 
 
 
IND #162616 
 
 
 
 
The Antiretroviral Therapy Strategies  
Transformative Science Group:  
 
 
 
Timothy Wilkin, MD, Chair 
 
Protocol Chair:  
 
 
 
 
 
Jordan E. Lake, MD, MSc 
 
Protocol Co-Chair:   
 
 
 
 
Kimberly Scarsi, PharmD, MS 
 
Protocol Vice Chair:  
 
 
 
 
Jorge A. Gallardo-Cartagena, MD 
 
 
DAIDS Clinical Representative: 
Pablo Belaunzaran Zamudio, MD, 
DTM&H, MSc 
 
Clinical Trials Specialist: 
 
 
 
 
Osarenoma Salawu, MS 
 
 
 
FINAL Version 2.0  
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Giving Standardized Estradiol Therapy In Transgender Women to Research Interactions with 
HIV Therapy: the GET IT RIgHT Study 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 

A5403 
 
 
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TABLE OF CONTENTS 
 
 
Page 
 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 6 
PROTOCOL TEAM ROSTER ..................................................................................................... 7 
STUDY MANAGEMENT ........................................................................................................... 11 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 13 
SCHEMA .................................................................................................................................. 15 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 17 
1.1 
Primary Hypotheses ........................................................................................... 17 
1.2 
Secondary Hypotheses ...................................................................................... 17 
1.3 
Exploratory Hypotheses ..................................................................................... 17 
1.4 
Primary Objectives ............................................................................................. 18 
1.5 
Secondary Objectives ........................................................................................ 18 
1.6 
Exploratory Objectives ....................................................................................... 18 
2.0 
INTRODUCTION ........................................................................................................... 19 
2.1 
Background ........................................................................................................ 19 
2.2 
Rationale ........................................................................................................... 21 
3.0 
STUDY DESIGN ........................................................................................................... 24 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 26 
4.1 
Inclusion Criteria ................................................................................................ 26 
4.2 
Exclusion Criteria ............................................................................................... 28 
4.3 
Study Enrollment Procedures............................................................................. 30 
4.4 
Co-enrollment Guidelines ................................................................................... 31 
5.0 
STUDY TREATMENT ................................................................................................... 31 
5.1 
Regimens, Administration, and Duration ............................................................ 31 
5.2 
Study Product Formulation and Preparation ....................................................... 32 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 32 
5.4 
Concomitant Medications ................................................................................... 33 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 37 
6.1 
Schedule of Evaluations..................................................................................... 37 
6.2 
Timing of Evaluations ......................................................................................... 40 
6.3 
Instructions for Evaluations ................................................................................ 42 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 50 
7.1 
Definition of Adverse Events .............................................................................. 50 
7.2 
Adverse Event Collection Requirements for This Protocol ................................. 50 
7.3 
EAE Reporting to DAIDS ................................................................................... 51 
7.4 
Study Monitoring ................................................................................................ 52 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 54 
8.1 
Toxicity .............................................................................................................. 54 

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CONTENTS (Cont’d) 
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8.2 
Deep Vein Thrombosis, Other Thromboembolic Event, or Major Adverse 
Cardiovascular Event (MACE) ......................................................................... 54 
8.3 
Elevated Liver Tests ........................................................................................ 55 
8.4 
Suicidal Ideation or Attempt, Worsening Depression, or Other Acute 
Psychiatric Condition ...................................................................................... 55 
8.5 
New Diagnosis of Breast Cancer ....................................................................... 56 
8.6 
New Cancer Diagnosis Other than Breast, Basal, and Squamous Cell Skin 
Cancer ............................................................................................................... 56 
8.7 
Sustained Hypertension ..................................................................................... 56 
8.8 
Detectable Viremia ............................................................................................. 56 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 56 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 56 
9.2 
Premature Study Discontinuation ....................................................................... 57 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 57 
10.1 
General Design Issues ....................................................................................... 57 
10.2 
Outcome Measures ............................................................................................ 58 
10.3 
Randomization and Stratification ........................................................................ 60 
10.4 
Sample Size and Accrual ................................................................................... 61 
10.5 
Data and Safety Monitoring ................................................................................ 64 
10.6 
Analyses ............................................................................................................ 65 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 69 
11.1 
Pharmacology Objectives .................................................................................. 69 
11.2 
Pharmacology Study Design .............................................................................. 69 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 70 
11.4 
Population Pharmacokinetic/Pharmacodynamic Analyses ................................. 70 
11.5 
Anticipated Outcomes ........................................................................................ 71 
12.0 
BEHAVIORAL SCIENCE ............................................................................................... 71 
12.1 
Rationale ........................................................................................................... 71 
12.2 
Design ............................................................................................................... 71 
12.3 
Measures of Satisfaction and Acceptability ........................................................ 72 
12.4 
Procedures and Analysis ................................................................................... 72 
13.0 
DATA COLLECTION AND MONITORING ..................................................................... 73 
13.1 
Records to Be Kept ............................................................................................ 73 
13.2 
Role of Data Management ................................................................................. 73 
13.3 
Clinical Site Monitoring and Record Availability .................................................. 73 
13.4 
Reporting Protocol Deviations ............................................................................ 74 
14.0 
PARTICIPANTS ............................................................................................................ 74 
14.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 74 
14.2 
Participant Confidentiality ................................................................................... 74 
14.3 
Study Discontinuation ........................................................................................ 74 

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15.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 74 
16.0 
BIOHAZARD CONTAINMENT ...................................................................................... 74 
17.0 
REFERENCES .............................................................................................................. 76 
INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION ........................................................................ 80 
ATTACHMENT A: OPTIONAL PROCEDURES ........................................................................ 97 
ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES ......................... 98 
INFORMED CONSENT FOR INTERVIEWS ........................................................................... 100 

 
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SITES PARTICIPATING IN THE STUDY 
 
A5403 is a multicenter study being conducted at US and non-US clinical research sites.  
 
 
 

 
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PROTOCOL TEAM ROSTER 
 
Chair 
Jordan E. Lake, MD, MSc 
Houston AIDS Research Team CRS 
6431 Fannin Street, MSB 2.112 
Houston, TX 77030 
Phone: 713-500-6759 
E-mail: jordan.e.lake@uth.tmc.edu 
 
Co-Chair 
Kimberly K. Scarsi, PharmD, MS, FCCP 
Northwestern University CRS 
University of Nebraska Medical Center 
College of Pharmacy 
Department of Pharmacy Practice, Room 3021 
986145 Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-9916 
E-mail: kim.scarsi@unmc.edu 
 
Vice Chair 
Jorge A. Gallardo-Cartagena, MD 
Barranco CRS 
Av. Almirante Miguel Grau 1010 
Lima 15063 PERU 
Phone: 51-1-2067800 
E-mail: jgallardo@citbm.pe 
 
DAIDS Clinical Representative  
Pablo Belaunzaran Zamudio, MD,  
  DTM&H, MSc 
HIV Research Branch 
TRP, DAIDS, NIAID, NIH  
5601 Fishers Lane, Room 9E40 
Rockville, MD 20852 
Phone: 240-292-4423 
E-mail: belaunzaranzapabf@niaid.nih.gov 
 
Clinical Trials Specialist 
Osarenoma Salawu, MS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3000 
E-mail: osarenoma.salawu@dlhcorp.com

 
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TEAM ROSTER (Cont'd) 
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Statisticians 
Laura Smeaton, MS 
Statistical and Data Analysis Center 
Harvard TH Chan School of Public Health 
FXB Building, Room 511, 651 Huntington Ave. 
Boston, MA 02115-6017 
Phone: 617-432-2525 
E-mail: smeaton@sdac.harvard.edu 
 
Joseph Puleo, MS 
Statistical & Data Analysis Center 
651 Huntington Avenue 
FXB Building, Room 535 
Boston, MA 02115-6017 
Phone: 617-432-4402 
E-mail: jpuleo@sdac.harvard.edu  
 
Data Managers 
Lillian Collins, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext. 7308 
E-mail: collins@frontierscience.org 
 
Elizabeth Siciliano, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext. 7276 
E-mail: siciliano@frontierscience.org 
 
DAIDS Pharmacist 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E16 
MSC #9830 
Rockville, MD 20852 
Phone: 240-627-3593 
E-mail: oladapo.alli@nih.gov
Virologist 
Sara Gianella, MD 
University of California, San Diego AntiViral 
Research Center CRS 
Center For AIDS Research (CFAR)  
9500 Gilman Drive 
La Jolla, CA 92093-0679 
Phone: 858-552-8585 Ext. 7193 
E-mail: gianella@ucsd.edu 
 
Pharmacologists 
Mackenzie Leigh Cottrell, PharmD, MS 
UNC Eshelman School of Pharmacy 
120 Mason Farm Road 
Chapel Hill, NC 27599 
E-mail: mlcottre@email.unc.edu 
 
Kimberly K. Scarsi, PharmD, MS, FCCP 
Northwestern University CRS 
University of Nebraska Medical Center 
College of Pharmacy, Room 3021 
986145 Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-9916 
E-mail: kim.scarsi@unmc.edu 
 
Immunologist  
Nicholas T. Funderburg, PhD 
Ohio State University CRS 
School of Health and Rehabilitation Sciences 
535A Atwell Hall 
453 West Tenth Avenue 
Cleveland, OH 43210 
Phone: 614-292-7303 
E-mail: nicholas.funderburg@osumc.edu 
 
Endocrinologist  
Todd Brown, MD, PhD 
Johns Hopkins University CRS 
Division of Endocrinology and Metabolism 
1830 East Monument Street 
Baltimore, MD 21287 
Phone: 410-502-2327 
E-mail: tbrown27@jhmi.edu

 
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Investigators  
Carrie Johnston, MD, MS 
Weill Cornell Chelsea CRS 
1300 York Avenue, A-4 
New York, NY 10065 
Phone: 518-339-5209 
E-mail: cmd9008@med.cornell.edu 
 
Yamikani Mbilizi, MBBS  
Blantyre CRS 
P.O. Box 1131, Chipatala Avenue 
Next to Lions Eye Hospital 
Blantyre 265 
MALAWI 
Phone: 265-1875129 
E-mail: ymbilizi@jhu.medcol.mw 
 
Amaya Perez-Brumer, PhD 
Dalla Lana School of Public Health 
University of Toronto 
155 College Street, 5th Floor, Room 554 
Toronto, ON, M5T 3M7 
CANADA 
Phone: 416-978-5178 
E-mail: a.perezbrumer@utoronto.ca 
 
Eileen Scully, MD, PhD 
Johns Hopkins University CRS 
Rangos Building 
855 N Wolfe Street, Room 530B 
Baltimore, MD 21205 
Phone: 410-502-4988 
E-mail: escully1@jhmi.edu 
 
Poongulali Selvamuthu, MBBS, MSc, PhD 
Chennai Antiviral Research and Treatment (CART) 
CRS Medical Clinic 
Rajiv Gandhi Road  
Taramani Chennai 6000113 
INDIA 
Phone: 91-4426215736 
E-mail: poongulali@cartcrs.org
Field Representatives 
Joan Gottesman, BSN, RN, CCRP 
Vanderbilt Therapeutics (VT) CRS 
One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-7143 
E-mail: joan.gottesman@vumc.org 
 
Morgan Lima, BSN, RN 
Vanderbilt Therapeutics (VT) CRS 
One Hundred Oaks  
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-7448 
E-mail: morgan.lima@vumc.org 
 
Laboratory Technologists 
Lori Caruso, BS 
University of Pittsburgh CRS 
PTEU/Department of Medicine, ID Division 
3550 Terrace Street 
Scaife Hall, Room 808 
Pittsburgh, PA 15261 
Phone: 412-648-9012  
E-mail: lcaruso@pitt.edu 
 
Christopher Lane, BS, AAS 
University of Rochester 
Adult HIV Therapeutic Strategies Network CRS 
Infectious Diseases Division 
Department of Medicine, Box 689 
601 Elmwood Avenue 
Rochester, NY 14642 
Phone: 585-2789-5574  
E-mail: christopher_lane@urmc.rochester.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Roslyn Swartz 
University of Cape Town Lung Institute 
(UCTLI) CRS 
George Street, Mowbray 
Cape Town 
SOUTH AFRICA 
Phone: 27-603843466 
E-mail: yvonieswartz@gmail.com 

 
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Community Representatives 
Javiera Arnillas  
José Santos Chocano 199 
Bellavista 07006, Callao 
PERU 
Phone: +51 902982804 
E-mail: a20130319@pucp.pe 
 
B’Yancha Lawson  
6431 Fannin Street, MSB 5.159 
Houston, TX 77030 
Phone: 713-500-5997 
E-mail: Byancha.Lawson@uth.tmc.edu 
 
International Site Specialist 
Mary Allegra Cermak, MFA 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3312 
E-mail: allegra.cermak@dlhcorp.com 
 
Laboratory Data Managers 
Frederic Bone 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext 7306 
E-mail: bone@frontierscience.org 
 
Sujith Valiyaparambil 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext 7291 
E-mail: valiyaparambil@frontierscience.org 
 
Laboratory Specialists 
Cherisse Heirs, BA 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
11075 Santa Monica Boulevard, Suite 200 
Los Angeles, CA 90025 
Phone: 585-397-4730 
E-mail: cheirs@milabcentral.org 
Laboratory Specialists (Cont’d) 
Sara Zabih, MS 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
University of California, Los Angeles 
675 Charles E. Young Dr. South 
MRL 4-774 
Los Angeles, CA 90095 
Phone: 310-794-9084 
E-mail: szabih@milabcentral.org 
 
Source Document Specialist  
Josie M. Marshall, BS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 303-724-0803 
E-mail: josie.marshall@dlhcorp.com 
 

 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5403@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5403@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon as 
possible to have the relevant personnel at the site added to the actg.protA5403 e-mail group. Include 
the protocol number in the e-mail subject line. Send an e-mail message to actg.user.support@fstrf.org.  
 
In order to remove site personnel from the actg.protoA5403 e-mail group, contact the 
User Support Group at the DMC. Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Clinical Management committee (CMC). Send an e-mail message to 
actg.cmcA5403@fstrf.org. Include the protocol number, patient identification number (PID), and 
a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic, virologic, or pharmacologic laboratory tests, 
contact the Protocol Immunologist, Virologist, or Pharmacologists. Send an e-mail message to 
actg.teamA5403@fstrf.org (ATTENTION: Nicholas Funderburg [Immunologist], Sara Gianella 
[Virologist], or Mackenzie Leigh Cottrell and Kimberly Scarsi [Pharmacologists]). 
 
Participant Registration  
For participant registration questions or problems and study identification number SID lists: send 
an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 716-834-
0900, extension 7301.  
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Lillian Collins 
and Elizabeth Siciliano directly.  
• 
For other questions, send an e-mail message to actg.teamA5403@fstrf.org (ATTENTION: 
Lillian Collins and Elizabeth Siciliano).  
• 
Include the protocol number, PID, and a detailed question. 
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. Send an e-mail message to actg.user.support@fstrf.org or call  
716-834-0900 x7302. 

 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist. Send an 
e-mail message to actg.teamA5403@fstrf.org (ATTENTION: Osarenoma Salawu). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites contact the Clinical Trials Specialist. 
Send an e-mail message to actg.teamA5403@fstrf.org (ATTENTION: Osarenoma Salawu). 
 
For questions related to protocol activation at non-US sites contact the ACTG Site Coordination 
Group. Send an e-mail message to actgsitecoordination@dlhcorp.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Oladapo Alli, Protocol Pharmacist, at 301-496-8213.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number is available on the protocol-specific web page (PSWP). For any questions related 
to the IND submission, contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5403 team members. Send an 
e-mail message to actg.teamA5403@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
3TC  
 
lamivudine 
3TC-TP 
lamivudine triphosphate 
ART   
antiretroviral therapy 
ARV 
 
antiretroviral  
AUC 
 
area under the concentration-time curve 
BIC  
 
bictegravir  
BMD  
bone mineral density 
CBC 
 
complete blood count 
CLIA  
Clinical Laboratory Improvement Amendments 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
 
coefficient of variation 
DAIDS  
Division of AIDS 
DDI 
 
drug-drug interactions 
DHHS   
United States Department of Health and Human Services 
DRV/c   
darunavir-cobicistat 
DTG   
dolutegravir 
DVT 
 
deep vein thrombosis 
EAE 
 
expedited adverse event 
EFV 
 
efavirenz 
eGFR  
estimated glomerular filtration rate 
FDA 
 
Food and Drug Administration  
FHT 
 
feminizing hormone therapy 
FTC   
emtricitabine 
FTC-TP 
emtricitabine triphosphate 
GCLP  
Good Clinical Laboratory Practice 
GMR  
geometric mean ratio 
HIV-1  
human immunodeficiency virus-1 
INSTIs  
integrase strand transfer inhibitors 
IQA 
 
immunology quality assurance 
MACE  
major adverse cardiovascular event 
NIAID  
National Institute of Allergy and Infectious Diseases 
PD 
 
pharmacodynamics 
PI 
 
protease inhibitor 
PK 
 
pharmacokinetics  

 
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PrEP  
pre-exposure prophylaxis 
PSWP  
protocol-specific web page  
PWH  
people with HIV 
SHBG  
sex hormone binding globulin 
SOC 
 
standard of care 
TAF  
 
tenofovir alafenamide 
TBL 
 
total bilirubin 
TDF   
tenofovir disoproxil fumarate 
TFV-DP 
tenofovir diphosphate 
TOST  
two-one sided tests 
TW 
 
transgender women

 
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SCHEMA 
 
A5403 
Giving Standardized Estradiol Therapy In Transgender Women to  
Research Interactions with HIV Therapy: the GET IT RIgHT Study 
 
DESIGN  
A5403 is a phase IIb, 48-week, open-label, non-randomized, three-group 
trial of adult transgender women (TW) and other individuals identifying as 
female or transfeminine but with male sex assigned at birth (henceforth 
referred to in aggregate as TW) living with human immunodeficiency 
virus-1 (HIV-1). Participants will be on antiretroviral therapy (ART) at entry 
and receive study-supplied 17- estradiol for feminizing hormone therapy 
(FHT) for study weeks 0-48. The primary objectives of the study are to 1) 
assess whether TW continue to achieve therapeutic concentrations of 
ART while receiving FHT for 48 weeks, and 2) assess whether serum 
estradiol concentrations on FHT (across a range of estradiol doses) vary 
between boosted and unboosted ART regimens. 
 
DURATION 
48 weeks on study. 
 
SAMPLE SIZE  
90 participants (30 per group).  
 
POPULATION 
TW with HIV, ≥18 years of age, on ART for ≥24 weeks prior to study 
entry, on a study-defined ART regimen at screening or willing to switch to 
one of the below regimens for at least 28 days prior to study entry. 
Participants must be virologically suppressed at screening (HIV-1 RNA 
<200 copies/mL or below the lower limit of detection if the local assay 
lower limit of detection is >200 copies/mL), must have the most recent 
HIV-1 RNA measurement obtained through routine clinical care between 
24 and 96 weeks prior to study entry that is <400 copies/mL, and not be 
on oral 17- estradiol for 14 days prior to study entry or injectable 17- 
estradiol 30 days prior to entry. Participants must be willing to initiate 
study provided 17- estradiol, refrain from any non-study provided 
estradiol for the study duration, and have no plans for anti-androgen use 
for weeks 0-24. The trial will aim to enroll at least 50% of participants 
identifying as non-white or Latine. 
 
REGIMEN 
At entry, participants are assigned to analysis groups based on their ART 
regimen, as below. Participants on other ART regimens at screening, who 
are willing to switch to one of the below regimens through standard of 
care, may be enrolled. Participants who switch ART will have to 
demonstrate continued virologic suppression at a pre-entry visit at least 4 
weeks post-switch. 
 
Group 1: Participants taking bictegravir (BIC) + tenofovir alafenamide 
(TAF) + emtricitabine (FTC)  
 

 
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Group 2: Participants taking dolutegravir (DTG) once daily + tenofovir 
disoproxil fumarate (TDF) + (FTC or lamivudine [3TC])  
 
Group 3: Participants taking any regimen containing darunavir plus 
cobicistat (DRV/c)  
 
Note for all groups: ART will not be provided by the study.  
 
Study treatment provided to all groups: Oral 17-β estradiol 2 mg once 
daily will be initiated at study entry. At weeks 4, 12, 24, and 36, study 
clinicians may titrate 17-β estradiol in 2 mg increments to achieve the 
desired participant goals and target hormone concentrations, as 
measured locally at each visit.  
 
As phenotypic (physical) changes will lag behind hormone concentrations 
in many cases, and participant goals will also influence titration decision, 
guidance on estradiol titration will be provided to sites (see A5403 Manual 
of Procedures [MOPS]). However, titration will generally occur until 
hormone concentration targets are achieved. Participants will not be 
required to titrate to the maximum estradiol concentration, but titration 
above the recommended therapeutic range will not be permitted for safety 
reasons. 
 
 
Schema Figure 1 

 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Primary Hypotheses 
 
1.1.1 Across oral 17-β estradiol doses from 2-10 mg daily, there will not be clinically 
significant reductions in ART exposure.  
 
1.1.2 Over 48 weeks, participants receiving DRV-containing ART will have lower 17- 
estradiol exposure than participants receiving DTG- or BIC-containing regimens. 
 
1.2 
Secondary Hypotheses 
 
1.2.1 Adverse events related to 17- estradiol will not differ by ART regimen but may 
differ by estradiol dose. 
 
1.2.2 Participants receiving DRV-containing ART will require higher doses of 17- 
estradiol to achieve similar feminizing hormone therapy (FHT) satisfaction as 
participants receiving BIC- or DTG-containing ART. 
 
1.2.3 Virologic effectiveness will be maintained in each ART regimen plus FHT over 48 
weeks. 
 
1.2.4 Higher 17- estradiol concentrations will be associated with greater weight gain 
and greater perturbations of lipids and insulin/glucose. 
 
1.2.5 The relationship between 17- estradiol dose and serum concentrations will 
reflect a dose proportional relationship. 
 
1.3 
Exploratory Hypotheses 
 
1.3.1 Higher 17- estradiol concentrations will be associated with decreased cellular 
HIV transcriptional activity, T cell cycling (Ki67), activation (HLA-DR+CD38+), and 
PD-1 expression. 
 
1.3.2  Participants in all arms will perceive the intervention acceptability similarly. 
 
1.3.3 17- estradiol administration will result in changes in sex hormone profiles (e.g., 
lower total and free testosterone, higher sex hormone binding globulin (SHBG) 
and free estradiol). 
 
1.3.4  Higher 17- estradiol concentrations will be associated with greater perturbations 
of inflammatory biomarker profiles. 
 

 
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1.4 
Primary Objectives 
 
1.4.1 To estimate trough concentrations of received ARVs before versus with each 
dose of oral 17- estradiol (2-10 mg), both in presence and in absence of 
concomitant anti-androgen use. 
 
1.4.2 To compare the trough serum estradiol concentrations achieved, at each 17- 
estradiol dose, between groups receiving boosted versus non-boosted ART.  
 
1.5 
Secondary Objectives 
 
1.5.1 To compare occurrence of FHT-associated adverse effects across ART groups 
and estradiol doses. 
 
1.5.2 To summarize intervention satisfaction across ART groups. 
 
1.5.3 To compare virologic suppression within ART groups, at each received 17- 
estradiol dose over 48 weeks. 
 
1.5.4 To compare the PK parameters (AUC, Ctrough, Cmax, Tmax) of 17- estradiol over 48 
weeks in a subset of TW undergoing intensive PK between groups receiving 
boosted versus non-boosted ART. 
 
1.5.5 To assess changes in weight, anthropometrics, lipids, glucose, and insulin 
sensitivity in relationship to estradiol concentrations.  
 
1.5.6 To assess the changes in estradiol concentrations across each 17- estradiol 
dosage and ART group. 
 
1.6 
Exploratory Objectives  
 
1.6.1 To explore the associations between 17- estradiol concentrations and cellular 
HIV transcriptional activity and T cell phenotype (cycling, activation, and 
exhaustion). 
 
1.6.2 To compare estradiol concentrations measured at a centralized research lab with 
real-time estradiol concentrations obtained through local labs. 
 
1.6.3 To describe changes in sex hormones following 17- estradiol administration. 
 
1.6.4 To assess changes in circulating biomarkers of inflammation in relationship to 
estradiol concentrations.  
 
1.6.5 To explore the relationship between ART and 17- estradiol PK parameters 
through population PK modeling and covariate analyses. 

 
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1.6.6 To examine the association of 17- estradiol concentrations and measures of 
satisfaction with gender affirming therapy using a population pharmacokinetic-
pharmacodynamic (PK-PD) model. 
 
1.6.7 To document intervention acceptability across ART groups. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Transgender women (TW) are the fastest-growing population of people with HIV (PWH) 
in the United States [1]. A survey of TW in the US in 2019-2020 found that 42.2% of 
1,561 participants were living with HIV [2]. TW also have an extremely high (19%) global 
prevalence of HIV, and TW of reproductive age have 49-fold higher odds of acquiring 
HIV compared to a similar age group [3]. Historically, TW have had very few 
opportunities to participate in clinical research and experience barriers to accessing and 
engaging in care [4]. As such, there are extremely limited data available on ART 
optimization for TW with HIV and no evidence-based clinical guidance on the choice of 
specific agents. 
 
Data suggest access to gender-affirming therapy improves time to initiation and uptake 
of HIV treatment and decreases treatment interruptions. Therefore, the Centers for 
Disease Control and Prevention (CDC) describes that access to gender-affirming care is 
critical to improving HIV outcomes among TW [2]. Data also suggest that provision of 
gender-affirming care has been associated with reduced rates of depression, 
anxiety, and suicidality among transgender persons [5, 6]. 
 
Feminizing Hormone Therapy (FHT): FHT is often an important component of gender-
affirming care for TW. FHT typically include exogenous estrogens with or without 
concomitant anti-androgens [7]. However, the doses and regimens used vary widely by 
provider, geography, and patient preference, and generally involve much higher doses 
than those used for oral contraception or menopausal transition in cisgender women [8] 
and/or for anti-androgen therapy in cisgender men.  
 
Currently, 17- estradiol is the preferred agent for FHT due to reduced risk of 
thromboembolic events compared to ethinyl estradiol. Route of administration varies, 
and may include pills, intramuscular injections, or transdermal patches. Dosing begins at 
1-2 mg daily but can approach 8-10 mg daily or more (in contrast to 0.02-0.045 mg of 
ethinyl estradiol daily for oral contraceptive use or 1-2 mg daily for post-menopausal 
replacement therapy). Dosing strategies vary widely by provider and geography, though 
guidelines such as those of The Endocrine Society and the World Professional 
Association for Transgender Health can help to guide care [9, 10]. Ultimately, 17- 
estradiol dosing is tailored to balance: 1) achieving target serum estradiol and total 
testosterone concentrations, 2) patient satisfaction with physical and emotional changes 
(i.e., clinical phenotype (physical), which typically progresses over 2-3 years following 

 
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FHT initiation), 3) side effect profiles, and 4) cost. Optimal dose titration of 17- estradiol  
is gradual over the first 1-2 years of use [11]. Thus, short-term studies cannot 
adequately assess FHT’s efficacy or safely test the doses required by many TW. 
 
Importantly, estradiol exposure (serum concentration) rather than dose is used to 
define safe thresholds for use and optimize efficacy. Estradiol is known to be a 
highly variable drug, due to individual differences in drug absorption, distribution, 
metabolism, and elimination. Therefore, irrespective of the dose administered, the 
serum concentration is what indicates if an individual is within the desired 
therapeutic range. More importantly, safety thresholds are established based upon 
estradiol exposure and not dose. This is a critical point as limited data suggest that 
nearly one third of trans women in clinical care do not achieve a serum estradiol 
concentration of >100 pg/mL on even 6 mg or 8 mg of oral estradiol daily [12]. As 
such, using the protocol-defined titration schematic will allow TW who need or 
want to maximize safe estradiol exposure to do so.  
 
Exogenous estrogen and antiretroviral drug-drug interactions (DDIs): Though concerns 
about adverse DDIs between ART and FHT have been documented by both providers 
and patients, few data exist to direct clinical care [13]. Importantly, patient concerns 
about DDIs may compromise adherence to ART [13-15]. The United States Department 
of Health and Human Services (DHHS) guidelines note that DDIs are an important 
consideration in ART choice for TW and that more data are needed to better guide 
therapeutic choices [16]. Documentation of an absence of significant DDIs with common 
ART strategies would offer reassurance to both patients and providers. 
 
Studies of low dose ethinyl estradiol used as oral contraception in cisgender females of 
reproductive age suggest that ethinyl estradiol exposure is influenced by some ART. For 
example, cobicistat-containing regimens decrease ethinyl estradiol exposure by 
approximately 30% [17, 18]. DDIs between ART and 17- estradiol are often extrapolated 
from ethinyl estradiol data, yet there are known differences in the metabolism of these two 
estrogens, limiting generalizability. Further, exogenous and endogenous hormones may 
influence drug metabolizing enzymes or drug transporters [19, 20], and therefore ART 
disposition and metabolism. In an ongoing study of females in Malawi on efavirenz (EFV)-
based ART and hormonal contraception (NCT03153709), higher estradiol concentrations 
were associated with lower plasma and cervico-vaginal fluid EFV concentrations, a finding 
hypothesized to be due to induction of P-glycoprotein by estradiol [21].  
 
No studies have explicitly been designed to understand the bidirectional relationships of 
modern ART and estrogen therapies at the doses typically used for FHT in TW [22, 23]. 
There are few data on the PK and pharmacodynamics of ART or 17- estradiol in TW using 
FHT. A recent phase III, randomized, controlled trial of HIV pre-exposure prophylaxis 
(PrEP) observed lower intracellular concentrations of tenofovir diphosphate (TFV-dp) in 
dried blood spot specimens from TW compared to cisgender men receiving TDF/FTC. 
While this finding could reflect a hormone-drug interaction [24], the investigators could not 
exclude adherence differences as a potential explanation [25], and standardized FHT was 
not provided by the study, leaving many open questions. In a study of 20 TW with HIV who 

 
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were receiving ART and initiating low-dose FHT (17- estradiol 2 mg daily), blood tenofovir 
concentrations were 13% lower after FHT initiation, though still above the concentration 
believed to be needed to stop viral replication [26]. In a separate study of 4 TW and 4 
cisgender women, the balance of TFV-dp to its competing substrate (dATP), an important 
effector of drug potency, was 7-fold lower in rectal biopsies of TW than cisgender women, 
and exhibited an inverse relationship with serum estradiol concentrations [19]. Finally, two 
additional studies identified lower plasma exposure of tenofovir or FTC in TW, while the 
intracellular TFV-dp was higher than observed in prior reports [27, 28].  
 
Taken together, these preliminary findings are inconclusive, with limited testing or 
unknown exposures to estrogen in small groups of participants, yet indicate that FHT 
may be relevant to the efficacy of ART. There is a clear need for a focused study in 
larger groups of TW with HIV on commonly used, contemporary ART regimens to inform 
our understanding of FHT and ART at the estrogen doses commonly used for FHT. 
Indeed, DHHS guidelines acknowledge that DDI recommendations regarding ART and 
FHT co-prescription are based on expert opinion, and more data from clinical trials is 
needed to provide an evidence-based approach to the care of TW with HIV [16]. 
 
2.2 
Rationale 
 
This protocol will address the existing gap in knowledge on optimization of ART and FHT 
for TW with HIV. FHT is a long-term medication, titrated over 1-2 years to optimal 
dosing. Thus, short-term studies cannot adequately assess FHT’s efficacy or safely test 
the doses ultimately required by many TW, including testing for dose-dependent DDIs.  
 
Additionally, FHT and ART are both known to contribute to clinically significant metabolic 
disturbances, including weight gain and lipid and insulin/glucose abnormalities, and 
anecdotal evidence suggests high rates of new or worsening metabolic disturbances 
with FHT titration in TW with HIV on ART. However, the severity and sequelae of these 
changes have not been previously documented in TW with HIV on ART and FHT, yet 
this knowledge could profoundly affect optimization of care. Therefore, we propose a 
study duration of 48 weeks to evaluate a range of 17- estradiol doses. Oral 17- 
estradiol was chosen for this evaluation due to ease and range of dose titration options, 
storage considerations, generic formulation, and international accessibility. All of these 
factors make oral 17- estradiol the most practical and widely available option for 
transition of participants following study closure. 
 
ART in TW with HIV: Integrase strand transfer inhibitors (INSTIs) that do not require PK 
boosters (e.g., cobicistat) are the drugs of choice for most PWH [16], and may be an 
optimal ART base for use with FHT due to the lower potential for DDIs, adverse effects, 
and food requirements compared to other ART classes. For example, regimens requiring 
cobicistat may result in the need for additional monitoring and/or FHT dose adjustment. 
Similarly, as both HIV and FHT are associated with increased cardiovascular 
disease/thromboembolic risk, abacavir-containing regimens may not be preferred. TW 
also have high rates of food insecurity and depression, making NNRTI-containing 
regimens that require dosing with meals or with concomitant neuropsychiatric side 

 
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effects less desirable. Given these considerations, a once daily, unboosted INSTI in 
combination with an abacavir-sparing NRTI backbone may be the preferred ART 
regimen for TW with HIV using FHT.  
However, the potential for excess weight gain with INSTIs [29, 30], which could be enhanced 
by concomitant FHT-induced anthropometric changes, individualized resistance profiles and 
other factors may not permit use of INSTIs or unboosted regimens. Therefore, protease 
inhibitors (PIs) will continue to play a role in ART optimization for some patients for the 
foreseeable future. Additionally, TW (on average) have lower bone mineral density (BMD) than 
age-matched controls [31], and agents with improved bone health profiles, such as TAF, may 
be beneficial [16]. In summary, evaluating an unboosted INSTI-based ART regimen in addition 
to a PI-based regimen will more comprehensively inform ART options for TW receiving FHT.  
 
Therefore, we propose investigating the two most commonly used INSTIs in the global ART 
landscape: BIC/TAF/FTC and DTG/TDF/FTC or 3TC. We selected DRV as a PI-based 
regimen available domestically and internationally. DRV is a common component of 
regimens for persons with resistance or virologic failure. We will enroll all participants 
receiving DRV plus cobicistat, and will allow inclusion of regimens including NRTIs or INSTIs 
along with DRV. Requiring relative virologic suppression will reduce inclusion of persons 
with medication adherence issues and reduce confounding of current or recent viremia for 
key secondary endpoints. In addition, there is a planned grant submission for an HIV 
reservoir and inflammatory biomarker banked sample substudy. 
 
ART-FHT potential for DDIs: Early data in small studies of individuals receiving FHT and 
either PrEP or ART indicated some cause for concern regarding the bidirectional DDIs 
between these two important therapies. Importantly, available data on ART-FHT DDIs in 
TW have not exceeded 17- estradiol doses of 2-4 mg daily, which are merely starting 
doses for many TW. These low doses in prior studies are reflected in low serum 
estradiol levels, which did not approximate the physiologic concentrations required for 
most feminization effects, and do not allow for the possibility of a dose-dependent DDI. 
 
Our approach will characterize ART and 17- estradiol PK and the 17- estradiol dosing 
required to achieve target serum estradiol concentrations and participant satisfaction. By 
addressing both issues, we hope to demonstrate to both TW and their providers that 
estradiol exposure at the doses used for FHT can be attained without compromise of 
virologic control or feminizing effects, despite any observed DDIs. This addresses a key 
research priority for domestic and international communities of TW, as identified in the 
findings of the ACTG Transgender Working Group.  
 
To determine whether a clinically significant ART-FHT DDI exists, plasma concentrations 
of BIC, DTG, and DRV will be evaluated in the context of therapeutic thresholds. In the 
absence of well-defined and widely recognized therapeutic drug monitoring (TDM) 
targets for all of these ARV, we will use the lower 95% percentile of their trough 
concentrations from intensive PK studies. However, if new PK/ pharmacodynamic (PD) 
data become available that improves on this current plan to declare therapeutic 
exposure, we will adapt our analysis plans.  
 

 
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The existence of a clinically significant DDI for NRTIs will be evaluated on the basis of their 
active moieties (TFV-DP, FTC-TP, and 3TC-TP) within PBMCs rather than plasma 
concentrations of the nucleoside analog. The reasoning for this is 2-fold. First, we are enrolling 
TW taking either TAF or TDF, and these tenofovir prodrugs result in very different plasma PK 
profiles. Additionally, to date 4 small clinical trials have explored whether an FHT-TFVdp DDI 
exists with inconsistency in conclusions [27, 28, 32, 33]. These trials have all been designed to 
evaluate TFVdp PK against cisgender controls and some have utilized historical controls. Given 
the relatively high degree of variability in TFVdp PBMC PK, a DDI study designed to explore 
between group differences increases risk of a type II error. Our proposed study design offers an 
improvement in that we will interrogate for individual changes pre- and post-FHT initiation.  
 
Finally, this is the first study that will be able to characterize 17- estradiol PK and PD 
measures of FHT effectiveness across a range of 17- estradiol doses over 48 weeks, 
given that FHT is titrated to clinical response and safety thresholds, characterizing whether 
a dose proportional relationship exists for FHT and whether that relationship is altered by 
DRV/c is an important consideration in interrogating whether a clinically significant ART-
FHT DDI exists. Previous studies have reported a predictable relationship between dose 
and concentrations for topically applied estradiol used as hormone replacement therapy in 
post-menopausal women [34, 35]; however, none have characterized this relationship in 
the context of FHT for TW or in patients with HIV taking ART. 
 
ART-FHT PK Measurements: To comprehensively address these scientific gaps, we 
propose serial trough concentrations at each visit, paired with intensive PK sampling in 
15 participants per ART group at baseline, and then at two time points (weeks 24 and 
48) with varying 17- estradiol dosing. By combining this sparse and intensive PK 
approach we have the ability to characterize the PK of both ART and 17- estradiol after 
an observed drug dose, which will enrich the sparse sampling after a self-reported dose. 
PK parameters of both ART and 17- estradiol can be efficiently compared with non-
compartmental methods, target threshold attainment, and combined in a population 
PK:PD analysis to assess the influence of covariates on PK exposure and PD outcomes. 
 
Rationale for participant intervention and FHT satisfaction surveys: The complexity of 
dire social realities faced by TW magnify HIV vulnerabilities and limit engagement in 
routine medical care and research [3, 36, 37]. Additionally, in clinical settings, FHT 
dosing is significantly impacted by individual patient goals and progress towards goals, 
which we hope to replicate in this study. The inclusion of study satisfaction and 
acceptability measures are a unique opportunity to not only understand psychosocial 
impacts of gender-affirming care through this intervention, but also to improve research 
processes targeting this community. Also, because individual participant goals of FHT 
vary, and because physical changes will lag behind study dose titrations and timelines 
for some participants, assessing progress towards individual participant goals over the 
48-week study period will be important to understand and contextualize. 
 
Study population: We will enroll only adult TW (individuals currently identifying as trans 
women, female or transfeminine, but with male sex assigned at birth) with HIV. Because 

 
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gender-affirming therapy in adolescents can involve puberty blockers and transition to 17-
 estradiol has additional safety considerations during physical development, this study 
will only enroll adults ≥18 years of age. We will enroll individuals relatively virologically 
suppressed on the ART regimens described above and who are not receiving FHT at 
entry to allow for standardized dose titration across groups. The ACTG Transgender 
Working Group survey of ACTG sites indicate sufficient number of potential participants 
who fulfill these important criteria already exist in the communities served by the sites. 
The Working Group’s findings also highlighted access to hormones through the study as 
a major incentive for trial participation due to restricted or difficult access/affordability in 
many domestic and international locations. Subsequent site surveys have validated the 
Working Group’s findings. 
 
2.2.1 Rationale Summary 
 
To address these open questions, we propose a 48-week, open-label, DDI study among 
adult TW with HIV on contemporary ART who are initiating or restarting FHT. The 
proposed ART regimens will allow for inclusion of diverse populations of TW domestically 
and internationally. Provision of algorithm-based escalation of standardized FHT 
regimens will allow us to answer the critical scientific questions noted above at the doses 
of 17- estradiol commonly used by TW and with a high degree of scientific rigor. As the 
study design will be modeled after routine clinical care, the study will also be highly 
clinically relevant. The primary outcome measures will be both 1) ART PK before and 
after FHT initiation and dose escalation and 2) the serum estradiol concentrations 
achieved at escalating 17- estradiol doses between groups receiving boosted versus 
non-boosted ART. We will assess virologic and safety endpoints as well as participant 
satisfaction with their FHT goals, and acceptance of our intervention in diverse 
communities of TW. These data will fill critically important gaps regarding optimization of 
ART and FHT co-administration for TW for both providers and patients. 
 
3.0 
STUDY DESIGN 
 
A5403 is a phase IIb, 48-week, open-label, non-randomized, 3-group trial, of 90 adult (18 
years) TW living with HIV on suppressive ART and not currently on FHT. All participants 
will continue on ART and receive study-supplied 17- estradiol for weeks 0-48. The primary 
objectives of the study are to determine whether 1) TW achieve therapeutic concentrations 
of ART while receiving escalating doses of FHT, assessed within each ART group and 2) 
the trough serum estradiol concentrations achieved at escalating 17- estradiol doses 
varies across ART groups, specifically compared between boosted and unboosted ART. 
 
The study consists of three groups, a BIC-treated group (BIC/TAF/FTC; n=30) (Group 1), a 
DTG-treated group (DTG/TDF/FTC or 3TC; n=30) (Group 2), and a boosted DRV-treated 
group (DRV/c; n=30) (Group 3), for a total of 90 participants. TW will receive study supplied 
17- estradiol for weeks 0-48. We will target at least 50% enrollment of participants 
identifying as non-white or Latine. 
 

 
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FHT regimen and monitoring  
Oral 17- estradiol 2 mg once daily will be initiated at study entry. At weeks 4, 12, 24, 
and 36, study clinicians may titrate 17- estradiol in 2 mg increments as described in 
section 5.1. 
 
Pharmacology Study Design 
Steady-state antiretroviral and steady-state 17- estradiol PK will be assessed 
throughout the study using intensive and sparse PK sampling. At entry (week 0), an 8-
hour intensive PK visit will occur to collect and store samples to assess ART exposure 
prior to FHT initiation in 15 participants per ART group (baseline). At week 24, intensive 
sampling will be repeated in the same 15 participants to assess 17- estradiol and ART 
exposure after 24 weeks of continuous FHT. A final intensive PK visit will occur at week 
48 (or premature discontinuation) to assess 17- estradiol and ART exposure at the 
maximal FHT dosing achieved during the study period. In addition, all participants not 
participating in an intensive PK sampling visit on the same day will have timed, sparse 
PK sampling collected at each visit to characterize the trough plasma (BIC, DTG, and 
DRV) and intracellular ART (TFV-DP, FTC-TP, 3TC-TP) concentrations to evaluate the 
relationship of ART PK exposure across a range of 17-β estradiol doses (see section 
6.3.10 for more details). 
 
FHT satisfaction and acceptability 
We will measure indicators of intervention satisfaction and acceptability throughout the 
study period. To measure acceptability, we will ask participants to self-report the degree 
to which they find the intervention appropriate and useful using Likert-type agreement 
scales at three study time points: entry, 24 weeks, and 48 weeks. To measure 
satisfaction, we will use the 12-question Transgender Congruence Scale (TCS), which 
will assess associations between gender-affirming treatments, perceived gender 
congruence, and satisfaction at three study time points: entry, 24 weeks, and 48 weeks 
[38]. The TCS has demonstrated high internal consistency (alpha >0.80) and has been 
utilized in numerous clinical settings [39-41]. In addition, we will conduct brief, 20-minute, 
semi-structured interviews with 30 purposively sampled participants across English- or 
Spanish-speaking sites to provide an opportunity for more in-depth (open-ended) 
feedback on intervention satisfaction and acceptability at three time points: entry, 24 
weeks, and 48 weeks (see section 12.0 for more details). 
 
Other assessments throughout the study 
Anthropometric measurements (including weight, height, minimum waist circumference, 
and maximum hip circumference), routine labs, HIV-1 RNA, CD4+ and CD8+ T cell 
counts and percentages, lipids, glucose and insulin, non-estradiol hormone 
concentrations, stored PBMC, plasma, and serum, suicidality assessments, and ART 
and FHT use and adherence assessments.  
 
Post-trial access 
17- estradiol will not be provided by the study post-trial. If applicable, sites will need to 
provide options to participants for transitioning to community resources for hormone 

 
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acquisition after the study (see MOPS for more detail). 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Age ≥18 years. 
 
4.1.2 HIV-1, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies, or for sites located in countries other than the United States, a kit 
that has been certified or licensed by an oversight body within that country and 
validated internally. Non-US sites are encouraged to use US FDA-approved 
methods for IND studies. 
 
World Health Organization (WHO) and CDC guidelines mandate that 
confirmation of the initial test result must use a test that is different from the one 
used for the initial assessment. A reactive initial rapid test should be confirmed 
by either another type of rapid assay or an E/CIA that is based on a different 
antigen preparation and/or different test principle (e.g., indirect versus 
competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.3 Assigned male sex at birth and identifies as a TW, female or transfeminine person.  
 
4.1.4 On ART for at least 24 weeks prior to study entry. Regimen changes within the 
24 weeks prior to study entry are acceptable, but candidates must have been on 
a stable regimen for at least 28 days prior to study entry. 
 
4.1.5 On BIC/FTC/TAF, DTG/TDF/FTC or 3TC, or DRV/c-containing ART for at least 
28 days prior to study entry (single tablet regimen not required), and with no 
plans to change ART regimen over the study duration of 48 weeks. 
 
NOTE: Candidates not on the required regimens at screening may switch ART to 
DRV/c-, DTG-, or BIC-based ART through routine clinical care, with the 
recommendation that TW on PI or NNRTI-based ART switch to DRV/c, and TW 
on other INSTI-based ART switch to BIC or DTG (as locally available). After 28 
days, TW who switched ART will have HIV-1 RNA rechecked at the pre-entry 
visit. Those who remain suppressed may proceed to study entry. TW already on 
the permitted ART regimens will proceed directly to study entry from screening. 
 

 
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NOTE: DTG dosing is restricted to once daily. Persons on bid dosing are 
not eligible. 
 
4.1.6 Desire to initiate or restart FHT, regardless of orchiectomy status. 
 
4.1.7 HIV-1 RNA <200 copies/mL (or below the assay limit of detection if local assay 
lower limit of detection is >200 copies/mL) at screening (within 60 days prior to 
entry) at any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent, or at any network-approved 
non-US laboratory that operates in accordance with Good Clinical Laboratory 
Practice (GCLP) and participates in appropriate external quality assurance 
programs.  
 
NOTE: For candidates switching ART after screening, an HIV-1 RNA 
<200 copies/mL (or below the assay limit of detection if local assay lower limit of 
detection is >200 copies/mL) at pre-entry (at least 4 weeks post-switch) will be 
required prior to study entry. 
 
4.1.8 HIV-1 RNA <400 copies/mL available through routine clinical care between 24 
and 96 weeks prior to study entry and while on ART. The HIV-1 RNA must be the 
most recent value obtained between 24 and 96 weeks prior to study entry.  
 
NOTE: Entry will be allowed if the most recent HIV-1 RNA available between 24 
and 96 weeks prior to entry through routine care is a single, unconfirmed plasma 
HIV-1 RNA >400 but <2000 copies/mL, and if this single measurement is 
preceded by an HIV-1 RNA <400 copies/mL and followed by an HIV-1 RNA <400 
copies/mL (latter allowable if measured in the 24 weeks prior to entry and before 
screening). 
 
4.1.9 The following laboratory values obtained within 60 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. 
• 
Hemoglobin ≥9.0 g/dL 
• 
Platelet count ≥75,000/mm3 
• 
Estimated Glomerular Filtration Rate (eGFR) ≥30 mL/min/1.73m2 if on or 
switching to TAF, ≥50 mL/min/1.73m2 if on or switching to TDF without 
cobicistat, or ≥70 mL/min/1.73m2 if on or switching to TDF in 
combination with cobicistat, calculated using the CKD-Epi equation (a 
calculator is available at: https://qxmd.com/calculate/calculator_251/egfr-
using-ckd-epi). 
• 
Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) 
(SGPT), and alkaline phosphatase are within normal range per local 
laboratory range 
• 
Prolactin <25 ng/dL 

 
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4.1.10 Serum estradiol level <75 pg/mL within 60 days prior to study entry.  
 
NOTE: If a participant is on estradiol therapy at screening, the participant may go 
off estradiol for the required period of time during the screening window and then 
have their estradiol level assessment performed (not required to be performed at 
the screening visit). Sites should be aware of the turnaround time for local 
estradiol levels so that the value can be obtained and the participant enrolled 
before the screening window ends. 
 
4.1.11 Willingness to avoid the use of prescribed, non-study provided FHT and non-
prescribed FHT during the study period, and no planned use of prescribed or 
non-prescribed anti-androgens for the first 24 weeks of the study.  
 
4.1.12 Ability and willingness of participant to provide informed consent and ability and 
willingness of participant to undergo study procedures.  
 
4.2 
Exclusion Criteria 
 
4.2.1 Known clotting disorders, active deep vein thrombosis (DVT), pulmonary 
embolism (PE), or history of these conditions, active arterial 
thromboembolic disease (e.g., stroke, myocardial infarction), or history of 
these conditions.  
 
4.2.2 Known liver impairment or disease.  
 
NOTE: Prior incidental ultrasound, CT, or transient elastography findings of 
hepatic steatosis (“simple steatosis”) without transaminase elevation or 
known hepatic fibrosis is not exclusionary. 
 
4.2.3 History of chronic hepatitis B virus (HBV) infection or active HBV infection. 
 
NOTE A: Persons with documented natural (spontaneous clearance) or 
vaccine-induced HBV immunity (anti-HBsAg >10 UI/mL) are not excluded. 
 
NOTE B: Laboratory results/medical records are required documentation. 
Participant self-report cannot be used for documentation of viral hepatitis 
status. 
 
4.2.4 History of current active hepatitis C virus (HCV) infection. 
 
NOTE A: Persons with documented spontaneous clearance of HCV are not 
excluded. 
 
NOTE B: Persons with documented cure of HCV, defined as negative HCV 
RNA ≥12 weeks after end of treatment, without known liver 

 
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impairment (as per exclusion 4.2.2) are not excluded. 
 
NOTE C: Persons with HCV antibody seropositive within 1 year prior to 
entry but without standard of care HCV RNA to determine if 
disease is active will be excluded. If HCV RNA testing is not  
locally available, then HCV antibody seropositivity alone will be a 
cause for exclusion. 
 
NOTE D: Laboratory results/medical records are required documentation. 
Participant self-report cannot be used for documentation of viral 
hepatitis status. 
 
4.2.5 Prohibited medication use (including drugs with known or expected DDIs with 
FHT or ART) at time of study entry. See section 5.4.2 for a list of prohibited 
medications. 
 
4.2.6 Receipt of any estrogen therapy within 14 days prior to study entry for persons 
on oral FHT, or within 30 days prior to entry for persons on injectable FHT. 
 
4.2.7 Known HIV-1 resistance mutations that would preclude remaining on current 
ART or a switch to a study regimen, in the opinion of the site investigator. 
 
4.2.8 Personal history of breast cancer or known personal history of breast cancer 
(BRCA) gene. 
 
4.2.9 Known or a history of testicular cancer. 
 
4.2.10 Known or a history of gall bladder disease. 
 
4.2.11 Known or suspected pituitary adenoma.  
 
4.2.12 Known allergy/sensitivity or any hypersensitivity to components of study drugs or 
their formulation. 
 
4.2.13 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.14 Suicidal ideation in the past 30 days or suicide attempt in the past 90 days, 
as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
NOTE: Refer to section 8.4 and the MOPS for C-SSRS interpretation and 
additional management recommendations. 
 
4.2.15 Serious illness requiring systemic treatment and/or hospitalization within 30 days 
prior to entry. Stable (in the opinion of the site investigator) treatments for chronic 
comorbidities are allowed. 

 
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4.2.16 Presence of any other medical condition that would preclude FHT administration 
for safety reasons, in the opinion of the site investigator.  
 
NOTE: Use of tobacco or other nicotine-containing products is not an absolute 
contra-indication to FHT. The thromboembolic risk associated with estrogen use 
in persons who use these products and options for smoking cessation 
resources will be discussed during the informed consent process. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) as well as 
meeting any additional study-specific requirements as determined by the 
protocol team, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. Site-specific ICF(s) WILL NOT be reviewed and approved by the DAIDS 
PRO, and sites will receive an Amendment Registration Notification from the 
DAIDS PRO that approves the site-specific ICFs and indicates successful 
completion of the amendment protocol registration process. A copy of the final 
Amendment Registration Notification issued by the DAIDS PRO should be 
retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form.  
 

 
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Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Study Enrollment System (SES).  
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
4.3.3 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Co-enrollment in A5128 does not require permission from the 
A5403 protocol chairs.  
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-US Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5403 protocol chairs.  
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the protocol team via e-mail as described in the 
Study Management section. 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as 17-β estradiol and will be provided through the study.  
 
5.1 
Regimens, Administration, and Duration 
 
At entry, participants will be assigned to analysis groups based on their ART regimen, as 
described below: 
 
Group 1: Participants taking bictegravir (BIC) + tenofovir alafenamide (TAF) + 
emtricitabine (FTC)  
 
Group 2: Participants taking dolutegravir (DTG) + tenofovir disoproxil fumarate (TDF) + 
(FTC or lamivudine [3TC])  
 

 
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Group 3: Participants taking any regimen containing darunavir plus cobicistat (DRV/c). 
 
Feminizing hormone therapy regimen, dose escalation, and monitoring 
Participants will be taking 17- estradiol 2 mg by mouth once daily, to be initiated at study 
entry. At weeks 4, 12, 24, and 36, study clinicians may titrate 17- estradiol in 2 mg 
increments. This titration schedule aligns with guidelines that suggest monitoring a 
minimum of every 3 months during the first year of FHT and to titrate dosage upward over 
the first 3-6 months and until goals are achieved [7, 42]. An example dose escalation  
schedule for a participant who chooses to dose escalate at every visit is shown below in 
Table 5.1-1. Participants who choose not to escalate, or to de-escalate at any given visit, 
will have a different schedule. 
 
Table 5.1-1: Possible Dose Escalation Schedule 
Maximum 17-β Estradiol Dose 
Weekly Titration Schedule 
2 mg/day (one 2 mg tablet) 
Weeks 0-4 
4 mg/day (two x 2 mg tablets) 
Weeks 4-12 
6 mg/day (three x 2 mg tablets) 
Weeks 12-24 
8 mg/day (four x 2 mg tablets) 
Weeks 24-36 
10 mg/day (five x 2 mg tablets) 
Weeks 36-48 
 
Refer to section 6.3.5 for more detailed clinical and laboratory considerations and to 
section 8.0 for safety considerations when considering dose escalation. Additional 
guidance for investigators and study site clinicians is provided in the MOPS. 
 
Participants will remain on study-provided 17- estradiol for 48 weeks or until study 
discontinuation procedures are performed. If participants cannot complete their 
discontinuation assessments within the 48-week time period, additional study drug 
should be dispensed to ensure participants are on drug at the time of discontinuation 
assessments.  
 
5.2 
Study Product Formulation and Preparation 
 
17-β estradiol will be supplied as 2 mg tablets. Tablets should be stored at controlled 
room temperature 15-30°C (59-86°F). Dispense in a tight, light resistant container, as 
defined by the United States Pharmacopeia. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
17-β estradiol is manufactured and supplied by Epic Pharma LLC and is available 
through the NIAID Clinical Research Products Management Center (CRPMC). The 
site pharmacist should obtain the study product(s) for this protocol by following the 
instructions in the manual Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks.  

 
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Any study product not provided by the study must comply with the NIAID (DAIDS) 
policy that outlines the process for authorizing the use of study products not 
marketed in the United States in NIAID (DAIDS)-supported and/or -sponsored clinical 
trials. This policy is available on the NIAID (DAIDS) website at 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 
17-β estradiol may be locally sourced by clinical research sites that are unable to 
import study-provided 17-β estradiol. The A5403 Site Implementation Plan (SIP) 
must be completed by each site for protocol team notification and authorization of 
locally sourced 17-β estradiol. 
 
17-β estradiol tablets locally procured by the site and approved for use in A5403 
by the protocol team must be stored in accordance with the manufacturer’s 
instructions. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC, locally sourced and subsequently dispensed. At 
US CRSs, all unused study products must be returned to the NIAID CRPMC (or as 
otherwise directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are provided in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks. At non-US CRSs, the site 
pharmacist must follow the instructions in the Pharmacy Guidelines and Instructions 
for DAIDS Clinical Trials Networks for the destruction of unused study products. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose is changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Required Medications 
 
ART in any of the following combinations: BIC/FTC/TAF, DTG 50 mg daily + 
TDF and FTC or 3TC, or DRV/c 800/150 mg daily + other ARVs. 
 
ART will not be provided; participants will obtain it through standard of care (SOC) 
or co-enrollment in a clinical study (latter if approved by the A5403 study team). 
 
5.4.2 Prohibited Medications 

 
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In addition to consulting the lists below, sites are advised to consult the most 
recent package insert of any medication. Note that topical or short-term use of 
some otherwise prohibited drugs may be allowed on a case-by-case basis, after 
discussion with and approval by the A5403 Clinical Management Committee 
(CMC). Please e-mail the CMC at: actg.cmcA5403@fstrf.org. 
 
5.4.3 Prohibited medications for all participants during the study 
 
5.4.3.1 All other hormones, including but not limited to: 
• 
Delestrogen  
• 
Depotestrogen 
• 
Desogestrel  
• 
Drospirenone  
• 
Estradiol cypionate  
• 
Estradiol Valerate 
• 
Estrogens, Conjugated 
• 
Estrogens, Esterfied 
• 
Ethinyl Estradiol  
• 
Ethynodiol Diacetate  
• 
Etonogestrel via a vaginal ring  
• 
Gestodene  
• 
Hydroxyprogesterone 
• 
Levonorgestrel  
• 
Medroxyprogesterone 
• 
Nandrolone decanoate  
• 
Norelgestromin 
• 
Norethindrone 
• 
Norethisterone enanthate 
• 
Norgestimate  
• 
Norgestrel  
• 
Segesterone 
• 
Progesterone 
• 
Testosterone 
• 
Non-prescribed FHT (“street hormones”)  
• 
Cyproterone acetate 
▪ 
Gonadotropin releasing hormone analogues (GnRH) (Goserelin, 
Leuprolide acetate, Triptorelin)  
 
5.4.3.2 Antiretroviral drugs other than those allowed by the study 
 
5.4.3.3 Moderate-to-strong inducers of CYP3A4, which may include, but not 
limited to the following:  
• 
St. John’s Wort preparations (Hypericum perforatum) 

 
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• 
Bosentan 
• 
Phenobarbital 
• 
Carbamazepine  
• 
Oxcarbazepine 
• 
Eslicarbazepine 
• 
Phenytoin 
• 
Fosphenytoin 
• 
Apalutamide 
• 
Enzalutamide 
• 
Mitotane 
• 
Rifampin 
• 
Rifapentine 
• 
Rifabutin  
• 
Betametasone 
• 
Dexamethasone 
 
5.4.3.4 Moderate-to-strong inhibitors of CYP3A4 which includes, but are not 
limited to:  
• 
African potato (hypoxis hemerocallidea) 
• 
Erythromycin 
• 
Clarithromycin  
• 
Fluconazole 
• 
Ketoconazole 
• 
Itraconazole 
• 
Posaconazole 
• 
Voriconazole 
• 
Nefazodone 
• 
Antiarrhythmics (amiodarone, drodenarone, ranolazine) 
• 
Calcium channel inhibitors (Diltiazem, verapamil) 
• 
Dasabuvir plus Paritaprevir/Ombitasvir/Ritonavir (Viekira Pak) 
• 
Ledipasvir/ Sofosbuvir* 
*Only applies to participants receiving TDF or TAF. 
 
5.4.4 Precautionary Medications 
 
The following medications are designated as precautionary for use in all 
participants in the study: 
• 
Thyroid hormone replacement therapy 
• 
Grapefruit juice  
• 
Nirmatrelvir/ritonavir (Paxlovid): When possible, participants receiving 
Paxlovid therapy should have PK visits at least 3 days after Paxlovid therapy 
is completed. 
 

 
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The following medications are designated as precautionary medications for all 
participants receiving bictegravir or dolutegravir containing regimens: 
• 
Antacids or supplements containing polyvalent cations (e.g., aluminum, 
calcium, copper, iron, magnesium, zinc): Follow product labeling for dose 
separation  
 
The following medications are designated as precautionary medications for all 
participants during the first 24 weeks of the study: 
• 
Spironolactone 
• 
Finasteride  
• 
Dutasteride 
 
Anti-androgen therapy will not be offered as part of the study. Participants and 
providers will be asked to refrain from initiating anti-androgen therapy obtained 
outside of the study for weeks 0-24, which is within the accepted spectrum of 
standard of care and will provide additional study rigor [4, 43]. The 
aforementioned references highlight the fact that, while concomitant initiation of 
estradiol and anti-androgen therapy may occur in some clinical settings, it is not 
the more widely accepted SOC, the effects of different anti-androgens are not 
equivalent, and concomitant initiation may have disadvantages [44, 45].  

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Schedule of Evaluations 
Evaluation 
Screening 
Pre-Entry 
(if needed) 
Entry / Day 0 
Post-Entry Evaluations 
(Weeks) 
Premature 
Study/Treatment 
Discontinuation  
Evaluations 
4 
8 
12 
24 
36 
48 
Visit Windows 
Within 60 
days prior to 
entry 
Minimum 28 
days after 
ART switch 
± 7 days 
± 14 days 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
Medication History 
X 
 
X 
 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Nicotine Use 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Concomitant Medications 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Targeted Medications 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Treatment Modifications 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Site Investigator FHT dose 
assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
 
 
 
X 
 
X 
X 
Liver Function Tests 
X 
 
X 
X 
 
X 
X 
X 
X 
X 

 
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Evaluation 
Screening 
Pre-Entry 
(if needed) 
Entry / Day 0 
Post-Entry Evaluations 
(Weeks) 
Premature 
Study/Treatment 
Discontinuation  
Evaluations 
4 
8 
12 
24 
36 
48 
Visit Windows 
Within 60 
days prior to 
entry 
Minimum 28 
days after 
ART switch 
± 7 days 
± 14 days 
Chemistries  
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Estradiol concentration 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Prolactin concentration 
X 
 
 
 
 
 
 
 
 
 
Total testosterone concentration  
 
 
X 
X 
 
X 
X 
X 
X 
X 
CD4+/CD8+ 
 
 
X 
 
 
 
 
 
X 
X 
Plasma HIV-1 RNA  
X 
X 
X 
 
 
X 
X 
X 
X 
X 
HBV surface antigen testing (see 
section 6.3.8) 
X 
 
 
 
 
 
 
 
 
 
HCV testing (see section 6.3.8) 
X 
 
 
 
 
 
 
 
 
 
Fasting lipid panel  
 
 
X 
 
 
X 
X 
 
X 
X 
Intensive PK subset (See section 
6.3.10) 
 
 
X 
 
 
 
X 
 
X 
X 
Timed trough PK sampling (See 
section 6.3.10) 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Stored Plasma/Serum  
 
 
X 
X 
 
X 
X 
X 
X 
X  
Stored PBMC 
 
 
X 
 
 
 
X 
 
X 
X 
C-SSRS questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ART adherence assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 

 
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Evaluation 
Screening 
Pre-Entry 
(if needed) 
Entry / Day 0 
Post-Entry Evaluations 
(Weeks) 
Premature 
Study/Treatment 
Discontinuation  
Evaluations 
4 
8 
12 
24 
36 
48 
Visit Windows 
Within 60 
days prior to 
entry 
Minimum 28 
days after 
ART switch 
± 7 days 
± 14 days 
FHT adherence assessments 
 
 
 
X 
 
X 
X 
X 
X 
X 
FHT Participant Goals 
 
 
X 
 
 
 
 
 
X 
X 
FHT acceptability and satisfaction 
surveys 
 
 
X 
 
 
 
X 
 
X 
X 
Semi-structured interview subset 
 
 
X 
 
 
 
X 
 
X 
X 
Remote visit 
 
 
 
 
X 
 
 
 
 
 
 

 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening and Pre-Entry Evaluations  
 
Screening and pre-entry evaluations must occur prior to the participant starting 
any study medications, treatments, or interventions. 
 
Screening 
Screening evaluations to determine eligibility must be completed within 60 days 
prior to study entry unless otherwise specified. The estradiol assessment can 
occur any time after screening has been initiated that is appropriate based upon 
timing of the participant’s last dose of estradiol. Confirmation of serum estradiol 
<75 pg/mL must be received prior to study entry. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database.  
 
Pre-Entry  
The pre-entry visit is only required for participants who switched ART at screening. 
HIV-1 RNA testing must be completed at least 28 days after ART switch. HIV-1 
RNA results must be received prior to study entry (refer to inclusion criterion 4.1.7). 
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur within 60 days following screening evaluations. 
Participants must begin 17-β estradiol within 3 days after study registration. 
Participants must arrive fasting (refer to section 6.3 for a definition of fasting). If a 
participant is not fasting, they must return in the fasting state for entry blood draw 
prior to starting 17-β estradiol. 
 
Site Investigator FHT dose assessment at week 0 will ensure the participant is 
still willing and able to safely initiate FHT at the starting dose of 2 mg daily. 
 
Intensive PK sampling will occur on a subset of participants at entry prior to 
initiation of 17-β estradiol. Sparse, timed, trough PK sampling will occur for all 
participants not participating in the intensive PK visit on the same day as entry. 
Because intensive PK sampling will capture the trough, those participants do not 
need a sparse sample collected at entry. 
 
Semi-structured interviews will occur on a subset of participants at entry prior to 
initiation of 17-β estradiol.  
 
6.2.3 Post-Entry Evaluations 
 
For all post-entry evaluations, if a participant is unable to attend a visit within the 

 
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specified window, every attempt should be made to bring the participant in for an 
out-of-window visit rather than skip the visit, unless the next visit window has 
opened. 
 
On-Treatment Evaluations  
A study visit will occur at weeks 4 and 8, with a window of ±7 days. Note that 
week 8, is a remote (phone, text, video chat, etc.) visit that will include the 
evaluations indicated in the SOE. Study visits will occur at weeks 12, 24, 36, and 
48, with a window ±14 days. Participants must arrive fasting for all in-person post-
entry visits (see definition of fasting in section 6.3). If a participant is not fasting, 
they must return in the fasting state within the study window for blood draw and 
prior to any 17-β estradiol dose escalation. Note that the participant should be on 
study-provided 17-β estradiol at the time of the week 48 blood draw. Additional 
medication should be dispensed, if necessary, to ensure this. 
 
Timed, trough PK sampling will occur for all participants at all in-person visits 
except those who are undergoing intensive PK sampling at the same visit. 
Intensive PK sampling on a subset of participants will occur at weeks 24 and 48 
visits. 
 
Semi-structured interviews will occur on a subset of participants at weeks 24 and 
48. See section 12.4 for additional details. 
 
Site Investigator FHT dose assessment at weeks 4, 12, 24, and 36 will include a 
determination of whether dose escalations, reductions or interruptions are 
warranted. Additionally, determination of whether any interventions/referrals for 
sequelae of FHT (e.g., lipid or glucose elevations, worsening depression) are 
warranted. At week 48 or premature study discontinuation, the site investigator 
assessment will include plans for transitioning FHT and associated care provision 
to local providers.  
 
NOTE: Lab results (fasting chemistries, liver function tests, local estradiol and 
total testosterone concentration) must be available prior to any changes in 17-β 
estradiol dose (unless changed to accommodate an adverse event).  
 
Event-Driven Evaluations  
Detectable viremia (as defined in section 8.8) and site investigator suspects failure 
with drug resistance requiring a change in ART will lead to premature treatment and 
study discontinuation evaluations. If the site investigator suspects non-adherence 
and would not otherwise change ART, the participant may remain on study. 
 
Participant report of suicidal ideation or attempt, worsening depression, or 
other acute psychiatric condition will lead to permanent discontinuation of 
study-provided 17-β estradiol, and the participant should be immediately 
referred to behavioral health and substance use counseling services for 
further evaluation and treatment. The A5403 CMC should be notified within 

 
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72 hours. When the participant is stable to do so, the premature study 
discontinuation evaluations must be completed, and the participant will be 
taken off study.  
  
NOTE: Suicidal ideation or attempt will be defined by answers provided on 
the C-SSRS. See the MOPS for scoring and interpretation instructions, and 
for additional considerations. 
  
NOTE: Though suicidal ideation or attempt, worsening depression, or other 
acute psychiatric condition necessitates discontinuation of study 
product,  if changes in mental health are documented to be transient and 
due to another cause such as acute intoxication, rechallenge may be 
considered if the participant has returned to their baseline mental status 
and if approved by the participant, study investigator, protocol team and 
CMC.  
  
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Study Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. 
 
Discontinuation Evaluations 
Participants should discontinue study once they complete all week 48 or 
premature discontinuation evaluations. Refer to the Discontinuation Log in the 
A5403 eCRF completion guide. Participants who require additional monitoring for 
follow-up of adverse events, etc., should be managed as per section 8.0. 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely permanently discontinue study treatment will have 
discontinuation evaluations performed per the schedule of evaluations (SOE) 
prior to being taken off the study and preferably prior to discontinuing 17-β 
estradiol (unless the reason for discontinuation is one that requires immediate 
cessation of study product for safety reasons). 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study before week 48 will 
have the study discontinuation evaluations performed per the SOE prior to being 
taken off the study and preferably prior to discontinuing 17-β estradiol (unless the 
reason for discontinuation is one that requires immediate cessation of study 
product for safety reasons).  
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 

 
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https://www.niaid.nih.gov/sites/default/files/score-source-documentation-requirements.pdf. 
 
Each study site and laboratory involved in this study must comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, 
which is available at https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of AE 
requirements. 
 
The protocol team and/or study monitoring entity (e.g., SMC) may determine that 
additional source data associated with procedures or evaluations performed per protocol 
should be entered into eCRFs so that the data can be used for analysis or to otherwise 
assist with interpretation of study findings. In such cases, sites will be officially instructed 
to enter the additional data into eCRFs from available source documentation.  
 
Fasting Instructions 
Fasting is required at entry, all post-entry visits, and the premature discontinuation visit. 
Fasting is defined as nothing to eat or drink, except for prescription medications or 
water, for at least 8 hours before a blood draw.  
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease, cardiovascular disease, myocardial infarction 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes or pre-diabetes 
• 
Blood clots or clotting disorders (exclusionary) 
• 
Cerebrovascular accident 
• 
Cholecystitis 
• 
Gallstones 
• 
Orchiectomy or chemical castration 
• 
Chronic active HBV  (exclusionary) 
• 
HCV status, including history of spontaneous clearance or cure 
(exclusionary) 

 
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Any allergies to any medications and their formulations must also be 
documented.  
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  
 
Table 6.3.3-1: Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy1 
24 weeks prior to study entry 
Immune-based therapy 
60 days prior to study entry 
Blinded study treatment 
60 days prior to study entry 
HIV-1-related vaccines 
60 days prior to study entry 
Prescription drugs for treatment of opportunistic 
infections 
60 days prior to study entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
60 days prior to study entry 
Prescription drugs (other) 
60 days prior to study entry 
Alternative therapies 
60 days prior to study entry 
Dietary supplements 
60 days prior to study entry 
Sex-hormone medications or sex-hormone 
analogues or antagonists* 
Most recent hormone use and 
type and estimate of total years 
on FHT2 
1  Record the start date of the current ART. 
2  Refer to hormone eCRF. 
* Includes: estrogens, progesterones, or testosterone therapy; leuprolide or other synthetic 
gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase inhibitors or any other 
androgen, anti-androgen, estrogen, or progesterone analogue or antagonist therapy.  
 
6.3.4 Clinical Assessments 
 
Complete Physical Examination 
A complete physical examination will be performed per the SOE and is to 
include, at a minimum: 
• 
Examination of the skin, head, mouth, and neck 
• 
Auscultation of the chest 
• 
Cardiac exam  
• 
Abdominal exam 
• 
Examination of the lower extremities for edema 
• 
Signs and symptoms 
• 
Diagnoses 
• 
Height (in cm) 
• 
Weight (in kg); calculated body mass index 
• 
Vital signs (temperature, pulse, respiration rate, and blood pressure) 

 
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Targeted Physical Examination 
A targeted physical examination will be performed per the SOE and is to be 
driven by any previously identified or new signs or symptoms including diagnoses 
or adverse events that the participant has experienced since the last visit. 
 
The exam must include: 
• 
Vital signs (temperature, pulse, respiration rate, and blood pressure) 
• 
Anthropometric measurements (weight, minimum waist circumference and 
maximum hip circumference). Refer to the A5403 MOPS. 
• 
Signs and symptoms assessment 
• 
Recording of interim orchiectomy per participant report, if applicable 
 
Refer to section 7.2 for AE collection requirements. 
 
Nicotine Use 
History of nicotine use is required to be recorded on the eCRF per the SOE. 
Post-entry, record nicotine use per the SOE. 
 
Concomitant Medications 
Per the SOE, any new and discontinued concomitant medications, including 
vaccines, must be recorded on the eCRFs.  
 
Targeted Medications 
Per the SOE, any new, discontinued or modified ART or non-study provided 
hormones or anti-androgens (and other non-study FHT) must be recorded on the 
eCRFs. Participants who pursue anti-androgen therapy outside the study within 
the first 24 weeks will not be discontinued from the study. The use of anti-
androgen therapy and other outside FHT use will be addressed during data 
analysis. 
 
Study Treatment Modifications 
Per the SOE, record all study drug modifications, including initial doses, 
participant-initiated and/or protocol-mandated modifications, and inadvertent and 
deliberate interruptions since the last visit. All interruptions of study-supplied 
drug, regardless of duration, must be recorded. Record any permanent 
discontinuation of treatment.  
 
6.3.5 Site Investigator FHT Dose Assessment 
 
Site investigator FHT dose assessment will be performed per the SOE, and dose 
will be modified per the investigator’s discretion based on discussion with the 
participant and review of clinical information. Participants will be reminded about 
potential side effects by study staff at each visit and be encouraged to call the 
site should they experience a side effect. Detailed guidance to investigators 

 
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regarding clinical considerations is provided in the MOPS. Date of participant 
contact to communicate dosing decisions will be reported on the eCRF. Reasons 
for no dose escalation at a visit, or dose decrease will also be reported on the 
eCRF. 
 
At weeks 4, 12, 24, and 36, study investigators may titrate 17- estradiol in 2 mg 
increments. At these visits, the decision to escalate the 17- estradiol will be 
individualized, after a discussion between the investigator and the participant, 
taking into consideration: a) the targeted serum hormone concentrations (as 
locally measured), b) achievement of desired phenotypic changes, and c) safety 
(refer to section 8.0 for safety considerations) and tolerability (see MOPS) 
considerations. At week 48, the investigator assessment will primarily focus on 
assessing tolerability of the final dose and transitioning of participant care to 
community-based settings, where available. 
 
Participants will not be required to titrate to the maximum estradiol concentration, 
but also will not be allowed to titrate above the recommended therapeutic range 
for safety reasons. Dose titration will generally occur until hormone concentration 
targets are achieved, as phenotypic changes will lag behind target hormone 
concentrations in many cases. Participant goals and safety assessments will also 
influence titration decisions (see MOPS for guidance on estradiol titration). 
Targets for hormone concentrations are based on the Endocrine Society 
guidelines [7, 11] and, for estradiol, from personal communication with Dr. Vin 
Tangpricha of the World Professional Association of Transgender Health 
(WPATH). Target hormone concentrations are defined as both:  
 
1) A serum estradiol concentration of ≤200 pg/mL; and  
2) A serum total testosterone concentration of <50 ng/dL*  
 
* There are some clinical scenarios where complete testosterone suppression is 
not in line with participant goals. In these cases (see MOPS), only serum 
estradiol concentrations will guide titration decisions.  
 
6.3.6 Laboratory Evaluations 
 
At screening, pre-entry, and entry all laboratory values must be recorded per the 
SOE. 
 
Blood draws for lab evaluations at screening and pre-entry will not be in fasted 
state. Blood draws for lab evaluations will be in fasted state starting at study 
entry and at all post-entry visits.  
 
For post-entry assessments, record all laboratory values for serum creatinine, 
glucose, AST, ALT, total cholesterol, LDL cholesterol, triglycerides, and HDL 
cholesterol regardless of grade; record abnormal laboratory findings as per 
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Hematology 
Complete blood count (CBC) with differential to include: hemoglobin, hematocrit, 
white blood cell count [WBC], differential WBC, absolute neutrophil count (ANC), 
platelets. 
 
Liver Function Tests 
Total bilirubin, AST [SGOT], ALT [SGPT], alkaline phosphatase, indirect bilirubin. 
 
Chemistries 
Serum glucose, potassium, creatinine, total protein, albumin. 
 
Estradiol Concentrations 
Estradiol hormone concentrations will be done per the SOE. Screening and entry 
values will be random levels. Post-entry, concentrations should be timed to be a 
trough concentration based on time of participant’s last dose (20-28 hours post-dose). 
 
Non-estradiol Hormone Concentrations 
Prolactin and total testosterone will be done per the SOE.  
 
6.3.7 Immunologic Studies 
 
CD4+/CD8+ 
Obtain absolute CD4+/CD8+ T-cell count and percentage per the SOE. All laboratories must 
possess a CLIA certification or equivalent (US sites) or IQA certification (non-US sites). 
 
6.3.8 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 60 days prior to study entry at a local 
laboratory that possesses a CLIA certification or equivalent (US sites) or appropriate 
External Quality Assurance (EQA) Program (non-US sites). Eligibility will be determined 
based on the screening value. Pre-entry HIV-1 RNA will be performed at the local 
laboratory only for participants who switched ART (per section 4.1.5). For entry and 
post-entry evaluations, the laboratory must be certified by an appropriate EQA Program. 
  
Viral hepatitis testing 
Testing for viral hepatitis status should be documented from medical 
records, if available. If HBV status prior to starting ART or HCV status 
within the last year (with the exception of documentation of prior 
spontaneous HCV clearance or cure) is not available, testing at screening 
should occur. HBV testing will be defined as HBV surface antigen testing. 
HCV testing will be defined as HCV antibody testing, followed by HCV RNA 
testing when HCV antibody testing is positive. 
 

 
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NOTE: In persons with positive HCV antibodies with no available HCV RNA 
testing, HCV antibody seropositivity alone will be a cause for exclusion, as 
per section 4.2.4. 
6.3.9 Metabolic Studies  
 
Fasting lipid panel  
Triglycerides, total cholesterol, direct LDL cholesterol and HDL cholesterol will be 
performed as a safety lab per the SOE. 
 
6.3.10 Pharmacokinetic Sampling 
 
For additional details regarding PK, please see section 11.0, the MOPS, and the 
laboratory processing chart (LPC) found on the A5403 PSWP. 
 
Intensive PK subset (n=15 per group) 
An 8-hr intensive PK visit will occur per the SOE for a subset of 15 participants 
per group identified at enrollment. Whole blood samples will be collected pre-
dose (within 30 min prior to ART and 17-β estradiol dosing), and then 1, 2, 3, 4, 
6, and 8 hours after dosing. Non-viable PBMC samples will be processed from 
blood collected at the pre-ART, 3- hour post, and 8-hour post time points. Note 
the pre-dose collection reflects the trough concentration. 
 
If the intensive PK visit is occurring on the same day as the study visit, draw 
fasting labs and then provide breakfast or allow the participant to eat food they 
brought to the visit. There are no fat or calorie content requirements. ART and 
17-β estradiol should be administered with food (during meal or at the conclusion 
of the meal) and should be given at the same time, or within 15 minutes of each 
other. 
 
Dates, times and dose amounts of the three doses of ART and 17-β estradiol 
prior to the intensive PK sampling period should be documented on the eCRF. 
The PK visit should be rescheduled if the participant reports missing any 
of the prior three doses of ART and 17-β estradiol. At entry, there is no 
expected 17-β estradiol doses prior to the PK sampling and 17-β estradiol 
should not be started until after the entry 8-hour intensive PK ART 
sampling is completed. Any ART or 17-β estradiol dose administered during 
the intensive PK sampling time period should be documented.  
 
Timed Trough PK samples 
Plasma, serum, and non-viable PBMCs will be collected before daily ART and 
17-β estradiol administration in all participants to assess trough PK of ART and 
17-β estradiol. For participants who are completing an intensive PK visit on the 
same day as the study visit, an additional trough sample is not required. All 
samples will be collected at each visit per the SOE, except non-viable PBMCs 
will not be collected at week 4. 
 

 
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Concentrations will be assessed from plasma and non-viable PBMC samples 
collected within 22-26 hours after the last dose of ART and 17-β estradiol. If 
necessary, participants should bring ART and 17-β estradiol to the clinic visit and 
may administer the doses after blood collection. Timing of the participant’s 
medication schedule should be reviewed at entry and at each visit to ensure 
sample collection will occur within the specified window.  
 
NOTE: Collection of NON-viable PBMCs for PK studies do not require IQA 
oversight. 
 
6.3.11 Stored Plasma/PBMC/Serum  
 
Per the SOE, plasma, viable PBMCs, and serum samples will be stored for 
inflammatory (hs-IL-6, EN-RAGE, oxLDL, d dimer), immunologic and virologic 
assessments, for metabolic testing (high molecular weight adiponectin and 
insulin), and for hormone testing, such as sex hormone binding globulin (SHBG), 
estradiol, total and free testosterone.  
 
NOTE: Only sites certified and in good standing by the IQA Cryopreservation PT 
Program at the Duke Human Vaccine Institute are required to collect VIABLE PBMCs. 
 
6.3.12 Columbia-Suicide Severity Rating Scale (C-SSRS) Questionnaire 
 
The C-SSRS will be administered per the SOE. The C-SSRS eCRF is posted 
on the DMC Portal in the Forms Management Utility. 
 
NOTE: Refer to section 8.4 and the MOPS for C-SSRS interpretation and 
additional management recommendations. 
 
6.3.13 ART Adherence Assessment 
 
ART adherence assessment eCRF will be administered per the SOE. The 
adherence eCRF is posted on the DMC Portal in the Forms Management Utility. 
 
NOTE: Site staff or investigators should review the results of the adherence 
assessment during the visit, and counsel participants on adherence if any 
concerns become apparent.  
 
6.3.14 FHT Adherence Assessments 
 
FHT adherence assessment eCRF will be administered, and the pill count 
eCRF will be completed per the SOE. The adherence eCRF and the pill count 
eCRF are posted on the DMC Portal in the Forms Management Utility. 
 
NOTE: Site staff or investigators should review the results of the adherence 
assessments during the visit, and counsel participants on adherence if any 

 
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concerns become apparent.  
 
6.3.15 FHT Participant Goals 
 
FHT participant goals will be collected per the SOE. The checklist eCRF is 
posted on the DMC Portal in the Forms Management Utility.  
 
6.3.16 FHT Acceptability and Satisfaction Surveys 
 
FHT acceptability and satisfaction surveys will be administered per the SOE. The 
survey eCRF is posted on the DMC Portal in the Forms Management Utility. 
 
6.3.17 Semi-structured Interview Subset 
 
For a subset of English- and Spanish-speaking participants, a semi-structured 
interview regarding FHT acceptability and satisfaction will be conducted by Dr. 
Amaya Perez-Brumer of the A5403 protocol team or her delegate per the SOE. 
Refer to section 12.0 for more information. Note that participants must consent to 
participating in the optional interviews (refer to Informed Consent for Interviews) 
to be considered for participation. Results from this are not required to be 
reported on an eCRF. 
 
6.3.18 Remote Visit 
 
A remote visit will be conducted by site staff, per the SOE. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to 
medical treatment/study product/device or procedure/intervention). This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition.  
 
7.2 
Adverse Event Collection Requirements for This Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
 
• 
All Grade ≥3 AEs 
• 
All AEs that lead to 17-β estradiol interruption or dose reduction, regardless of grade. 
• 
All AEs meeting serious adverse event (SAE) definition or Expedited AE (EAE) 
reporting requirement (see section 7.3.2) 

 
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• 
The following AEs will be recorded at Grade ≥1 if: 
o Lipid abnormalities, if values were normal at baseline (if abnormal at baseline, 
worsening by at least 1 grade should be reported) 
o Glucose abnormalities, if values were normal at baseline (if abnormal at baseline, 
worsening by at least 1 grade should be reported) 
• 
The following AEs will be recorded at Grade ≥2: 
o Cholecystitis 
o Elevated liver enzymes 
o Hypertension 
• 
The following will be recorded regardless of grade: 
o Coronary heart disease or other cardiovascular disease 
o Cancer (exclusive of basal/squamous cell skin cancer) 
o Diabetes mellitus or pre-diabetes 
o Any vascular events, including arterial events (strokes and myocardial 
infarctions) or deep venous thrombotic events (venous thromboembolism, deep 
venous thrombosis, retinal vein thrombosis, and pulmonary embolism) 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into the 
DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting system. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, which can be  
found on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
SAEs 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above). 
 
7.3 
EAE Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-
expedited-reporting-adverse-events-daids.  

 
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The DAERS, an internet-based reporting system, must be used for EAE reporting 
to DAIDS. In the event of system outages or technical difficulties, EAEs may be 
submitted using the DAIDS EAE Form. This form is available on the DAIDS RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting.  
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agent for which expedited reporting is required is 17-β estradiol.  
• 
In addition to the SAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are:  
o Any vascular events, including arterial events (strokes and myocardial 
infarctions) or deep venous thrombotic events (venous thromboembolism, 
deep venous thrombosis, retinal vein thrombosis, and pulmonary 
embolism) 
o Severe headache of new onset (Grade ≥3) or worsening of headache 
leading to Grade ≥3 headache 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table, corrected Version 2.1, July 2017, must be used 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables.  
 
7.3.4 Expedited AE Reporting Period 
• 
The expedited AE reporting period for this study is no later than 3 days as per 
the EAE manual. 
• 
After the protocol-defined EAE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the DAIDS EAE Manual, will be reported to DAIDS if the study 
staff become aware of the events on a passive basis (from publicly available 
information). 
 
7.4 
Study Monitoring 
 

 
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The protocol team will monitor the conduct and safety of the study via regularly 
scheduled summaries of accrual, study discontinuation, study treatment disposition, 
AEs, and data and specimen completeness, as appropriate, as per the Study Progress, 
Data, and Safety Monitoring Plan (SPDSMP).  
 
During the study, the safety and tolerability of the study medication will be monitored by 
toxicity reports presenting laboratory and clinical data. The subset of the team receiving 
these reports (as per the specifications in the SPDSMP) will discuss these reports on 
regularly scheduled conference calls or by e-mail. Any concerns will be presented to the 
DAIDS Clinical Representative. 
 
The DAIDS Clinical Representative will review and assess select EAE reports for 
potential impact on the study participant safety and protocol conduct as per DAIDS 
policies, guidance documents, and SOPs as applicable.  
 
This trial will be formally monitored at least annually by an ACTG-appointed Study Monitoring 
Committee (SMC) (as per appointment via the ARTS TSG). The study will undergo interim 
feasibility and safety review by the SMC. The first interim review will occur no more than one 
year after enrollment of the first participant or 25 participants complete 24 weeks of follow-up 
(in order to have conduct and safety data on at least two possible estradiol dose titrations), 
whichever occurs earlier. An additional SMC review may be triggered if accrual at 18 months 
after first enrollment is less than 50% of the total expected accrual (e.g., fewer than 45 of 
anticipated 90 participants across all groups). An interim review by the SMC will also be 
triggered if, at any time the following occurs: if greater than 25% of currently accrued 
participants (if at least 30 participants have been enrolled) are lost or withdrawn from study 
follow-up. Any of the following will trigger an expedited safety review for potential trial 
modification by the SMC:  
• 
Any death that is not clearly attributed to a cause other than the study product 
(e.g., accident, trauma)  
• 
2 or more Grade 3 or higher, treatment-related adverse events 
• 
2 or more Grade 2 or higher allergic/hypersensitivity reactions related to study 
treatment  
• 
2 or more of the same Grade 3 or higher, unexpected, treatment-related 
adverse events (and screening and accrual will be held until the SMC 
expedited safety review has occurred).  
An interim review may also be convened if a concern is identified by the DAIDS clinical 
representative, the study chairs, or study statistician in consultation with the team, based 
on safety reports distributed to the team at frequency specified in the SPDSMP or as 
requested by any member of the CMC. See section 10.5.1 for statistical and other 
considerations related to interim monitoring. 
 
Detailed plans for study monitoring are outlined in a Study Monitoring Plan developed by 
the Statistical and Data Management Center (SDMC) prior to enrollment of the first 
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8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
8.1.1 General instructions for management of Grades 1-4 AEs are provided in this 
section. Refer to section 8.2 and further for information on specific toxicities. 
 
8.1.2 Grade 1 or 2  
 
Participants who develop a Grade 1 or 2 AE or toxicity thought to be related to 
study-supplied 17-β estradiol may continue 17-β estradiol at the discretion of the 
site investigator, and will be followed carefully until resolution or stabilization.  
 
If the site investigator or participant chooses to discontinue any study-supplied 
17-β estradiol, the site should notify the A5403 CMC within 72 hours. The 
premature treatment/study discontinuation evaluations must be completed, and 
then the participant will be taken off study.  
 
8.1.3 Grade 3 or 4 
 
For Grade 3 or 4 AE or toxicity that is related to study-supplied 17-β estradiol, 17-β 
estradiol must be held, participants must be followed carefully, and the A5403 CMC 
should be notified within 72 hours.  
 
The participant should be followed until the AE has decreased to Grade ≤2. After 
the AE has decreased to Grade ≤2, the A5403 CMC should be consulted to see 
whether study medication rechallenge at a current or reduced dose is 
permissible. If it is not, the premature study discontinuation evaluations must be 
completed, and then the participant will be taken off study. 
 
8.1.4 Serious Adverse Event  
 
For Grade 3 or 4 SAE (as defined in section 7.2) that is related to study-supplied 
17-β estradiol, 17-β estradiol must be permanently discontinued and the A5403 
CMC should be notified within 72 hours. The participant should be followed 
until the AE has decreased to Grade ≤2. The premature study discontinuation 
evaluations must be completed, and then the participant will be taken off study. 
 
8.2 
Deep Vein Thrombosis, Other Thromboembolic Event, or Major Adverse 
Cardiovascular Event (MACE)  
 
If DVT, thromboembolic event, or MACE is suspected or diagnosed, 17-β estradiol 
should be discontinued immediately, and the A5403 CMC should be notified within 72 
hours. If an alternate diagnosis is confirmed, rechallenge at the current or a reduced 
dose may be permitted after consultation with the A5403 CMC and local providers. 

 
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The sudden onset of partial or complete loss of vision, or a sudden onset of proptosis, 
diplopia, or migraine should lead to discontinuation of treatment, pending 
examination. If examination reveals papilledema or retinal vascular lesions, estrogens 
should be permanently discontinued. 
 
8.3 
Elevated Liver Tests 
 
If any of the following criteria are met, the study-provided 17-β estradiol must be 
permanently discontinued and the A5403 CMC should be notified within 72 hours. The 
participant should be followed until the AE has decreased to Grade ≤2. The premature 
study discontinuation evaluations must be completed, and then the participant will be 
taken off study. 
 
Specific criteria: 
• 
ALT or AST >8 times (x) upper limit of normal (ULN)  
• 
ALT or AST >5 x ULN for more than 2 weeks 
• 
ALT or AST >3 x ULN and total bilirubin (TBL) >2 x ULN or international  
normalized ratio (INR) >1.5 
• 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).  
NOTE: If a participant experiences elevated ALT or AST >3 times ULN, liver tests 
(ALT, AST, bilirubin, alkaline phosphatase) will be repeated within 3 to 5 days. 
 
8.4 
Suicidal Ideation or Attempt, Worsening Depression, or Other Acute Psychiatric 
Condition 
 
If a participant reports suicidal ideation or attempt, worsening depression, or other 
acute psychiatric condition, the study-provided 17-β estradiol must be permanently 
discontinued and the participant should be immediately referred to behavioral 
health and substance use counseling services for further evaluation and treatment. 
The A5403 CMC should be notified within 72 hours. When the participant is stable 
to do so, the premature study discontinuation evaluations must be completed, 
and the participant will be taken off study.  
 
NOTE: Suicidal ideation or attempt will be defined by answers provided on the C-
SSRS. See the MOPS for scoring and interpretation instructions, and for 
additional considerations. 
 
NOTE: Though suicidal ideation or attempt, worsening depression, or other acute 
psychiatric condition necessitates discontinuation of study product,  if changes in 
mental health are documented to be transient and due to another cause such as 
acute intoxication, rechallenge may be considered if the participant has returned to 
their baseline mental status and if approved by the participant, study investigator, 

 
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protocol team and CMC.  
 
8.5 
New Diagnosis of Breast Cancer 
 
The premature treatment/study discontinuation evaluations must be completed, and then 
the participant will be taken off study.  
 
8.6 
New Cancer Diagnosis Other than Breast, Basal, and Squamous Cell Skin Cancer 
 
17-β estradiol should be held. Rechallenge at the current or a reduced dose may be 
permitted after consultation with local oncologist and the A5403 CMC. If it is not, the 
premature study discontinuation evaluations must be completed, and then the participant 
will be taken off study. 
 
8.7 
Sustained Hypertension  
 
Sustained hypertension is defined as new hypertension or significant increase in blood 
pressure in a participant with hypertension while on 17-β estradiol and that persists at 
Grade ≥2 despite antihypertensive therapy. 17-β estradiol should be held, the A5403 
CMC should be notified within 72 hours, and attributability should be assessed by the 
site investigator. Rechallenge at the current or a reduced dose may be permitted. If it is 
not, the premature study discontinuation evaluations must be completed, and then the 
participant will be taken off study. 
 
8.8 
Detectable Viremia 
 
If a participant has a detectable viral load at >200 copies/mL, the HIV-1 RNA should be 
repeated at least 7 days later and the participant should have a review of recent medication 
adherence. If detectable viremia is confirmed, the investigator should assess whether this is 
likely to be (a) failure due to drug resistance, or (b) failure due to treatment interruptions or 
incomplete adherence. If, in the opinion of the site investigator, the detectable viremia is 
likely due to (b) and reinitiation of the same regimen with enhanced adherence would 
achieve resuppression, then the participant may continue on study on the same regimen. If 
the site investigator suspects failure with drug resistance and/or considers that the 
participant should change treatment regimen, then the participant will have the premature 
study discontinuation evaluations completed, and then the participant will be taken off study. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 8.1). 
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
section 8.0 of the protocol. 

 
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• 
Requirement for prohibited concomitant medications. 
• 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, or investigator 
9.2 
Premature Study Discontinuation 
 
• 
Failure by the participant to attend 3 consecutive clinic visits. 
• 
Detectable viremia and site investigator suspects failure with drug resistance (as 
defined in section 8.8) requiring change of ART. 
• 
ART change or discontinuation. 
• 
17-β estradiol discontinuation. 
• 
Participant repeatedly does not adhere to study medications as prescribed, per the 
site investigator’s discretion. 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant. 
• 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, or investigator. 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
This is an open label, non-randomized, multicenter trial to evaluate both ART and 
estradiol exposure (PK) in TW living with HIV who are suppressed on one of three 
targeted ART regimens and are starting or restarting FHT with oral 17- estradiol. 
 
While the ultimate goals of FHT are internal/external gender congruence, how this is 
defined varies greatly across individuals (i.e., high heterogeneity within the 
sample/population), and the time horizon for goal attainment is longer (1 to 3 years), 
than is feasible for a one-year trial. Therefore, this trial will use mixed methods approach 
on participant satisfaction/progress towards transgender congruence, as outlined in the 
behavioral analysis (section 12.0).  
 
Also, the current trial focuses on two primary PK-related questions related to the 
interaction between estradiol FHT and ART: Does titration to estradiol doses needed for 
long-term use to attain FHT goals of gender congruence cause changes in ART PK that 
could impact ART efficacy? Are there differences observed between ART regimens in 
serum estradiol exposure across the FHT dosing titration scheme? Since most of the PK 
studies of FHT in this key population have been short in duration and have tested fixed 
and low doses of estradiol, this trial is designed to fill important knowledge gaps. 
 
All participants will start oral 17- estradiol at 2 mg/day, and will be evaluated at weeks 
4, 12, 24, and 36 for the purposes of titrating the estradiol dose in 2 mg increments 
based on safety, tolerability and participant preference, using locally tested, real-time 
total serum estradiol and total testosterone. The titration algorithm, as described in the 

 
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MOPS, does not permit escalation of FHT that exceeds hormone target ranges. 
Potential adjustment of doses of oral 17- estradiol over the 48-week period of the trial 
following the trial visits include to 4, 6, 8 and 10 mg/day. De-escalation for tolerability or 
toxicity will be allowed. 
The PK analysis approaches for the primary objectives utilizes both a multi-period, fixed 
sequence (participants as their own control) design for the primary objective for ART PK, and a 
parallel group design (where groups are defined and compared based on current ART 
regimen) for the primary objective for estradiol PK. Each of these primary objectives utilizes 
sparse, but timed (i.e., trough) PK sampling. At entry, participants are assigned to one of 3 
cohorts based on their current ART regimen (ART = required concomitant medication) 
containing BIC, DTG or DRV/c. Other required ART are as defined in the study schema.  
 
Parallel group comparisons (i.e., between ART groups for the estradiol primary PK 
outcome) are subject to two sources of bias: 1) imbalances between non-randomized 
ART groups on known or unknown factors associated with estradiol PK outcomes; and 
2) informative missingness due to the titration scheme whereby estradiol dose 
adjustment is partially based upon the outcome being analyzed (i.e., confounding by 
indication). Therefore, caution is warranted for inference at the higher estradiol doses. 
These issues are described in more detail in the Analyses section below (section 10.6). 
 
The total sample size accrual goal is 90; or 30 per ART cohort. As analyses are specified 
at each dose of oral 17-β estradiol, the effective sample size based on observed titration 
of estradiol over time, is anticipated to be smaller than the enrolled sample. Refer to the 
sample size section (section 10.4) and Analyses section (section 10.6) below for more 
details. 
 
A subgroup of participants (who opt-in via informed consent) will undergo intensive PK 
sampling at a subset of study visits (weeks 0, 24, and 48) for the purposes of estimating 
the following 17- estradiol and ART PK parameters which cannot be reliably estimated 
from sparse trough-timed sampling: Area under the concentration-time curve (AUC), 
Cmax, and Tmax. (Note: additional PK parameters may be modeled and so this is not an 
exhaustive list.) The sample size for this intensive PK subgroup is 15 per ARV group, 
and is derived in the sample size section below (section 10.4).  
 
This trial is open label at all levels (participants, clinic research staff, and trial team). 
 
All trial outcomes are defined for the 48-week period following oral 17- estradiol 
initiation. The primary completion date (PCD) for the study is when the final participant 
enrolled is evaluated at week 48 for the primary outcomes. 
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study's 
primary Statistical Analysis Plan (SAP), which will define the content of the Primary 
Analysis Report. This report will form the basis for the primary study manuscript(s) and 
results reporting to ClinicalTrials.gov. Outcome measures related to other objectives 

 
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intended for subsequent publications are listed under Other Outcome Measures. 
 
10.2.1 Primary Outcome Measures  
 
10.2.1.1 Trough concentration of the analytes BIC, DTG, and DRV in plasma at 
each received dose of oral 17-β estradiol (0 (pre-FHT or baseline), 2, 4, 
6, 8, 10 mg) summarized at the participant level as the following two 
outcomes: 
a. Intra-person geometric ratios of trough ART concentration at each 
received estradiol dose relative to pre-FHT (i.e., baseline). 
b. Indicator of concentration being above drug-specific externally 
defined threshold. 
 
10.2.1.2 Trough serum total estradiol assessed at each received dose of oral 17-
β estradiol (i.e., 2 mg, 4 mg, 6 mg, 8 mg, 10 mg), as quantified via batch 
testing at central lab. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 Trough concentration of the analytes TFV-DP, FTC-TP, and 3TC-TP in 
non-viable PBMCs at each received dose of oral 17-β estradiol (0 (pre-
FHT or baseline), 2, 4, 6, 8, 10 mg) summarized at the participant level 
as the following two outcomes: 
1. Intra-person geometric ratios of trough ART concentration at each 
received estradiol dose relative to pre-FHT (i.e., baseline). 
2. Indicator of concentration being above drug-specific externally 
defined threshold. 
 
10.2.2.2 Occurrence of any reported adverse event deemed related to 17-β 
estradiol over 48 weeks.  
 
10.2.2.3 Occurrence of SAEs and new events of CAD/CVD, cancer, DM/pre-
DM, and vascular event, defined in section 7.2, over 48 weeks. 
 
10.2.2.4 Indicators of testosterone suppression at each received dose of oral 
17-β estradiol, defined as any serum total testosterone <50 ng/dL. 
 
10.2.2.5 Indicators of virologic suppression of HIV, defined as plasma HIV-1 
viral load <50 copies/mL, measured over 48 weeks. 
 
10.2.2.6 Changes in overall transgender congruence score from baseline, 
measured over 48 weeks. 
 
10.2.2.7 Area under the curve over 8 hours (AUC 0-8h) of estradiol based on 
intensive sampling among a subset of participants. 
 

 
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10.2.2.8 Absolute and percent changes in weight and BMI from baseline, 
measured over 48 weeks. 
10.2.2.9 Absolute and percent changes from baseline in minimum waist and 
maximum hip circumference and waist-hip ratio measured over 48 
weeks. 
 
10.2.2.10 Absolute changes in fasting lipids from baseline (e.g., direct LDL, total 
cholesterol, triglycerides, HDL), measured over 48 weeks. 
 
10.2.2.11 Absolute changes in glucose and insulin sensitivity (HOMA-IR) from 
baseline, measured over 48 weeks. 
 
10.2.3 Other Outcome Measures 
 
10.2.3.1 Changes in overall intervention acceptability (per participant self-report 
via survey and interview) between baseline and weeks 24 and 48. 
 
10.2.3.2 Changes in inflammation from baseline to weeks 4, 12, 24, 36, and 48 
post initiation of oral 17-β estradiol, as measured by select biomarkers 
of inflammation (see section 6.3). 
 
10.2.3.3 Serum total estradiol at 4, 12, 24, 36, and 48 weeks post initiation of 
oral 17-β estradiol, as measured in real time at local labs for the 
purposes of real-time estradiol titration. 
 
10.2.3.4 Cellular HIV transcriptional activity. 
 
10.2.3.5 PK parameters (e.g. Cmax, Tmax) of estradiol based on intensive 
sampling, among a subset of participants. 
 
10.2.3.6 T-cell cycling and activation, as measured by Ki67, HLA-DR+CD38+ and 
PD-1 expression. 
 
10.2.3.7 Absolute changes from baseline, measured at 4, 12, 24, 36, and 48 
weeks post initiation of oral 17-β estradiol in sex hormones.  
 
10.2.3.8 PK parameters (e.g., AUC, Cmax, Tmax) of ART based on intensive 
sampling at 24 and 48 weeks, among a subset of participants. 
 
10.3 
Randomization and Stratification 
 
There is no randomization to study groups or stratification in this trial. During the 
enrollment process, participants will be assigned to cohorts/groups for the purposes of 
analysis, based upon their current ART regimen. Further partitioning or other 
adjustments for analyses will be based on post-enrollment events including adherence to 
or changes to ART and study treatment of 17-β estradiol, use of anti-androgens (e.g., 

 
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spironolactone) after week 24, and observed oral 17-β estradiol dosing based on titration 
over 36 weeks. The subgroup for intensive PK will be self-selected by endorsement via 
informed consent. See section 10.6 for more details. 
10.4 
Sample Size and Accrual  
 
10.4.1 Sample Size for ART Primary PK Objective 
 
For the primary objective/outcome of trough ART concentration using fixed 
sequence design, the sample size is derived using assumptions on the standard 
deviation of intra-person differences in natural log-transformed trough 
concentrations (i.e., transformed geometric ratios). Since direct estimates of 
these standard deviations are rarely reported, even in fixed-sequence designs, 
we used published estimates of between-person coefficient of variation of trough 
concentrations of the respective ARTs. Combining these various assumptions of 
correlations of log-transformed trough concentrations within a person (e.g., 0 = 
no correlation, or independent observations, 0.25 and 0.5), and the following 
relationship between coefficient of variation (CV) and standard deviation of the 
log-transformed trough concentration under the assumption of log-normally 
distributed troughs {s.d. = square root [ln(CV^2+1)]}, we calculated the standard 
deviation of the difference (on the log scale, which corresponds to the geometric 
ratio), using the formula : var(x1 – x2) = var(x1) + var(x2) – [2* correlation(X1,X2) 
* stdev(X1)*stdev(X2)].  
 
The published inter-person coefficient of variation of Ctrough of BIC = 0.352 from 
PK fact sheet from University of Liverpool PK Research Labs [46]; of C24 of DTG 
= 0.47 (using largest estimated from dosing with high fat meal, other CVs range 
from .34 to 0.44) [47]. Max intrasubject variability on log Cmax of components 
among DRV/c, FTC, and TAF was 0.36 and thus the range of standard 
deviations below covers DRV as well [47, 48].  
 
Table 10.4.1-1: Variation in Ctrough for BIC and DTG 
Reference for Between 
Person CV in Ctrough 
Hypothesized Correlation Between 
Ctrough Concentrations in Same 
Participant 
Standard Deviation of Intra-
Person Difference in Log 
Ctroughs 
BIC = 0.352 
0.0 
0.48 
 
0.25 
0.42 
 
0.50 
0.34 
DTG = 0.47 
0.0 
0.63 
 
0.25 
0.55 
 
0.5 
0.45 
 
Once the standard deviation on the log difference is assumed, then normal 
assumptions on the natural log-scaled trough concentrations, may be applied. The 
hypothesis for the ART primary PK objective is an equivalence hypothesis (i.e., not 
clinically significant reductions). Therefore, two-one sided tests (TOST) using the t-
test and pre-specified no effect bounds for the geometric mean ratio (i.e., the mean 
of the intra-person geometric ratios) can be used to calculate statistical power for 

 
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the equivalence hypothesis.  
 
Additional assumptions include what effective sample sizes might be expected at 
higher than 2 mg doses of estradiol based on the realization of the titration 
scheme. Since participants might titrate up at different rates, the assumptions in 
the immediate table below use the simplifying assumption to equate number of 
“late titraters” with numbers lost to follow-up (i.e., these cancel out). In primary 
analyses, only one observation per estradiol dose will contribute to calculation of 
outcomes. (See Analyses section (section 10.6).for more details.)  
 
The following hypothesized effective sample sizes (Table 10.4.1-2) representing 
the assumptions above are used for statistical power calculations below in Table 
10.4.1-3. These estimates are purposely conservative. 
Table 10.4.1-2: Projected Sample Sizes Across Doses of 17-Beta EstradiolDose of 
Oral 17-β Estradiol 
Dosing 
Hypothesized Effective 
Group Sample Size per ART 
Basis of Effective 
Sample Size 
2 mg/day 
30 
100% of 30 
4 mg/day 
28 
95% of 30 
6 mg/day 
25 
90% of 28 
8 mg/day 
20 
80% of 25 
10 mg/day 
15 
75% of 20 
 
Assumptions in Table 10.4.1-3 below include true (alternative) geometric mean 
ratio (GMR) of 1.0 (i.e., equivalence), and alpha (significance level) of 0.05 
(which is equivalent to a 90% CI due to two-one sided tests at 0.05).  
 
Table 10.4.1-3: Statistical Power for ART Primary Objective 
Standard deviation 
of intra-person 
differences in log 
Ctrough of ARV 
Effective Sample size 
per 17-β estradiol dose 
and ART group 
No Effect Bounds 
Statistical power 
0.35 
28 (or higher) 
(0.80, 1.25) 
0.90 (or higher) 
25 
0.85 
15 
(0.75, 1.33) 
0.83 
 
0.45 
25 
(0.75, 1.33) 
0.85 
20 
(0.70, 1.43) 
0.92 
15 
0.80 
 
0.50 
30 
(0.75, 1.35) 
0.84 
28 
0.81 
20 
(0.70, 1.43) 
0.85 
 

 
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Standard deviation 
of intra-person 
differences in log 
Ctrough of ARV 
Effective Sample size 
per 17-β estradiol dose 
and ART group 
No Effect Bounds 
Statistical power 
0.55 
28 
(0.70, 1.43) 
0.91 
25 
0.87 
20 
0.75 
0.65 
30 
(0.70, 1.43) 
0.80 
28 
0.77 
25 
0.69 
 
Thus, from the table above, for an effective sample size of 20 within an ART analysis 
group, standard deviation of intra-person differences in log Ctrough (ARV) of 0.45, 
there is 92% power to declare equivalence under no-effect bounds of (0.70, 1.43). 
 
While various NEB are given above to demonstrate statistical power under 
various scenarios, the reference interval used in analysis will be (0.70,1.43) due 
to the higher variability of the Ctrough parameter [49]. 
 
10.4.2 Sample Size for Estradiol Primary Objective 
 
For the primary objective/outcome of comparing serum estradiol between groups 
defined by ART regimen at each of the doses of oral 17-β estradiol, a parallel groups 
PK design is utilized so that the geometric mean ratio is formed by difference in log-
transformed means between ART groups. To size for this design, a key assumption 
is the between participants CV in the PK of serum estradiol. The CV of Ctrough of 
serum estradiol is extracted from the iFACT trial, which tested for the drug-drug-
interaction of another form of oral estradiol (estradiol valerate) given at 2 mg/day with 
ART regimen EFV/FTC/TDF in ART naïve transgender women in Thailand [26]. 
From this trial, the CV on the C24 of estradiol was 0.60 (i.e., highly variable). For this 
objective, testing framework is superiority (as opposed to equivalence in the previous 
objective), comparing the DRV/c ART group against the other 2 ART groups.  
 
Under the following alternative GMRs, power is calculated for various 
hypothesized effective sample sizes (see Table 10.4.1-2 above for estimates on 
effective sample sizes at various doses of oral 17-β estradiol) (other assumptions 
include 0.05 significance level using TOST): 
 
Table 10.4.2-1: Statistical Power for Estradiol Primary Objective 
Alternative GMR for Serum 
Estradiol (DRV/other ART) 
Sample Size in DRV Group 
Sample Sizes in Other 
ART Groups Combined 
Statistical 
Power 
0.70 
30 (e.g., 2 mg dose) 
60 (e.g., 2 mg dose) 
0.81 
28 (e.g., 4 mg dose) 
56 (e.g., 4 mg dose) 
0.78 
0.65 
25 (e.g., 6 mg dose) 
50 (e.g., 6 mg dose) 
0.88 
0.63 
20 
40 
0.85 
0.60 
15 
30 
0.81 

 
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By Table 10.4.2-1 above, as the effective sample sizes decrease over increasing 
estradiol doses (since not all participants are anticipated to dose-escalate to the 
highest levels), the alternative GMR that can be detected with adequate power 
(~80% or higher) decreases from 0.70 to 0.60. Note, the sample sizes above 
make the simplifying assumption that the effective sample sizes in ART group will 
be similar across the increasing oral 17-β estradiol doses by observed titration. 
 
10.4.3 Sample Size for Intensive PK Subsample 
 
The approach for calculation is similar to the primary objective for PK, but utilizes 
intensive sampling for estimation of estradiol PK parameters of Cmax (and Tmax), 
and AUC. From the iFACT trial [26] the maximum CV between AUC(24hrs) and 
Cmax of estradiol was 0.27. Using this assumed CV, the estimated standard 
deviation of the log transformed parameters is 0.265. Under normality 
assumptions for log transformed parameters, a sample size of 15 has 80% power 
(conditional probability) that a 2-sided, 95% CI on the estradiol PK parameter has 
a half-width of 0.168. Exponentiating provides example CIs of (422.7, 591.5) 
around a hypothetical mean of 500 (e.g., AUC), and (42.3, 59.1) around a 
hypothetical mean of 50 (e.g., Cmax). 
 
10.4.4 Accrual 
 
Complete accrual to all study groups is anticipated to take 12-18 months. However, it 
is not assumed for this accrual to be uniform over this time period, or by ART group. 
Since there are not any previous network trials accruing exclusively from this key 
population, other trials do not inform benchmarks for the rate of accrual. The survey to 
potential participating network sites suggests that sufficient numbers of potential 
participants exist in the communities already targeted by those sites to allow 
enrollment within this time frame. Due to differences in regulatory approvals in 
different locations, it is anticipated that accrual during the first 6 months of the study 
may be primarily from US sites. But it is anticipated that accrual will be rapid following 
the approval of the study at non-US CRSs. 
 
There is a target to enroll at least 50% participants who identify as non-white or Latine. 
 
10.5 
Data and Safety Monitoring  
 
10.5.1 Interim Monitoring Guidelines 
 
It is recommended that the trial be stopped in the case of any death that is 
caused by study treatment, and that trial modification (including stopping) 
should be considered in the case of unexpected serious illness (i.e., SAE) 
caused by the study treatment. Section 7.4 also lists AE triggers for 
expedited safety review, which may also result in trial modification 
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Any/all SMC reviews will include administrative/trial conduct data (e.g., accrual, 
adherence to ART and study treatment, ART changes, realization of titration 
scheme, including timing of estradiol dose changes relative to study visits, drop-out 
[including withdrawals and losses to follow-up]); as well as safety information 
(reported AEs and SAEs) including safety-related outcomes (e.g., protocol defined 
virologic failure and targeted events). Because there are no plans to initiate 
batched centralized PK testing prior to study completion, there are no plans for 
inclusion of early information on either of the primary outcomes (ART or estradiol). 
Locally measured estradiol concentrations will be available to sites for clinical 
management of FHT, but will not be summarized for SMC review due to inter-
assay variability between laboratories. The realization of titration will provide 
information on how these local hormone concentrations were used in trial conduct. 
 
Between SMC review, routine monitoring reports are distributed to the team and 
are detailed in the Study Progress, Data, and Safety Monitoring Plan (SPDSMP): 
screening, accrual, data delinquency and availability, study and treatment status, 
ART changes, collected specimen availability with attention to samples for 
batched PK testing (both sparse and intensive), and safety. These routine reports 
are distributed as per the SPDSMP to the team (exact distribution as per 
SPDSMP), which includes the DAIDS clinical representative. 
 
Detailed plans for study monitoring will be outlined in a SPDSMP developed by 
the SDMC prior to enrollment of the first participant. 
 
10.5.2 Analysis Plan 
 
See section 10.5.1 for monitoring guidelines. 
 
10.6 
Analyses 
 
For both of the primary PK analyses, inclusion in the analysis is based upon no evidence 
of non-adherence or misuse of either ART regimen or oral 17-β estradiol, from any 
source (e.g., including but not limited to self-report and objectives measures of 
adherence, such as undetectable drug levels, or estradiol levels indicative of extra-trial 
dosing such as PK results) around the timing of samples drawn for PK that would violate 
steady state assumptions for the drugs in question (i.e., estradiol and targeted ART). 
Because participant preference is part of the titration process, analyses will be as-
treated, based on the received dose of estradiol, rather than the prescribed dose. This is 
because the study goal is to understand the biologic associations between oral 17-β 
estradiol and ART drug concentrations. Analyses will also be as-treated with respect to 
changes in ART regimen. 
 
All analyses will use log-transformed concentrations of drug or hormones or PK 
parameters calculated from those concentrations of drug or hormones in order to utilize 
normality assumptions in the analysis. 

 
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Analyses will be informed and adjusted by the following (and details on subgroup 
approaches will be described in the primary SAP [publicly posted]): Subset of trial 
sample restarting FHT versus naïve to FHT (with particular relevance to transgender 
congruence scale and FHT acceptability outcomes), and use of anti-androgen during 
study follow-up. Specifically, supplementary analyses will be within subgroups by 
naïve versus restarting FHT, and separately, by use versus non-use of anti-
androgens.   
 
While the plan is to conduct the primary (final) analysis once the last participant has met 
the primary completion date (week 48 evaluations), and the routine process for final 
analysis preparation of the database has completed, the following is an alternate plan 
under the contingency that one (or more) ART cohort completes accrual and follow-up far 
in advance of the others. In this case, objectives which do not require inclusion of the 
ART cohort still under accrual or in follow-up (e.g., objectives which include analyses 
within ART cohort) may undergo final analysis and public presentation once the data to 
support those analyses have completed the quality control and assurances process and 
are considered final. In this contingency, the final analysis will occur in 2 stages. 
 
10.6.1 Primary Analysis 
 
For the primary ART PK analysis, participants serve as their own control; thus no 
bias is introduced by absence of randomization.  
 
10.6.1.1 
The primary objective will be approached with 2 primary analyses. 
The first is to calculate the GMR of the Ctrough of each ARV, using the 
fixed sequence design, and at each dose of oral 17-β estradiol. The 
reference period for each GMR will be the pre-FHT (baseline) period 
when Ctrough of the ARV is measured in the absence of oral 17-β 
estradiol. To handle cases of multiple observations at the same 
estradiol dose; the first sampled among qualifying Ctrough 
concentrations at steady-state will be used in the primary analysis. 
(Note: other approaches [e.g., geometric mean or observed minimum, 
or repeated measures modeling to include all concentrations] may be 
employed as supplementary analyses on this objective and will be 
detailed in the SAP.)  
 
The geometric means and CVs of Ctroughs of each ARV analyte within 
each estradiol dose will be calculated. Other descriptive statistics at 
each estradiol dose include key percentiles (e.g., 25th, 50th, 75th). 
 
The 90% confidence interval about each GMR will be calculated (and 
compared to a reference interval of [0.7,1.43]), and will not be adjusted 
for multiplicity due to evaluation at 2, 4, 6, 8 and 10 mg/day doses of oral 
17-β estradiol. The location and coverage of the confidence interval will 
be the focus of inference, rather than the p-value from a hypothesis test. 

 
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A reference interval wider than the conservative (0.8,1.25) 
bioequivalence interval was chosen due to the higher variability of Ctrough 
parameter (versus other parameters like AUC that combine multiple 
measurements). This approach has been used in other trials when the 
PK parameter has exhibited high variability [49, 50].  
 
The second component of the ARV primary analysis is to address the 
hypothesis that ART exposure in the presence of potentially 
increasing doses of oral 17-β estradiol remains above externally 
defined thresholds. This analysis will calculate the absolute number 
and proportion of participants whose Ctrough of ARV is below a 
specified reference level at a particular dose of oral 17-β estradiol. 
Thresholds will be defined from the lower 95% percentile of their 
trough concentrations from intensive PK studies (exact values will be 
provided in the SAP). See the trial rationale section 2.2 above for 
more details on the rationale of these thresholds. Exact (based on 
Wilson-score) 95% confidence intervals about the observed 
proportions will be calculated. 
 
10.6.1.2 
Primary analysis of estradiol PK objective 
 
For this primary objective, participants are compared between ART 
groups (boosted versus not), and thus utilizes a parallel groups PK 
design. At each oral 17-β estradiol dose, the GMR of Ctrough of serum 
total estradiol between groups will be calculated along with the 
respective 90% CI. Cases of multiple observations within a participant 
at the same estradiol dose will be handled by utilizing the earliest (in 
calendar time) for the primary analysis. [Note: additional methods are 
being explored for supplementary analyses including geometric mean.] 
Both unadjusted and adjusted GMRs will be calculated, where adjusted 
GMRs will be based on pre-specific prognostic factors, and may rely on 
prioritizing factors included for adjustment based on significance tests 
for imbalance on these factors between analysis groups. See 
discussion below on bias for the rationale for adjustment of GMRs. 
 
The geometric means and CVs within each analysis group will also be 
calculated. Other descriptive statistics at the analysis group level include 
key percentiles (e.g., 25th, 50th, 75th) of the serum total estradiol 
measured as well as Wilcoxon-Rank Sum tests between analysis groups. 
 
If ART regimen changes occur that would represent switch to the 
other comparison group, then subsequent estradiol concentrations will 
be excluded from analysis. 
 
Unlike the ART PK objective where a fixed sequence design was possible, 
comparisons here are subject to bias based on confounding by prognostic 

 
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factors for serum total estradiol which may be imbalanced between analysis 
groups not allocated via randomization in this trial, as well as confounding by 
indication via the estradiol titration scheme as described above (10.1). While 
the former source of bias may be mitigated via calculating adjusted GMR for 
known and measured prognostics factors which have large imbalances 
between analysis groups (as proposed above), the later bias is more difficult 
to tackle. Importantly, confounding by indication is not anticipated to occur or 
impact the analysis and interpretation at the same rate throughout the trial. If 
confounding by indication is present, it is expected to be greater at higher 
FHT dose levels. For instance, because everyone is started at the 2 mg 
dose and evaluated at week 4 at this dose before implementing the titration 
scheme, confounding by indication does not apply for this estradiol dose. It 
is anticipated that this bias may be minimal at the lower doses of estradiol, 
which represent the earlier phases of the titration scheme (e.g., 4 mg/day 
and potentially 6 mg/day). Therefore, this issue is of more concern at the 
higher doses of estradiol (6-10 mg/day, where it could substantively impact 
the results. Therefore, the interpretation of comparisons at higher doses, as 
well as interpretation of results at lower versus higher doses, will require 
caution and acknowledgment of this issue. 
 
10.6.2 Secondary Analyses 
 
Each of the safety outcomes will be summarized by ART group and also by 17-β 
estradiol dose at time of outcome. Two degree of freedom tests will explore if the 
number of participants with qualifying safety outcomes differs across the three 
ART groups, with pairwise comparisons informed by the results of the omnibus 
testing. Association of 17-β estradiol dose with safety outcomes will utilize 
estimation of each safety outcome incidence in order to adjust for time of 
exposure to various estradiol doses. For laboratory outcomes where results are 
reported regardless of grade, changes from pre-FHT and from lower estradiol 
doses will be summarized. 
 
Analyses of 17-β estradiol PK parameters from intensive sampling on a subset of 
participants will use parallel methods to the primary methods described above, 
where the difference may be the reference interval for no interaction. 
Proportion of participants with VL <50 copies/mL over time by ART group, and by 
17-β estradiol dose at time of measurement will be reported. Missing viral loads 
will be excluded from this analysis. 
 
Proportion of participants with suppressed testosterone (among those not taking 
anti-androgens and who have not undergone orchiectomy, missing results 
excluded) will be summarized by ART group and by 17-β estradiol dose at time 
of measurement. 
 
Overall transgender congruence scores and changes from baseline to weeks 24 
and 48 will be summarized by ART group and by 17-β estradiol dose at time of 

 
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measurement. Mean Scores will be modeled by both ART group and 17-β 
estradiol dose to test secondary hypothesis. 
 
Anthropometric (weight, BMI, waist, hip, and waist-to-hip ratio) outcomes, and both 
absolute and percent changes will be summarized by ART group and by 17-β 
estradiol dose at time of measurement. The hypothesized association of 17-β 
estradiol dose with increased changes will be assessed by comparing changes 
within each person adjusting for time and 17-β estradiol dose (e.g., change in 
outcome per month at a given dose). The reference for each person will be the pre-
FHT measurement (i.e., baseline), resulting in a ratio at each dose.  
 
A comprehensive SAP will be prepared to further address analyses of all 
outcomes to address all objectives. 
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objectives 
 
See section 1.0 for study objectives. If changes or unexpected results in ART trough 
concentrations are observed, additional analysis of intensive PK samples may be  
conducted to better describe those changes. If that occurs, the following objectives will 
be explored: 
 
11.1.1 
To describe the PK parameters (area under the concentration-time curve 
[AUC], Ctrough, Cmax, Tmax) of ART in a subset of TW undergoing intensive PK in 
the context of historical data from cisgender individuals. 
 
11.1.2 
To determine if intra-individual ART PK parameters (AUC, Ctrough, Cmax, Tmax) 
change with increasing 17- estradiol dosage over 48 weeks in a subset of TW 
undergoing intensive PK. 
 
11.2 
Pharmacology Study Design 
 
This is a pharmacology study, thus, the pharmacology study design is specified in the 
overall study design described in section 3.0. 
 
A combined intensive and sparse sampling strategy will be used to characterize the 
steady-state ART and steady-state 17- estradiol PK. Intensive sampling will occur, in 
a subset of participants, at baseline prior to 17- estradiol exposure in this population of 
TW, and weeks 24 and 48 at escalating 17- estradiol doses. Sparse sampling will 
enrich these data and contribute to a population PK model that can investigate 
covariates on drug exposure and to assess the relationship between drug exposure and 
study-related outcomes. 
 
Intensive PK samples will be analyzed in batch for 17- estradiol at defined time point(s) 

 
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(see LPC). Samples of plasma and PBMC from each time point will be stored and 
evaluated for ART concentrations, as needed, to explain pharmacokinetic results related 
to the sparse trough concentrations.  
 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
Intensive PK analysis 
The plasma PK parameters for 17- estradiol include: maximum concentration (Cmax), 
time to maximum concentration (Tmax), minimum concentration (Cmin), time to minimum 
concentration (Tmin), oral clearance (CL/F), volume of distribution (Vd), elimination half-life 
(T1/2), Ctrough, time of Ctrough, and area under the concentration-time curve over 8 hours 
(AUC0-8h). Standard noncompartmental techniques will be used to determine these PK 
parameters using the software package Phoenix WinNonLin (Certara®). The AUC will 
use the linear up/log down version of the trapezoidal rule. This version of the trapezoidal 
rule uses linear interpolation between untransformed data up to Cmax, and between log-
transformed data from Cmax through Clast. Cmax will be taken as the maximum observed 
concentration. Tmax is the time at which Cmax occurs. Ctrough will be taken as the pre-dose 
measurement. Apparent oral clearance will be calculated as CL/F. The T1/2 will be 
determined using regression analysis when possible along with other estimates of 
exposure as deemed appropriate based on review of the data. This noncompartmental 
analysis may be supplemented with a compartmental analysis and or a nonlinear mixed 
effects population PK analysis. 
 
If intensive ART samples are evaluated, the same methods will be used to evaluate these 
intensive samples. TFV-DP and FTC-TP or 3TC-TP concentrations in PBMCs will be 
collected on a limited basis therefore no PK parameters will be calculated. Descriptive 
statistics will be used to summarize the concentrations as follows: C3h, C8h, Ctrough, Caverage.  
 
Trough and intracellular concentrations 
ARV will be measured from pre-dose samples according to section 6.3.9 to derive Ctrough. 
BIC, DTG, DRV, TFV, FTC, and 17- estradiol will be measured from plasma and TFV-
DP and FTC-TP or 3TC-TP will be measured from PBMCs. The concentrations will be at 
a single time point; therefore, no PK parameters will be calculated.  
 
See section 10.6 for statistical analyses on all PK outcomes (PK parameters or timed 
concentrations). 
 
11.4 
Population Pharmacokinetic/Pharmacodynamic Analyses 
 
The objective and intended outcome of this analysis is to investigate relationships 
among the concentrations of ART and 17- estradiol with any participant characteristics 
that influence the PK of the medications and relationships with treatment outcomes. 
Conventional measures of exposure will be obtained from the pharmacokinetic analyses. 
PD models may be in the form of a linear or a sigmoid Emax relationship. 
 

 
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For this analysis, we will determine the population PK characteristics of ART and 17- 
estradiol using all PK data collected across multiple observations in order to inform 
between- and within-individual variability. This will be approached using appropriate 
modeling software with a goal to identify participant characteristics (covariates) that may 
influence these parameters, including the influence of concomitant medications. An error 
model will be identified and selected using a stepwise process and based on improvements 
in standard diagnostic plots and estimate precision. If necessary, poorly identified structural 
parameters, such as the absorption rate constant, may be fixed to usual adult values. 
Covariates will include age, weight, body mass index, race, estimated glomerular filtration 
rate, and concomitant medications. The influence of each covariate on the PK 
characteristics of the drug will be tested sequentially. At the end of the analysis, all 
covariates that show an influence on the parameters will be evaluated again by comparison 
of the full model (with all factors included) with a model from which each of the factors is 
deleted sequentially.  
 
After the model that best describes the plasma PK characteristics of ART and 17- 
estradiol is identified, we will next develop a linked PK and PD model to investigate 
relationships among the PK parameters of the drug, and measure effectiveness.  
 
11.5 
Anticipated Outcomes 
 
These PK studies will provide information on ART and 17- estradiol when combined in 
TW living with HIV. The PK data will fill gaps in our knowledge about effective co-
prescribing of ART and hormones for gender-affirming therapy. 
 
12.0 
BEHAVIORAL SCIENCE  
 
12.1 
Rationale 
 
The complexity of dire social realities faced by TW can magnify HIV vulnerabilities and 
limit engagement in the HIV continuum of care and research [3, 36, 37]. The inclusion of 
study satisfaction and acceptability measures are a unique opportunity within A5403 to 
not only understand psychosocial impacts of gender-affirming care through this 
intervention but also improve research processes targeting this community.  
 
Importantly, because not all TW will enter this study FHT-naïve, and because individual 
goals of FHT initiation vary widely between participants, additional qualitative work in a 
subset of participants will be critical to interpreting the quantitative data obtained. 
 
12.2 
Design 
 
The embedded behavioral science study is a two-pronged, concurrent, design. The 
quantitative survey component will be administered to all A5403 participants. Semi-
structured, in-depth interviews will be conducted at the same time points on a smaller 
sample of TW purposively recruited from English- or Spanish-speaking sites (due to 
interviewer language restrictions and the need for qualitative interviews to have accurate 

 
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interpretation/not be biased by 3rd party translation variation). Participants will be 
selected from the subset of persons providing written informed consent to be considered 
for this optional component. 
 
12.3 
Measures of Satisfaction and Acceptability 
 
We will measure/track indicators of intervention satisfaction and acceptability at study 
weeks 0, 24, and 48 (or premature treatment or study discontinuation). To measure 
acceptability, we will ask participants to self-report the degree to which they find the 
intervention appropriate and useful using Likert-type agreement scales at weeks 0, 24, 
and 48 (or premature discontinuation). To measure satisfaction, we will use the 12-
question Transgender Congruence Scale (TCS), which will assess associations between 
FHT, perceived gender congruence, and satisfaction at weeks 0, 24, and 48 (or 
premature discontinuation) [38]. The TCS has demonstrated high internal consistency 
(alpha >0.80) and has been utilized in numerous clinical settings [39, 40, 41].  
 
In addition, Dr. Perez-Brumer and her team (as opposed to site staff) will conduct brief, 
20-minute, semi-structured, web-based interviews with 30 purposively sampled English-
and Spanish-speaking participants by group: BIC-treated group (n=10) (Group 1); a 
DTG-treated group (n=10) (Group 2) ; and a DRV/c-treated group (n=10) (Group 3). This 
design will provide an opportunity for more in-depth (open-ended) feedback on 
intervention satisfaction and acceptability across groups and over time. The semi-
structured interview guide in English and Spanish is posted on the A5403 PSWP.  
 
12.4 
Procedures and Analysis 
 
For the survey components assessing acceptability and satisfaction, participants will 
complete these at weeks 0, 24, and 48 (or premature discontinuation). Participants may be 
assisted by a study staff member, if necessary. Survey may be conducted via paper. Study 
staff will provide real-time support to participants and receive training to ensure confidentiality 
and standardized data collection at weeks 0, 24, and 48 (or premature discontinuation). 
 
For qualitative interviews assessing satisfaction, all planned interviews are expected to last 
around 20 minutes and will be conducted online via an online video conferencing platform 
(i.e., Microsoft Teams, Skype, Zoom, WhatsApp). Participants will be purposively recruited 
from survey completers based on clinical site, and by group (i.e., BIC-treated group, a 
DTG-treated group, and a DRV/c-treated group (see MOPS for recruitment guidelines) [51, 
52]. Interviews will be conducted in English and Spanish by a bilingual medical sociologist 
(Dr. Amaya Perez-Brumer) with extensive experience conducting qualitative data collection 
with transgender communities and/or a University of Toronto transgender doctoral trainee 
who is a licensed social worker and has experience in qualitative research methods. All 
interviews will be audio-recorded, and transcribed by an outside company. Once the 
interview is transcribed, the audio recording will be erased from the digital recorder. Audio 
recordings are considered source documents, and a copy will be kept on a secure 
password protected server for 5 years at the University of Toronto. Dr. Amaya Perez-

 
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Brumer will have access to personal information and information provided in the interviews. 
Data will be de-identified. Audio recordings and other information will be kept strictly 
confidential. For more detail about confidentiality, refer to Informed Consent for Interviews. 
 
For qualitative data, our sample size is driven by the goal of saturation [53]. Guided by 
immersion crystallization, we will analyze transcripts based on inductive and deductive 
approaches to identify themes and relations between themes [54, 55]. Anticipated main 
analysis will assess lived experience of taking FHT and ART and participating in the research 
study, and both quantitative and qualitative assessments will collect information in the following 
key domains: to assess goals (body modification and study participation), perceived impacts of 
ART and FHT, and experience with clinic and staff. These qualitative assessments will provide 
invaluable, supplemental, contextual support to the quantitative data obtained through the 
participant survey, informing the current data interpretation and future interventions. 
 
13.0 
DATA COLLECTION AND MONITORING  
 
13.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon registration. 
 
13.2 
Role of Data Management 
 
13.2.1 
Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
13.2.2 
It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
13.3 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include 
remote source document verification using methods specified for this purpose by NIAID. 
Remote monitoring visits may be performed in place of, or in addition to, onsite visits to 
ensure the safety of study participants and data integrity [56]. The site must make 
available study documents for site monitors to review utilizing a secure platform that is 
HIPAA and 21 CFR Part 11 compliant. The Data Management Center will configure 
Medidata Remote Source Review (RSR) and make it available to all sites. We 
encourage sites to use the DMC provided Medidata RSR platform but other potential 
platform options include: Veeva SiteVault, site-controlled SharePoint or cloud-based 
portal, and direct access to Electronic Medical Record (EMR). Other secure platforms 
that are 21 CFR Part 11 compliant may be utilized, as allowed by the DAIDS Office of 
Clinical Site Oversight (OCSO). 

 
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13.4 
Reporting Protocol Deviations 
 
This protocol follows the requirements to report protocol deviations per SOP 
ACTG-153. The site principal investigator and personnel are responsible for 
identifying and reporting deviations. Once protocol deviations are identified, 
corrective actions are to be developed by the site and implemented promptly. 
Protocol deviations must be sent to the IRB/EC per their guidelines. 
 
Protocol deviations must be recorded on the study protocol deviation eCRF. 
 
14.0 
PARTICIPANTS 
 
14.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Informed Consent and Authorization 
to use and Disclose Protected Health Information) and any subsequent modifications will 
be reviewed and approved by the IRB or EC responsible for oversight of the study. A 
signed consent form will be obtained from the participant. The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the participant and this fact will 
be documented in the participant’s record. 
 
14.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, or and international regulatory entities as part of their duties.  
 
14.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
or other country-specific government agencies as part of their duties to ensure that 
research participants are protected. 
 
15.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies.  
 
16.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 

 
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handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  
 

 
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17.0 
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56. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards, March 2020, Updated on January 27, 2021. Accessed at: 
https://www.fda.gov/media/136238/download. 
 
 
 

 
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INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE PROTECTED 
HEALTH INFORMATION 
Sponsor / Study Title: 
  
National Institute of Allergy and Infectious Diseases (NIAID) / 
“Giving Standardized Estradiol Therapy In Transgender Women to 
Research Interactions with HIV Therapy: the GET IT RIgHT Study” 
 
Protocol Number: 
 
A5403 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. The reasons this study 
is being conducted are: 
• 
To see if human immunodeficiency virus (HIV) antiretroviral medicines that you are taking 
continue to work well in transgender women and other individuals identifying as female or 
transfeminine but with male sex assigned at birth (referred to as transgender women 
throughout this form) when taken with feminizing hormone therapy (FHT), also known in this 
study as estradiol; and  
• 
To see if estradiol levels in blood vary between boosted and un-boosted HIV medicines 
when transgender women are taking different doses of FHT. 
 
STUDY TREATMENT 
The study drug in this trial is 17-β estradiol. Throughout this consent form, the study drug will be 
referred to as estradiol. At study entry, you will start oral estradiol 2 mg tablet once daily. At 
weeks 4, 12, 24, and 36, the study doctor may change the estradiol dose by 1 tablet to achieve 
any goals you may have and depending upon your blood hormone levels. 
 
NUMBER OF PARTICIPANTS 
There will be 90 participants: 30 in three different groups. The groups are based on what HIV 
medicines individuals are taking. 
 
LENGTH OF STUDY  
The study will last for 48 weeks, or about 12 months.  
 
REQUIRED ACTIVITIES 
At all visits, some blood will be collected from a vein in your arm. At all visits, you will arrive fasting. 
This means that you will not eat or drink anything other than water and your prescribed medications for 

 
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at least 8 hours before the visit. You will also complete surveys, and you may participate in interviews. 
RISKS 
The following serious side effects have been reported with the study drug, estradiol: 
• 
Numbness or weakness on one side of your body, or in your arm or leg, sudden or severe 
headache, problems with speech or walking (stroke). It is possible that this risk may be 
increased if you are using tobacco or nicotine products. Options for resources to 
help you quit smoking will be provided to you if you are using these products and if 
you desire to learn about these resources. 
• 
Swelling in your hands, ankles, or feet 
• 
Fever, diarrhea, muscle pain, dizziness, fainting 
• 
Sudden and severe stomach pain, nausea, vomiting, gallbladder disease 
• 
Changes in thyroid function 
• 
Vision changes 
• 
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your 
mouth or throat, chest tightness, trouble breathing 
• 
Breast tenderness and breast enlargement 
• 
Chest pain that may spread, coughing up blood, trouble breathing/shortness of breath 
(blood clot in lungs) 
• 
Blistering, peeling, red skin rash 
• 
Lumps in breast  
• 
Pain in your leg (calf) that may be a blood clot 
• 
Changes in hair growth or hair loss 
• 
Stomach cramps, bloated feeling 
• 
Weight gain 
• 
Headaches 
• 
Increase in cholesterol (a type of fat) 
• 
Increase in triglycerides (a type of fat) 
• 
Blood sugar increases 
• 
Heart attack 
• 
High blood pressure 
• 
Breast cancer 
• 
Liver problems 
• 
Mood changes 
 
It is not fully known how well HIV is controlled in the body when HIV medications and estradiol 
are taken together. 
 
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 
enters the body, lightheadedness, and in rare cases, fainting, or infection.  
 
There is the possible risk that taking estradiol could lead to your HIV medications not 
controlling your HIV as well, which could increase the chance of passing HIV to other 
people. You should discuss your choices with your health care provider to choose the 
best way for you to prevent the spread of HIV to your partner(s). 

 
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BENEFITS 
As part of this study, you will receive estradiol as FHT. FHT is used by some transgender 
women as part of their gender-affirming care. However, it is possible FHT may not benefit you.  
 
OTHER CHOICES 
You may choose to not participate in the study. Instead of being in this study, you have the option 
of FHT available to you or starting FHT under the care of your regular doctor or other health care 
provider. Please talk to your regular doctor about these and other choices available to you. 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you take medicines for HIV, 
and you are a transgender woman or a female or transfeminine person but with male sex 
assigned at birth. We will say transgender woman throughout this form.  
 
This study is sponsored by the National Institutes of Health (NIH). The study doctor is in charge 
of this study at this site. Before you decide if you want to be a part of this study, we want you to 
know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
This research study is being done to help us understand if the feminizing hormone, estradiol, 
affects commonly used HIV medication drug levels in blood. Estradiol is used for gender-
affirming therapy by transgender women. Its use in this study is considered investigational, 
which means it is not approved by the Food and Drug Administration (FDA) for gender-affirming 
therapy by transgender women. It is FDA approved for other uses. The reason this is important 
to understand is because if estradiol does affect HIV medication drug levels in blood, this may 
mean that the HIV medication may not work as well in transgender women taking hormones as 
it should. We will also try to understand whether the feminizing effects of estradiol in 
transgender women vary depending upon what HIV regimen it is combined with. This study will 
help us understand whether HIV medications and estradiol have an effect on one another when 
taken together. This study will fill important gaps in knowledge about HIV medications and 
estradiol co-administration for transgender women living with HIV and clinical providers.  
 
The study has three (3) groups: 
1. Group 1: Participants taking the HIV medications Bictegravir (BIC) + tenofovir alafenamide 
(TAF) + emtricitabine (FTC)  
2. Group 2: Participants taking the HIV medications Dolutegravir (DTG) + tenofovir disoproxil 
fumarate (TDF) + FTC or lamivudine (3TC)  

 
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3. Group 3: Participants taking any HIV medications containing darunavir plus cobicistat 
(DRV/c). 
Which group you are in is determined by the HIV medication you are taking. 
 
You will continue taking your existing HIV medications while on the study or switch to one of the 
above regimens prior to study entry. Your HIV medications will not be provided by the study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an AIDS Clinical 
Trials Group (ACTG) study. As part of your screening visit, some demographic (for example, 
age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory (for 
example, viral load) information will be collected from you. We also collect information on 
whether you use (or have used) intravenous (IV – into a vein) drugs. 
 
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may help determine whether there are patterns or common 
reasons why people do not join a study. 
 
If you agree to join this study, you will be asked to sign this consent form. After you have signed 
the form, the research staff will determine if you are eligible to join the study. If you are eligible, 
you may also be able to participate in three 20-minute interviews for this study. If you are 
interested, you will indicate your interest on Attachment A at the end of this form, and you will 
sign a separate consent form. 
 
Estradiol 
The study drug in this trial is estradiol. Starting at study entry, you will start taking estradiol by 
mouth 2 mg once daily. At weeks 4, 12, 24, and 36, the study doctor may change the estradiol 
dose by 1 tablet to achieve any goals you may have. The study doctor will talk to you about 
what hormone levels they are trying to achieve, depending upon your personal goals. They will 
monitor hormone levels in your blood to make sure you are on target towards those goals but 
also that your hormone levels are staying within safe ranges.  
 
Blood Draw 
Throughout the study you will have blood drawn. You will be told the results for routine 
laboratory tests for safety and local hormone level testing. 
 
Screening 
If you would like to be in this study, after you have read and signed this consent form, you will 
come to the clinic for a screening visit to make sure you meet the requirements for joining the 
study. This will take about an hour. At this visit: 
• 
You will have a physical exam and answer questions about your medical history and any 
medications you are taking or have taken in the past.  
• 
You will complete a questionnaire related to suicidal thoughts or attempts. 

 
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• 
You will have blood drawn. This blood will be used for the following tests: 
o For routine lab tests for safety. 
o To measure the amount of HIV in your blood.  
o To measure the level of prolactin in your blood. Prolactin is a protein best known in 
helping with milk production. 
o Blood estradiol level if you report that you have not recently taken estradiol. If you have 
recently taken estradiol, you will be asked to come back later to have your estradiol level 
checked (but before you enter the study). 
o You may need to be tested for hepatitis B virus and hepatitis C virus if you don’t 
have documentation for this testing. 
 
Pre-Entry 
If you change your HIV medication to one of the regimens allowed in the study, you will need to 
take that medication for at least 28 days (about 4 weeks) before you can enter the study. You 
will have a Pre-Entry visit at least 4 weeks after you have changed your HIV medication to 
measure the amount of HIV in your blood. This visit will take about 20 minutes. You will have 
this visit before you officially enter the study. 
 
If you enter the study 
If the tests at screening show that you are eligible for the study, you will be assigned to one of 
three groups, depending on the HIV medicines you are taking.  
 
Entry / Day 0 
After your screening visit (and pre-entry visit, if applicable), you will come in for an entry visit. 
You will arrive fasting for this visit. This means that you will not eat or drink anything other than 
water and your prescribed medications for at least 8 hours before the visit. Do not take your HIV 
medications before your study visit. If you usually take them in the morning, bring them with you 
to the study visit. The study staff will remind you when you need to fast. If you are not fasting for 
this visit, the visit will be rescheduled, and you will need to return to the clinic on a different day. 
 
At this visit: 
• 
You will have a shortened physical exam and answer questions about your medical history 
and any medications you are taking or have taken in the past. 
• 
You will be asked about nicotine use. 
• 
You will have blood drawn that will be used for the following tests: 
o For routine lab tests for safety. 
o To measure the amount of HIV and CD4+/CD8+ (strength of your immune system, the 
system that helps your body fight infections) in your blood.  
o Total testosterone (a hormone that stimulates development of male secondary sexual 
characteristics) and estradiol concentration. 
o Some of the blood will be used for study-required testing during or at the end of the 
study. You will not receive the results of this testing. 
o Timed trough sampling: Blood will be collected before daily antiretroviral therapy (ART) 
and estradiol administration, except participants completing an intensive 
pharmacokinetic (PK) visit. 

 
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• 
About 15 participants in each group will have blood drawn for PK testing over 8 hours after 
you take your HIV medication. PK testing is testing to see how the levels of the study drugs 
rise and fall in your blood over time. Please refer to Attachment A to indicate your interest in 
participating in PK testing. 
o For PK testing, the blood collection time points will be at hour 0 (before you take your 
HIV medicine), and at 1, 2, 3, 4, 6, 8 hours after taking the HIV medicine.  
• 
You will be asked about your goals for estradiol use. 
• 
You will start taking oral estradiol 2 mg (1 tablet) once daily. If you are participating in PK 
testing, you will start taking estradiol after the 8-hour PK testing is complete.  
• 
You will complete a few surveys about satisfaction and acceptability of estradiol and the 
trial.  
• 
You will complete a questionnaire related to suicidal thoughts or attempts. 
 
Post-Entry Evaluations 
You will have five more in-person visits after your entry visit (total of six visits). These visits will 
be at weeks 4, 12, 24, 36, and 48. You will arrive fasting for these visits. Do not take your HIV 
medications before your study visit. If you usually take them in the morning, bring them with you 
to the study visit. The study staff will remind you when you need to fast. If you are not fasting for 
these visits, these visits will be rescheduled, and you will need to return to the clinic on a 
different day. 
 
At these visits: 
• 
You will have a shortened physical exam. 
• 
You will be asked about nicotine use. 
• 
You will be asked about your HIV medication and study drug use and adherence (including 
study staff performing pill counts). 
• 
You will have blood drawn that will be used for the following tests: 
o For routine lab tests for safety. 
o To measure the amount of HIV and CD4+/CD8+ (strength of your immune system, the 
system that helps your body fight infections) in your blood.  
o Total testosterone and estradiol concentration. 
o Some of the blood will be used for study-required testing during or at the end of the 
study. You will not receive the results of this testing. 
o Timed trough sampling: Blood will be collected before daily ART and estradiol 
administration, except participants completing an intensive PK visit. 
• 
At weeks 24 and 48 (or premature discontinuation), the same 15 participants in each group 
who had blood drawn for intensive PK at entry will have blood drawn for PK testing over 8 
hours as described above. Blood will be drawn before ART and estradiol dosing. 
• 
At weeks 4, 12, 24, 36, and 48 oral estradiol dose may be increased, decreased, or stay the 
same, depending upon your goals, how you are feeling on the study drug, and the results of 
your blood tests. 
• 
At weeks 24 and 48, you will complete a few surveys about satisfaction and acceptability of 
estradiol and the trial.  
• 
You will complete a questionnaire related to suicidal thoughts or attempts. 

 
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If you are having suicidal thoughts or feel in crisis, call the study doctor at the 
telephone number listed on the first page of this form.  You can also call or text the 
National Suicide & Crisis Lifeline at 9-8-8 or 1-800-273-TALK (8255). The Lifeline 
numbers are answered 24 hours a day every day of the year by a skilled, trained 
counselor. You can also present to a healthcare provider, your local emergency room, 
or call 9-1-1 to be connected to local emergency services. 
• 
At week 48, you will be asked again about your goals for estradiol use. 
• 
At week 48, you will be referred to community resources for continuing estradiol after the 
study is over. 
 
You will have a remote visit at week 8. At this visit: 
• 
You will be asked about medications you’re taking and any modifications to study 
treatment. 
• 
You will complete a questionnaire related to suicidal thoughts or attempts. 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
You cannot choose the types of research that your samples and information are used for 
because some of your blood will be stored and used for study-required PK, virologic [viruses], 
immunologic [blood cells] and metabolic or inflammatory [the physical and chemical changes that 
take place in the body] testing. You will not be told the results from these study-required tests. 
 
The labels on your samples, including those that are stored for later testing, will be coded and 
will not include any private information that has been collected about you. This means that no 
one looking at the labels or at other information will be able to know that the samples or 
information came from you.  
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study. If you stop the study early, 
investigators may keep and analyze already-collected data. 
 
Please refer to Attachment B to consent for use of your samples in other studies. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 90 participants will take part in this study: 30 in each of the three groups. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in the study for 48 weeks, or about 1 year. 
 
 

 
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WHY WOULD THE STUDY DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early if: 
• 
You do not attend three consecutive study visits. 
• 
The study doctor suspects HIV medication drug resistance and needs you to change your 
HIV meds. 
• 
You are not able to take the study drug as prescribed. 
• 
The study doctor discontinues the study drug based on how you answer questions 
about and or report suicidal ideation or attempts, or other changes in your mental 
health, or worsening depression. 
• 
You are not taking estradiol as prescribed by the study (such as taking higher or lower 
doses than what you agreed with your study doctor). 
• 
You change your HIV medications for some other reason.  
• 
You request to be taken off the study. 
• 
Your primary care doctor decides the study is no longer in your best interest or that it is 
unlikely that you will be able to comply with the study requirements. 
• 
The study is stopped or cancelled. 
 
The study doctor may also need to take you off estradiol without your permission if: 
• 
The study doctor or your primary care doctor identifies a reason why continuing the estradiol 
may be harmful to you. 
• 
You need a treatment that you may not take while taking estradiol. 
• 
You have adverse events (side effects) related to estradiol. 
 
If you must permanently stop taking 17-β estradiol due to suicidal ideation or attempt, 
worsening depression, or other acute psychiatric conditions, you will be immediately 
referred to behavioral health and substance use counseling services for further 
evaluation and treatment. 
 
If you have to stop taking estradiol early or you are taken off the study early, you will have a 
Premature Study Treatment or Study Discontinuation visit and have several evaluations.  
 
 
IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED DRUGS OR ONCE I 
LEAVE THE STUDY, HOW WOULD DRUGS BE PROVIDED? 
 
If you must permanently stop taking estradiol before your study participation is over, you may 
check with your regular doctor or local clinic for options. The study staff will discuss other 
options that may be of benefit to you. 
 
After the study 
After you have completed your study participation, the study will not be able to continue to 
provide you with estradiol you received on the study. If continuing to take these or similar 
drugs/agents would be of benefit to you, the study staff will discuss how you may be able to 
obtain them. 

 
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WHAT ARE THE RISKS OF THE STUDY? 
 
The study will assess interactions between estradiol and your HIV medicines. It is important for 
you to be aware of the side effects of estradiol, so you and the study team can manage the 
risks. The list below is what is known from studies of estradiol involving women who are peri- or 
post-menopausal. 
 
Estradiol 
The following serious side effects have been reported with the study drug, estradiol: 
• 
Numbness or weakness on one side of your body, or in your arm or leg, sudden or severe 
headache, problems with speech or walking (stroke). It is possible that this risk may be 
increased if you are using tobacco or nicotine products. Options for resources to help you 
quit smoking will be provided to you if you are using these products and if you desire 
to learn about these resources. 
• 
Swelling in your hands, ankles, or feet 
• 
Fever, diarrhea, muscle pain, dizziness, fainting 
• 
Sudden and severe stomach pain, nausea, vomiting, gallbladder disease 
• 
Changes in thyroid function 
• 
Vision changes 
• 
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your 
mouth or throat, chest tightness, trouble breathing 
• 
Breast tenderness and breast enlargement 
• 
Chest pain that may spread, coughing up blood, trouble breathing/shortness of breath 
(blood clots in lungs) 
• 
Blistering, peeling, red skin rash 
• 
Lumps in breast  
• 
Pain in your leg (calf) that may be a blood clot 
• 
Changes in hair growth or hair loss 
• 
Stomach cramps, bloated feeling 
• 
Weight gain 
• 
Headaches 
• 
Increase in cholesterol (a type of fat) 
• 
Increase in triglycerides (a type of fat) 
• 
Blood sugar increases 
• 
Heart attack 
• 
High blood pressure 
• 
Breast cancer 
• 
Liver problems 
• 
Mood changes 
 
It is unknown how well HIV is controlled in the body when HIV medications and estradiol are 
taken together. 

 
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Risks of Blood Draws 
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 
enters the body, lightheadedness, and in rare cases, fainting, or infection.  
 
Passing HIV to Other People 
There is the possible risk that taking estradiol could lead to your HIV medications not controlling 
your HIV as well, which could increase the chance of passing HIV to other people. You should 
discuss your choices with your health care provider to choose the best way for you to prevent 
the spread of HIV to your partner(s). 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
As part of this study, you will receive estradiol for 48 weeks. FHT is used by transgender women 
to enhance their gender-affirming care and well-being. For example, the estradiol you receive 
could help in development of female physical characteristics, such as breast growth, weight gain 
in the hips and buttocks, reduced or softer facial hair growth, etc. However, it is possible FHT 
may not benefit you. Information learned from this study may help others who are transgender 
women and who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Enrollment in the study is voluntary. You may choose to not participate in the study. Instead of 
being in this study, you have the option of starting FHT under the care of your regular doctor or 
other health care provider.  
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff to 
help keep your personal information private, we have gotten a Certificate of Confidentiality from the 
US Federal Government. This certificate means that researchers cannot be forced to tell people 
who are not connected with this study, such as the court system, about your participation. The 
researchers with this Certificate may not disclose or use information, documents, or biospecimens 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
action, suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, 
unless you have consented for this use. Information, documents, or biospecimens protected by this 
Certificate cannot be disclosed to anyone else who is not connected with the research except, if 
there is a federal, state, or local law that requires disclosure (see below); if you have consented to 
the disclosure, including for your medical treatment; or if it is used for other scientific research, as 
allowed by federal regulations protecting research participants.  
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 

 
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program evaluation by the agency which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you from voluntarily 
releasing information about yourself or your involvement in this research. If you want your 
research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. 
 
Having a Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. The Certificate of Confidentiality will not be used to 
prevent disclosure for any purpose you have consented to in this informed consent document. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties, Advarra Institutional Review Board (IRB) (a committee 
that protects the rights and safety of participants in research), National Institutes of Health 
(NIH), study staff, study monitors, and their designees.  
 
Also, any publication of this study will not use your name or identify you personally. 
 
A description of this clinical trial will be available on https://ClinicalTrials.gov as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
The study will pay for the study drug (estradiol), research-related tests and assessments. 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study. Costs may include but not limited to transportation costs, time 
away from work or home. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
«Compensation» 
 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the visits 
you complete according to the following schedule: 
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx.  
 

 
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If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid ___________ [“following each completed visit”, “monthly”, “quarterly”, “at the 
end of your participation in the research study”, “following each completed visit or at the end of 
your participation in the research study, whichever you prefer”]. 
 
If you have any questions regarding your compensation for participation, please contact the 
study staff. 
[OR] 
You will not receive any monetary compensation for your participation in this study.  
 
[If applicable:] We will reimburse you for the cost of [describe: e.g., traveling to your study visits]. 
You will be reimbursed approximately [e.g., 2 weeks, 1 month, etc.] after you submit your travel 
receipts to the study staff. 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of this study, you will be given immediate treatment for your 
injuries. The cost for this treatment could be charged to you or your insurance company.  
 
There is no program for compensation through the NIH.  
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. Your site will share a summary of the results when 
they are ready to be presented. Your study staff can answer any questions you may have. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study such as: 
 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a research participant; 

 
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• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to withdraw you from participation; 
• 
Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this consent 
document.  
 
If you seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, contact: 
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:         adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00066234. 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 

 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH 
INFORMATION 
 
If you decide to be in this study, the study doctor and study staff will use 
and share health data about you to conduct the study. Health data may 
include: 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records 
kept by your doctor or other health care workers.  
 
For this study, the study staff may share health data about you with 
authorized users. Authorized users may include: 
• Representatives of University of California, Los Angeles (UCLA) and 
National Institute of Allergy and Infectious Diseases (NIAID). 
• Representatives of ACTG. 
• Representatives of Advarra IRB (an Institutional Review Board that 
reviews this study). 
• The Food and Drug Administration (FDA) and other US federal and 
state agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, 
and STDs) must be reported. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data 
storage companies, that work with the researchers and sponsor and 
need to access your information to conduct this study. 
• Other research doctors and medical centers participating in this 
study, if applicable.  
• A data safety monitoring board which oversees this study, if 
applicable. 

 
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Your health data will be used to conduct and oversee the research, 
including for instance: 
• To see if the study drug works and is safe. 
• To compare the study drug to other drugs. 
• For other research activities related to the study drug.  
 
Once your health data has been shared with authorized users, it may no 
longer be protected by federal privacy law and could possibly be used or 
disclosed in ways other than those listed here.  
 
Your permission to use and share health data about you will end in 50 
years unless you revoke it (take it back) sooner.  
 
You may revoke (take back) your permission to use and share health data 
about you at any time by writing to the study doctor at the address listed on 
the first page of this form. If you do this, you will not be able to stay in this 
study. No new health data that identifies you will be gathered after your 
written request is received. However, health data about you that has 
already been gathered may still be used and given to others as described 
in this form.  
 
Your right to access your health data in the study records will be 
suspended during the study to keep from changing the study results. When 
the study is over, you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part 
in the study. 
 
STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have 
been answered. I voluntarily agree to allow study staff to collect, use and 
share my health data as specified in this form. I will receive a signed and 
dated copy of this form for my records. I am not giving up any of my legal 
rights by signing and dating this form.  

 
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______________________  
____________________________ 
Participant’s Name (print) 
 
Signature and Date 
 
_____________________ 
 
____________________________ 
Witness’s Name (print)  
 
Signature and Date  
 
 

 
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ATTACHMENT A: OPTIONAL PROCEDURES 
 
There are two different optional procedures (as described below) that will advance the scientific 
goals of this study. Not all participants can do these optional procedures, but we would like to 
know if you would be interested in doing these optional procedures. You may indicate your 
interest in both procedures, if you wish. If you are not interested in the optional procedures, it 
will not affect your ability to take part in the main study.  
  
1. Blood drawn for pharmacokinetic (PK) testing 
About 15 participants in each group will have blood drawn for PK testing. You will be asked to 
remain at the clinic all day (about 10 hours) for an intensive PK blood sampling. For this 
intensive PK sampling, you will have blood drawn several times over a period of 8 hours to 
measure the amount of HIV medicine and estradiol in your blood. Except the entry visit, the 
sample collection time points will be at hour 0 (before you take your HIV medicine and 
estradiol), and at 1, 2, 3, 4, 6, and 8 hours after taking the HIV medicine and estradiol doses. At 
the entry visit, the sample collection time points will be at hour 0 (before you take your 
HIV medicine), and at 1, 2, 3, 4, 6, and 8 hours after taking the HIV medicine. At the entry 
visit, you will start taking estradiol after the 8-hour PK testing is complete. To avoid many 
needle sticks, a small tube (intravenous [IV] device) may be placed into a vein in your arm and 
left in place during your stay. You will be able to move around and should not have any 
significant pain or discomfort once the tube is in place. The site will provide food for you, or you 
may bring food, if you prefer. 
 
Blood drawn for PK testing will occur at entry and weeks 24 and 48 and at the Premature 
Study Treatment or Study Discontinuation visit, if you discontinue the study or study 
treatment early. 
 
Please indicate below if you are interested in this optional procedure. No matter what you 
decide, it will not affect your participation in the main study.  
 
________ (initials) YES, I am interested           ________ (initials) NO, I am not interested 
 
 
2. Interviews 
Interviews will be conducted among 30 participants who speak English or Spanish. The 
interviews are expected to last around 20 minutes and will be conducted online via an online 
video conferencing platform. All interviews will be audio-recorded. Interviews will occur at weeks 
0, 24, and 48.  
  
Please indicate below if you are interested in participating in the interviews. No matter what you 
decide, it will not affect your participation in the main study. If you indicate you are interested, 
you will be asked to review and sign a separate consent form. 
  
________ (initials) YES, I am interested             ________ (initials) NO, I am not interested 
 
 

 
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ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples”. 
The ACTG will only allow your extra samples to be used in other studies if you agree to this. 
If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will 
know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository located in the United States.  
 
There is no limit on how long your extra samples will be stored. 
 
When a researcher wants to use your samples and information, their research plan must be 
approved by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan.  
 
IRBs/ECs protect the rights and well-being of people in research. If the research plan is 
approved, the ACTG will send your samples to the researcher’s location. This means that 
researchers who are not part of the study team may use your samples without asking you again 
for your consent. 
 
You will not be paid for your samples. Also, a researcher may make a new scientific discovery 
or product based on the use of your samples. If this happens, there is no plan to share any 
money with you.  
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the staff any questions that you have before you indicate your selection.  
 
Research Without Human Genetic Testing  
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protection of your identity) and used for ACTG-approved HIV-related research 
that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my blood.  
 
OR 
 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 

 
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Research with Human Genetic Testing 
The ACTG has two different studies that collect samples for genetic testing. 
 
If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed Consent to 
Use Stored Human Biological Materials (HBM) for Currently Unspecified Analyses. 
 
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like to participate in one of these studies if it is being done 
where you live. If you would like to participate, you will sign a separate consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign and date a 
consent form for A5128 or A5243. 
 
 

 
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INFORMED CONSENT FOR INTERVIEWS 
 
Sponsor / Study Title: 
  
National Institute of Allergy and Infectious Diseases (NIAID) / 
“Giving Standardized Estradiol Therapy In Transgender Women 
to Research Interactions with HIV Therapy: the GET IT RIgHT 
Study” 
 
Protocol Number: 
 
A5403 
 
Principal Investigator: 
(Study Investigator) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
SUMMARY 
 
PURPOSE 
To help the research team understand how satisfied you are with the study and 
your experience with gender-affirming care and human immunodeficiency virus 
(HIV) services more broadly. 
STUDY  
ACTIVITY 
Interviews will be conducted throughout the study. 
 
NUMBER OF  
PARTICIPANTS 
30 participants. 
 
LENGTH OF  
ACTIVITY 
Approximately 20 minutes per interview.  
 
REQUIRED  
ACTIVITY 
Participate in three audio-recorded 20 minute virtual interviews.  
 
RISKS 
You may feel uncomfortable discussing some topics. The interviews will 
be audio-recorded, so there is a risk that someone may recognize your 
voice. However, there are procedures in place to reduce this risk, which 
are described later in this form. 
 
BENEFITS 
These discussions will help the research team understand how satisfied 
you are with the study and your experience with gender-affirming care 
and HIV services more broadly. You may also learn more about your 
experiences and motivations for study participation through discussion 
during your interview. 
 
OTHER CHOICES 
You do not have to take part in these interviews. 

 
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INTRODUCTION 
 
Extreme stigma faced by many transgender women can increase vulnerability to HIV and, at 
times, limit access to needed healthcare. By participating in interviews (brief conversations) 
about your experience participating in the GET IT RIgHT Study, you will help the research team 
understand how satisfied you are with the study and your experience with gender-affirming care 
and HIV services more broadly. Everything in the main study consent form you signed before 
still applies to your participation in this study unless otherwise noted in this form. 
 
This is a consent form. It gives you more information about the interviews. The study staff will 
talk with you about this information. You are free to ask questions about these interviews at any 
time. You can contact the study investigator using the information on the first page of this form 
with any interview-related questions. Please make sure that each of your questions have been 
answered before providing consent. If you agree to participate in the interviews, you will be 
asked to sign this consent form. You will get a copy to keep.  
 
 
WHAT DO I HAVE TO DO? 
 
You will be asked to participate in a 20-minute interview via an online video conferencing 
platform (for example, Microsoft Teams, Skype, Zoom, WhatsApp) at three different times 
during the study. Interviews will occur at entry and weeks 24 and 48 (or if you stop estradiol 
or the study early). Interviews will be conducted with 30 participants. These interviews will be 
completely confidential and will not impact your participation in the GET IT RIgHT Study. 
Your participation is completely voluntary and you can stop at any moment.  
 
Before beginning the interview, the interviewer will ask you if your understanding of the 
interview’s aims and the content of the questions is clear. During the interview, you will be 
asked about your demographics (ethnicity, race, current living situation, school/employment, 
social support, and health background). You will also be asked questions about your 
participation and satisfaction regarding this study, prior experiences accessing care, and 
your plans in accessing future care.  
 
Interviews will be conducted in English or Spanish by a bilingual medical sociologist with 
extensive experience conducting interviews with transgender communities and/or by a 
University of Toronto transgender doctoral trainee who is a licensed social worker and has 
experience with interviews.  
 
All interviews will be audio recorded. Once your interview is transcribed (put into written 
form) word-for-word, the audio-recording will be erased from the digital recorder. A copy of 
your recording will be kept on a secure password protected server for 5 years. 
 
Individuals will be recruited based on clinical site and by group. In order to schedule the 
interview, study staff at your site will collect your contact information and send it to a GET IT 

 
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RIgHT study investigator, and the study investigator may contact you, if you are selected, to 
schedule the interviews.  
 
WHAT ARE THE RISKS RELATED TO THE STUDY ACTIVITY? 
 
A potential risk of participating in this study is that a question may make you feel uncomfortable, 
during and/or after your participation, if it touches upon a personal or sensitive topic. If, while 
participating in an interview, you experience any feelings of discomfort or otherwise do not wish 
to continue, you may skip a question at any time, stop the interview, and/or withdraw from the 
interview. Your withdrawal from the interview will not have any negative impacts on your 
participation with the GET IT RIgHT study. 
 
You will have audio recording of your voice so there is the risk that someone may recognize your 
voice. However, once the audio recordings are collected, each audio file will be coded. The 
recordings will be transcribed by the study staff and no names will appear in the written transcripts. 
 
 
ARE THERE BENEFITS TO THE STUDY ACTIVITY? 
 
By participating in interviews (brief conversations) about your experience participating in the 
GET IT RIgHT Study, you will help the research team understand how satisfied you are with the 
study and your experience with gender-affirming care and HIV services more broadly. You may 
also benefit from these interviews by learning more about your experiences and motivations for 
study participation through discussion during your interview. Information learned from the 
interviews may help other people in the future. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THESE INTERVIEWS? 
 
You do not have to participate in these interviews. This will not affect your study participation in 
GET IT RIgHT study nor your routine healthcare. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
The study investigator will have access to personal information and to information that you 
provide during the interview. Your interview data, including direct quotes, may appear in 
academic journals, university seminar presentations, in research conference presentations, and 
other relevant work where academic research is shared; however, your name and other 
personally identifying information will never appear or be communicated publicly when the study 
findings are shared. Demographic information, such as age range, ethnic or cultural background, 
sexual orientation, gender identity, and school/employment status may be used to describe the 
study participants. The study investigator will make every effort possible to ensure that the data 
cannot clearly identify you. It is important to consider, however, that unless you specifically 
request that certain information (such as things that you’ve said) not be shared, any comments 

 
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that you make during the interview will be available to the research team to integrate into their 
communication of the study findings. 
 
Data Collection 
Your interview will be audio-recorded. The study investigator will save these recordings on a 
password-protected computer and ensure that the recordings, as well as all other information, are 
kept strictly confidential. Any personal identifying information will be removed (de-identified) from 
the audio-recordings, and de-identified audio recordings will be transcribed at an outside company 
that will sign a non-disclosure agreement to ensure the utmost confidentiality. Please avoid 
mentioning specific names (such as first and last names) during your interview, including those of 
partners, friends, family members, or healthcare providers that you may reference during your 
interview. You may instead choose to use a pseudonym (a fake name) or nickname. A random 
nickname will be chosen to represent you as a participant by the research team during data 
analysis. 
 
Study information that does not identify you  
Any personal identifying information will be removed (de-identified). The research team will 
remove information that you share with us that can identify you and will replace it with a random 
and anonymous study number (for example, Participant 01). The information that you provide 
that is identifiable, such as demographic information, will be stored separately from your 
interview recording and transcript. This will further safeguard the link between your personal 
identifying information and the comments that you share with us in your interview. All 
information that you share with us, including personal health information, will be kept 
confidential and will not be shared with anyone outside the study team unless required by law. 
Your identifying information will not be shared in any publications, reports, or presentations that 
come from this study. During and after your interview, you reserve the right to explicitly request 
that information that you have shared not be mentioned in publications, presentations, or other 
methods of sharing the study findings. You may request to withdraw your interview from the 
study at any time, and without any negative impact on your participation in the GET IT RIgHT 
study. 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, this research is covered by a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your participation. The researchers with this Certificate may not disclose or use information, 
documents, or biospecimens that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or be used as evidence, for 
example, if there is a court subpoena, unless you have consented for this use. Information, 
documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or local law that 
requires disclosure (see below); if you have consented to the disclosure, including for your 
medical treatment; or if it is used for other scientific research, as allowed by federal regulations 
protecting research participants.  
 
The Certificate cannot be used to refuse a request for information from personnel of the United 

 
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States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the agency which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you from voluntarily 
releasing information about yourself or your involvement in this research. If you want your 
research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. 
 
The Certificate of Confidentiality does not prevent you from releasing information about yourself 
and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the AIDS 
Clinical Trials Group (ACTG), the US Office for Human Research Protections (OHRP), or other 
local, US, and international regulatory entities as part of their duties, Advarra Institutional 
Review Board (IRB) (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees.  
Also, any publication of this study will not use your name or identify you personally.  
 
A description of this clinical trial will be available on https://ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
Costs are described in the study consent you already signed. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the visits 
you complete according to the following schedule: 
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx.  
• 
$xx.xx for Visits xxx.  
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid ___________ [“following each completed visit”, “monthly”, “quarterly”, “at the 
end of your participation in the research study”, “following each completed visit or at the end of 
your participation in the research study, whichever you prefer”]. 

 
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If you have any questions regarding your compensation for participation, please contact the 
study staff. 
[OR] 
You will not receive any monetary compensation for your participation in this study.  
[If applicable:] We will reimburse you for the cost of [describe: e.g., traveling to your study visits]. 
You will be reimbursed approximately [e.g., 2 weeks, 1 month, etc.] after you submit your travel 
receipts to the study staff. 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of this study, you will be given immediate treatment for your 
injuries. The cost for this treatment could be charged to you or your insurance company.  
 
There is no program for compensation through the NIH.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
These interviews are completely voluntary. You may choose not to continue in this study or you 
may leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. Your site will share a summary of the results when 
they are ready to be presented. Your study staff can answer any questions you may have. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you have questions, concerns or complaints about the study such as: 
 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a research participant; 
• 
Eligibility to participate in the study; 
• 
The study investigator’s or study site’s decision to withdraw you from participation; 
 
Please contact the study investigator at the telephone number listed on the first page of this 
consent document.  
 
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are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, contact: 
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00066234. 
 
 
 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to continue with this study activity, please sign your name below. 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate)