Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men (TRAVERSE) Study
Phase: PHASE4
Conditions: Hypogonadism, Cardiovascular Diseases
Sponsor: AbbVie



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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
15 December 2017
Amendment 1
26 February 2018
Amendment 2
13 February 2019
The purpose of this amendment is to:
●
Make COVID-19 related protocol modifications.
Rationale: To assure subjects' safety, maintain compliance with good clinical 
practice (GCP), and minimize risks to trial integrity.
●
Updated Section 3.2 to include information on re-evaluation of benefits and 
risks to subjects participating in the study.
Rationale:  Necessary protocol modifications due to COVID-19 pandemic.
●
Updated Section 5.1 to increase screening period to 90 days.
Rationale:  Optimize screening window time in order not to screen fail 
subjects due to COVID-19 pandemic related logistic challenges such as 
delayed laboratory test results, potential quarantine of eligible subjects for 
14 days, etc.
●
Updated wording in Section 5.1.
Rationale: To align the protocol language regarding the proportion of 
randomized subjects in CV risk factors and CV disease strata with the closure 
of enrollment in CV risk factors stratum
●
Updated wording regarding Re-screening.
Rationale: To clarify subject eligibility for re-screening.
●
Updated Inclusion Criterion 2
Rationale:  To align inclusion criterion 2 with exclusion criterion 2 and clarify 
when Screening Visit 3 with confirmatory testosterone test level is needed to 
exclude subjects with two testosterone levels of < 100 ng/dL from participation 
in the study. 
 

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Hypogonadal men with two testosterone levels < 100 ng/dL (confirmed) need 
additional evaluation to rule out primary disorders of the hypothalamus, 
pituitary, and the testis and should not participate in the long-term placebo-
controlled trial with a possibility of getting placebo.
●
Added COVID-19 vaccine information to Section 5.2.3.
Rationale:  To allow subjects that received COVID-19 vaccine to enroll or 
continue in the study and capture vaccine under concomitant medications and
document adverse event information related to COVID-19 vaccination in 
EDC.  
●
Added COVID-19 information related to virtual visits throughout 
Section 5.3.1.
Rationale:  To allow the subject to complete applicable procedures during 
virtual visits and clarify how to proceed with study drug dosing if subject is not 
able to come to the site for in-person visit(s).
●
Updated Section 5.4.1 to clarify discontinuation language.
Rationale:  Information provided on how Investigators should discontinue 
subjects during COVID-19 pandemic.
●
Updated Section 5.5.2.1 to add direct to subject shipment.
Rationale:  To allow study drug to be shipped to subjects' home if subjects are 
unable to come to the site to receive study drug due to COVID-19.
●
Updated Section 6.1.1.1 Adverse Event to update information on how to 
document adverse events of cancers in EDC.
Rationale: To clarify that Cancers should be reported on AE/SAE form as 
well as on a separate Cancer Report Form in EDC.
●
Updated Section 6.1.4 to include COVID-19 information related to AEs.
Rationale:  Provide guidance on how to capture AEs related to COVID-19 
including those leading to study drug discontinuations, and how to document 
study drug discontinuations related to COVID-19 due to logistical reasons.  
Information added on how to document MACE related to COVID-19. 
●
Updated Section 7.0 contact information and protocol deviations.
Rationale:  Added new study team members contact information.  Added 
information on how to document the protocol deviations related to COVID-19.
 

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●
Clarified Section 8.3 randomization information.
Rationale:  Align the protocol language regarding proportion of randomized 
subjects in CV risk factors and CV disease strata with closure of enrollment in 
the CV risk stratum.
●
Updated Section 9.3 to include COVID-19 modifications. 
Rationale:  To allow for additional protocol modifications due to COVID-19 
pandemic with additional consent (verbal).
●
Updated Section 10.2 vendor information.
Rationale:  Updated vendor name change from CRF Health to Signant Health.
●
Added new COVID-19 procedures for questionnaires in Section 10.2.
Rationale:  To allow subjects to complete missed questionnaires at 
unscheduled visits.
●
Updated Appendix B.
Rationale:  Updated signatory list with the current team members.
●
Updated Appendix E
Rationale: To align Appendix E (Endpoint questionnaire form) with 
Appendix D in the protocol and Appendix C in the CV/Neuro Adjudication 
Charter; Visit Form (Subject to be queried at each visit).  As agreed with the 
Agency on 15Aug2017, Arrythmia and Syncope are defined as AESI within the 
protocol, not endpoints. Therefore, they are reported on the AE/SAE form, not 
on the Endpoint form and are not undergoing adjudication as also agreed with 
the Agency within the above-mentioned correspondence. Other AESI on the 
Endpoint Questionnaire form (Hospitalization for Unstable Angina and TIA) 
are potential endpoints, are reported on the Endpoint form and are 
undergoing adjudication.  Diabetes (new or worsening) is an endpoint.
●
Apply administrative and editorial changes/corrections throughout the 
protocol.
Rationale:  Revised text to provide clarity and improve consistency and 
readability of the protocol.
 

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1.2
Synopsis
Sponsor:
Testosterone Replacement Therapy (TRT) 
Manufacturer Consortium acting through AbbVie 
Inc.
*Members of the Consortium on File
Protocol Number:  M16-100
Name of Study Drug:  AndroGel 1.62%
Phase of Development:  4
Name of Active Ingredient:  Testosterone
Date of Protocol Synopsis:  06 May 2021
Protocol Title:  Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and 
Efficacy ResponSE in Hypogonadal Men (TRAVERSE) Study
Objective:  To compare the effect of testosterone replacement therapy (TRT) and matching placebo on 
major adverse cardiovascular events (MACE).  Other safety and efficacy endpoints will be evaluated.
Investigators:  Multi-center
Study Sites:  Approximately 400
Study Population:  Hypogonadal men with increased risk for cardiovascular disease
Number of Subjects to be Enrolled:  The planned study enrollment is approximately 6,000 subjects 
based on the projected timing when 256 MACE will occur under the initial assumptions of the annual 
event rate, subject accrual rate, and study discontinuation rate.  The appropriateness of these assumptions 
and their impact on the overall sample size will be evaluated by blinded review during the course of the 
study.
Methodology:
This is a randomized, double-blind, placebo-controlled, multi-center study.  All subjects who are 
randomized will be followed until the study is completed.  
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
Men 45 to 80 years of age with low serum testosterone concentrations (< 300 ng/dL) who exhibit 
hypogonadal symptoms and have evidence of cardiovascular (CV) disease or are at an increased risk for 
CV disease and who have not been treated with testosterone in the past 6 months.
Main Exclusion:
Men with congenital or acquired hypogonadism for whom long-term therapy with placebo would not be 
medically appropriate; prostate specific antigen (PSA) > 3.0 ng/mL; men for whom testosterone therapy 
is contraindicated.
 

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Investigational Product:
AndroGel 1.62%
Dose:
Five dose levels, titrated in 20.25 mg increments starting from 20.25 mg 
to 101.25 mg (1.25 g to 6.25 g of gel)
Mode of Administration:
Topical
Reference Therapy:
Matching AndroGel 1.62% Placebo
Dose:
Same as investigational product (above)
Mode of Administration:
Topical
Duration of Treatment:  Enrolled subjects may be on study drug for the entire duration of the study, 
which may span up to approximately 5 years.
Criteria for Evaluation:
Safety:
Primary Safety Endpoint:  Time to MACE, is defined as time from randomization to first component 
event occurrence of the composite MACE endpoint.  MACE is defined as a composite endpoint 
consisting of any of the following:

Nonfatal myocardial infarction (MI)

Nonfatal stroke

Death due to CV causes
Secondary CV safety endpoint, is defined as time from randomization to first component event 
occurrence of the composite endpoint consisting of any of the following:

Nonfatal MI (note:  silent MIs will not be adjudicated or counted toward the non-fatal MI 
endpoint during this study)

Nonfatal stroke

Death due to CV causes

Coronary revascularization procedures/cardiac percutaneous coronary intervention (PCI) and 
coronary artery bypass graft (CABG) surgery
Secondary Prostate Safety Endpoint:

High grade prostate cancer (Gleason score of 4 + 3 or higher)
Tertiary Safety Endpoints:

All-cause mortality 

Heart failure events (hospitalization or urgent visit)

Thromboembolic events including deep vein thrombosis (DVT)/pulmonary embolism 
(PE)/venous thromboembolism (excluding superficial thrombophlebitis)

Peripheral arterial revascularization
 

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Criteria for Evaluation (Continued):
Safety (Continued):
Tertiary Prostate Safety Endpoints:

Prostate biopsy

Any prostate cancer

Acute urinary retention

Starting pharmacologic treatment for lower urinary tract symptoms

Invasive prostate surgical procedures (e.g., prostatectomy, transurethral prostate resection, 
brachytherapy or other prostate surgical procedure) for benign prostatic hyperplasia
Efficacy Outcome Variables:
The following efficacy endpoints will be evaluated in sub-studies or analyses of subpopulations:
1.
Improvement in sexual function in hypogonadal men with low libido
2.
Remission of depression in hypogonadal men with late-onset, low grade persistent depressive 
disorder (PDD) (dysthymia)
3.
Reduction in incidence of clinical fractures
4.
Correction of anemia in subset of subjects with Baseline anemia
5.
Reduction in progression from pre-diabetes to diabetes
Statistical Methods:
Analysis Sets:
The following data sets will be used for the analyses of safety and efficacy endpoints for this study:
The Full Analysis Set (FAS) comprising all randomized subjects.  Subjects will be categorized according 
to treatment assigned at randomization.  The FAS will be mainly used for the summary of subjects'
disposition and summary of subjects' demographics and Baseline characteristics for the study.
The Safety Set comprising all randomized subjects who receive at least one dose of study drug (TRT or 
placebo).  Subjects will be categorized according to treatment received.  Unless otherwise specified, the 
Safety Set will be used for the analysis of all safety endpoints of the study.
The Efficacy Analysis Sets (EAS) are pre-specified subgroups of the FAS comprising of eligible 
subjects from the main study who satisfy the criteria for sub-studies for sexual function, PDD, bone 
fracture, anemia and diabetes.  The EAS will be used for the analyses of these sub-studies (Section 5.3.3 
and Appendix O).  For instance, the EAS for the analysis of sexual function sub-study will include 
subjects with Baseline DISF-SRII Section I:  Sexual Desire domain score ≤ 20.
Safety:
The primary endpoint of the study, time to MACE, is defined as time from randomization to 
first component event occurrence of the composite MACE endpoint.  Time to MACE for subjects who 
do not experience an event in study will be right-censored at the time of their last available observation.  
Primary treatment comparison will be based on the hazard ratio of MACE for TRT compared to placebo 
observed in the Safety Set.  The primary statistical criterion for establishing non-inferiority of TRT will 
be to exclude a hazard ratio (HR) of 1.5 at the upper limit of a 95% two-sided confidence interval (CI).  
Kaplan-Meier (KM) estimates of the survival curves of time to first MACE for TRT and placebo will be 
derived.
 

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Statistical Methods (Continued):
Safety (Continued):
Subjects will continue to be followed for the protocol-specified CV events until completion of the study 
or death, regardless of whether they continue on treatment or not (unless consent to obtain follow-up 
information has been withdrawn).  These analyses for the primary endpoint will be repeated for the FAS 
as supportive analyses.  The principal sensitivity analyses will also be performed using events that 
occurred during treatment or within 365 days post-treatment.
Adverse Events of Special Interest (AESI), adverse events (AEs) leading to study drug discontinuation 
and serious adverse events (SAEs) will be summarized by treatment group and overall in descending 
order of overall frequency by Medical Dictionary for Regulatory Activities (MedDRA) preferred term 
(PT), as well as in a lexicographic order by system organ class (SOC) and MedDRA PT.  Additionally, 
AESI, AEs leading to study drug discontinuation and SAEs will also be summarized by the relationship 
to study drug and their maximum severity.
Efficacy Assessments:
While the primary objective is to evaluate CV risk in middle-aged and older hypogonadal men treated 
with TRT, this study presents an opportunity to examine a number of efficacy endpoints in a much larger 
population and for longer treatment duration than other studies reported to date.  This study will assess 
the efficacy of TRT versus placebo for these co-morbidities in sub-studies or analyses of subpopulation:

Sexual Function:  Will examine whether TRT (relative to placebo) improves overall sexual 
activity, sexual desire, and erectile function.

Persistent Depressive Disorder (PDD):  Will examine whether TRT (relative to placebo) 
improves depressive symptoms in men with low-grade, late-onset PDD (dysthymia).

Bone Fracture:  Will examine the effect of TRT (relative to placebo) on the incidence of 
adjudicated clinical bone fractures.

Anemia:  Will examine the efficacy of TRT (relative to placebo) in correcting anemia in 
middle-aged and older hypogonadal men.

Diabetes:  Will examine if TRT (relative to placebo) is associated with a lower rate of 
progression to Type 2 diabetes mellitus in middle-aged and older hypogonadal men with 
pre-diabetes at Baseline.
Statistical comparisons will be made for these efficacy variables between the active- and 
placebo-treatment groups.
 

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1.3
List of Abbreviations and Definition of Terms
Abbreviations
5-ARI
5-Alpha Reductase Inhibitor
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ARO
Academic Research Organization
AST
Aspartate aminotransferase
BMD
Bone mineral density
BMI
Body mass index
BPH
Benign Prostatic Hyperplasia
BSSR
Blinded Sample Size Re-estimation
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CBC
Complete blood count
CEC
Clinical Events Committee
CI
Confidence interval
CKD
Chronic Kidney Disease 
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COPD
Chronic Obstructive Pulmonary Disease 
COVID-19
Coronavirus Disease – 2019
CRF
Case report form(s)
CRO
Clinical Research Organization
CV
Cardiovascular
CVOT
Cardiovascular outcomes trial
D
Diagonal
DBP
Diastolic blood pressure
DEA
Drug Enforcement Administration
DHEA
Dehydroepiandrosterone
DHT
Dihydrotestosterone
DISF-SRII
DeRogatis Interview for Sexual Function – Self Report (Male)
DMC
Data Monitoring Committee
DRE
Digital rectal exam
 

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DSM-5
Diagnostic and Statistical Manual of Mental Disorders
DTP
Direct-to-patient
DVD
Digital versatile disc
DVT
Deep vein thrombosis
EAS
Efficacy Analysis Set
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
EDC
Electronic data capture
eGFR
Estimated Glomerular Filtration Rate 
EOS
End of Study
EP
Endpoint
ePRO
Electronic patient reported outcome
ESC
Executive Steering Committee
FAS
Full Analysis Set
FDA
Food and Drug Administration
FV
Final Visit
GCP
Good Clinical Practice
GDS-15
Geriatric Depression Scale
GGT
Gamma-glutamyl transferase
GnRH
Gonadotropin-releasing hormone
Hct
Hematocrit
HDL-C
High-density lipoprotein cholesterol
Hgb
Hemoglobin
HbA1c
Hemoglobin A1c
HIS-Q
Hypogonadism Impact of Symptoms Questionnaire
HR
Hazard ratio
hsCRP
High-sensitivity c-reactive protein
ICH
International Conference on Harmonization
IND
Investigational New Drug
IEC
Independent Ethics Committee
IIEF-5
International Index of Erectile Function (5 question version)
IRB
Institutional Review Board
I-PSS
International Prostate Symptom Score
 

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IRT
Interactive Response Technology
KM
Kaplan-Meier
LAD
Left Anterior Descending
LCX
Left Circumflex Artery
LDL-C
Low-density lipoprotein corrected
LM
Left Main
LTFU
Lost to follow-up
MACE
Major Adverse Cardiac Event
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
mRS
Modified Rankin Scale
OM
Obtuse Marginal
OTC
Over-the-counter
PCI
Percutaneous coronary intervention
PCPT
Prostate Cancer Prevention Trial
PDA
Posterior Descending Artery
PE
Pulmonary embolism
PD
Premature discontinuation
PDD
Persistent depressive disorder
PDQ
Psychosexual Daily Questionnaire
PGI-I
Patient Global Index of Improvement
PHQ-9
Patient Health Questionnaire-9
PRO
Patient Reported Outcomes
PSA
Prostate specific antigen
PT
Preferred term
QTcF
QT interval corrected for heart rate (Fridericia's correction formula)
RBC
Red blood cell
RCA
Right Coronary Artery
RI
Ramus Intermedius
RMST
Restricted mean survival time 
 

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S
Septal
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
SOC
System organ class
SV1
Screening Visit 1
SV2
Screening Visit 2
SV3
Screening Visit 3
T
Testosterone
TA MD
Therapeutic Area Medical Director
TIA
Transient Ischemic Attack
TOM
Testosterone in Older Men Trial
TRT
Testosterone Replacement Therapy
TTE
Time to Event
ULN
Upper limit of normal
UTI
Urinary Tract Infection
US
United States
WBC
White blood cell
Definition of Terms
AbbVie TA MD
AbbVie Therapeutic Area Medical Director
 

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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms..........................................9
2.0
Table of Contents...................................................................13
3.0
Introduction ...........................................................................18
3.1
Differences Statement..............................................................................21
3.2
Benefits and Risks....................................................................................21
4.0
Study Objective......................................................................22
5.0
Investigational Plan...............................................................23
5.1
Overall Study Design and Plan:  Description ..........................................23
5.2
Selection of Study Population..................................................................26
5.2.1
Inclusion Criteria .....................................................................................26
5.2.2
Exclusion Criteria ....................................................................................29
5.2.3
Prior and Concomitant Therapy...............................................................32
5.2.3.1
Prohibited Therapy...................................................................................34
5.2.3.2
Rescue Therapy........................................................................................35
5.3
Efficacy and Safety Assessments/Variables ............................................35
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................35
5.3.1.1
Study Procedures .....................................................................................35
5.3.2
Safety Variables.......................................................................................48
5.3.2.1
Primary Outcome Variables.....................................................................48
5.3.2.2
Secondary Safety Variables .....................................................................49
5.3.2.3
Tertiary Safety Endpoints and Tertiary Prostate Endpoints ....................49
5.3.2.4
Adjudicated Events ..................................................................................50
5.3.3
Efficacy Variables....................................................................................50
5.4
Removal of Subjects from Therapy or Assessment.................................51
5.4.1
Discontinuation of Individual Subjects....................................................51
5.4.2
Discontinuation of Entire Study...............................................................57
5.5
Treatments................................................................................................57
5.5.1
Treatments Administered.........................................................................57
 

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5.5.2
Identity of Investigational Product...........................................................58
5.5.2.1
Packaging and Labeling...........................................................................59
5.5.2.2
Storage and Disposition of Study Drugs..................................................60
5.5.3
Method of Assigning Subjects to Treatment Groups...............................61
5.5.4
Selection and Timing of Dose for Each Subject......................................62
5.5.5
Blinding....................................................................................................63
5.5.5.1
Blinding of Data for Independent Data Monitoring Committee 
(DMC)......................................................................................................64
5.5.5.2
Blinding of Data for Executive Steering Committee (ESC)....................65
5.5.6
Treatment Compliance.............................................................................65
5.5.7
Study Drug Accountability ......................................................................65
5.6
Discussion and Justification of Study Design..........................................67
5.6.1
Discussion of Study Design and Choice of Control Groups....................67
5.6.2
Appropriateness of Measurements...........................................................67
5.6.3
Suitability of Subject Population .............................................................68
5.6.4
Selection of Doses in the Study ...............................................................68
6.0
Complaints .............................................................................69
6.1
Medical Complaints.................................................................................69
6.1.1
Definitions................................................................................................70
6.1.1.1
Adverse Event..........................................................................................70
6.1.1.2
Serious Adverse Events ...........................................................................70
6.1.1.3
Adverse Events of Special Interest (AESI), AEs Leading to Study 
Drug Discontinuation and Serious Adverse Events (SAEs)....................72
6.1.2
Adverse Event Severity............................................................................72
6.1.3
Relationship to Study Drug......................................................................72
6.1.4
Adverse Event Collection Period.............................................................73
6.1.5
Adverse Event Reporting.........................................................................76
6.1.6
Pregnancy.................................................................................................77
6.1.7
Management of Abnormal Laboratory Results (PSA, Hct, and 
Testosterone)............................................................................................77
6.1.8
Elevated Prostate Specific Antigen Management....................................77
6.1.9
Testosterone and Hematocrit/Hemoglobin Management ........................79
6.2
Product Complaint ...................................................................................79
 

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6.2.1
Definition .................................................................................................79
6.2.2
Reporting..................................................................................................80
7.0
Protocol Deviations................................................................80
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................82
8.1
Statistical and Analytical Plans................................................................82
8.1.1
Analysis Sets............................................................................................82
8.1.2
Demographics, Other Baseline Characteristics, Subject 
Disposition and Concomitant Medication................................................83
8.1.3
Analysis of Treatment..............................................................................83
8.1.4
Analysis of Safety....................................................................................84
8.1.4.1
Primary Safety Endpoint..........................................................................84
8.1.4.2
Secondary CV Safety Endpoints..............................................................85
8.1.4.3
Secondary Prostate Safety Endpoints ......................................................86
8.1.4.4
Other Safety Endpoints............................................................................86
8.1.5
Efficacy....................................................................................................87
8.1.6
Interim Analyses ......................................................................................88
8.1.7
Type 1 Error Adjustment .........................................................................88
8.2
Determination of Sample Size .................................................................89
8.2.1
Blinded Sample Size Re-Estimation (BSSR) ..........................................89
8.3
Randomization Methods ..........................................................................91
9.0
Ethics.......................................................................................91
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................91
9.2
Ethical Conduct of the Study ...................................................................92
9.3
Subject Information and Consent.............................................................92
10.0
Source Documents and Case Report Form 
Completion .............................................................................93
10.1
Source Documents ...................................................................................93
10.2
Case Report Forms...................................................................................94
11.0
Data Quality Assurance ........................................................96
12.0
Use of Information.................................................................96
13.0
Completion of the Study .......................................................97
 

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14.0
Investigator's Agreement......................................................98
15.0
Reference List ........................................................................99
List of Tables
Table 1.
Pre-Existing CV Disease..........................................................................27
Table 2.
Cardiovascular Risk Factors ....................................................................28
Table 3.
Clinical Laboratory Tests.........................................................................41
Table 4.
Identity of Investigational Product...........................................................59
Table 5.
Approximate Dosage and Duration of Use for 1 Bottle of Study 
Drug .........................................................................................................60
Table 6.
Dose Titrations.........................................................................................63
Table 7.
End of Study (EOS) Scenarios.................................................................74
Table 8.
Sample Size for Efficacy Endpoints ........................................................88
List of Figures
Figure 1.
Application Sites......................................................................................58
Figure 2.
Adverse Event Collection ........................................................................75
Figure 3.
Right-Dominant and Left-Dominant Circulations.................................146
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................110
Appendix B.
List of Protocol Signatories....................................................................112
Appendix C.
Study Activities......................................................................................113
Appendix D.
Event Reporting Example......................................................................117
Appendix E.
Site Endpoint Questionnaire Form Example .........................................119
Appendix F.
International Prostate Symptom Score (I-PSS) Example ......................120
Appendix G.
DeRogatis Interview for Sexual Function – Male (DISF – SR II)©
Example .................................................................................................122
Appendix H.
Hypogonadism Impact of Symptoms Questionnaire (HIS – Q) 
Example .................................................................................................123
Appendix I.
Patient Global Index of Improvement (PGI – I) Example.....................126
 

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Appendix J.
International Index of Erectile Function (IIEF-5) Example...................127
Appendix K.
Psychosexual Daily Questionnaire (PDQ) Question 4 Example ...........128
Appendix L.
Patient Health Questionnaire-9 (PHQ-9) Example................................129
Appendix M.
Geriatric Depression Scale (GDS-15) Example ....................................130
Appendix N.
Additional Persistent Depressive Disorder (PDD) Sub-Study 
Questions – Example .............................................................................131
Appendix O.
Sub-Studies and Sub-Population Analyses for Sexual Function, 
Persistent Depressive Disorder (PDD), Bone Fracture, Anemia 
and Diabetes...........................................................................................133
Appendix P.
Modified Rankin Scale ..........................................................................143
Appendix Q.
Coronary Artery Disease Definition ......................................................144
 

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3.0
Introduction
Testosterone products have been approved in the United States (US) for over 50 years for 
the treatment of testosterone deficient men.  These products are currently indicated for the 
treatment of congenital or acquired primary hypogonadism and hypogonadotropic 
hypogonadism in men.1
Hypogonadism is an endocrine disorder characterized by absent or deficient testosterone 
levels along with signs and symptoms of androgen deficiency, including delayed 
development or regression of secondary sexual characteristics, impaired sexual function, 
impaired sense of well-being, depressed mood, decreased muscle strength associated with 
a loss of muscle mass, and reduced bone mineral density (BMD).2-7
Current guidelines for the use of testosterone replacement therapy (TRT) outline the 
appropriate assessment and monitoring of men who are candidates for testosterone 
therapy.  Key components of the Endocrine Society Guidelines2 include criteria for 
selecting candidates with signs and symptoms consistent with hypogonadism and 
documented evidence of low testosterone levels, for whom TRT may be indicated.  The 
Endocrine Society Guidelines also offer recommendations for confirmatory testing of 
serum testosterone concentrations, additional evaluation, and TRT.2
Cardiovascular (CV) Safety of Testosterone
In 2010, the Food and Drug Administration (FDA) began an investigation of the CV 
safety of approved testosterone products after a small, placebo-controlled testosterone trial 
in elderly men (TOM Trial) was discontinued prematurely due to increased frequency of 
CV events in the active TRT treatment arm.  After reviewing the TOM Trial results and 
other available published literature, the FDA determined that there was insufficient 
evidence to conclude that testosterone therapy in older men was associated with an 
increased risk of adverse CV outcomes.8,9  In late 2013 and early 2014, 
two publications10,11 based on retrospective observational data reported a possible 
association with the use of TRT and adverse cardiac outcomes in patients treated with 
TRT versus matched control groups.  These studies had a number of limitations such that 
 

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conclusions on causality between TRT and CV outcomes could not be established.9,12,13  
Additionally, other epidemiologic studies published prior to and following the above 
studies observed no increased CV risk, or risk reduction.14-20
Rationale for a CV Safety Study of Testosterone in Hypogonadal Men
A 2014 FDA Advisory Committee examined the CV safety of testosterone and 
recommended that a CV outcome study be conducted.  FDA requested that testosterone 
manufacturers work together to conduct an adequately sized study to rule out increased 
CV risk in hypogonadal men treated with TRT.  The rationale for such a study includes 
the conflicting data for a signal of CV risk in men treated with testosterone and the lack of 
robust, registration-level clinical efficacy data for TRT in men with hypogonadism 
associated with aging or co-morbidities.  The current TRAVERSE study is designed to 
fulfill the FDA requirement for a CV safety study as the primary research objective with 
other safety and efficacy endpoints included as secondary objectives.9,21  The primary 
objective of this study is to assess the CV (including coronary cerebrovascular and 
peripheral vascular) safety of TRT compared to placebo in men with a history of CV 
disease or with multiple CV risk factors by measuring the treatment effect on adjudicated 
major adverse cardiovascular events (MACE) including non-fatal myocardial infarction 
(MI), non-fatal stroke and CV death.  
Given the unique nature of this study, which will study the effects of testosterone 
treatment compared to placebo in several thousand men for up to 5 years, the study will 
also examine as secondary outcomes the impact of therapy on development of high grade 
prostate cancer and several efficacy outcomes whose rationale is described below.
Impact of Testosterone Replacement on the Incidence of High-Grade Prostate 
Cancer
Evidence of a relationship between TRT and the incidence of prostate cancer is mixed.  In 
the Baltimore Longitudinal Study of Aging, aggressive prostate cancers were reported to 
be associated with higher levels of total and free testosterone.22  Also, testosterone 
administration increases prostate specific antigen (PSA) in men and can promote the 
 

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growth of metastatic prostate cancer.23  On the other hand, most population-based studies 
have not associated high total or free testosterone levels with increased cancer risk,24-26
and an analysis of the placebo arm from the Prostate Cancer Prevention Trial (PCPT) 
found no significant associations of total or free testosterone and risk of total, low 
(Gleason < 7) or high-grade (Gleason 7 – 10) prostate cancer.27,28
Occult prostate cancer is common in middle-aged and older men, and the prevalence 
increases with increases in PSA and age.27,29  The designers of the current study recognize 
that testosterone therapy increases PSA in circulation and thus, in the current study more 
men randomized to testosterone will be referred for prostate evaluation and possible 
biopsy based on this laboratory finding.  Consequently, testosterone-treated men may 
have an increased risk of detection of subclinical prostate disease that was present prior to 
treatment.25,30,31  This inherent surveillance bias could result in a greater number of 
prostate biopsies that are positive for low-grade indolent prostate cancers in men 
randomized to the testosterone arm than in those randomized to the placebo arm.  With 
this recognition of the inherent detection bias from testosterone treatment leading to the 
detection of low grade prostate cancers, this study will assess the effect of testosterone 
and placebo on the development of high grade prostate cancer, defined as Gleason 4 + 3 
or greater.
Benefits of Testosterone Therapy
While it has been suggested that the benefits of testosterone treatment are clearer in 
"classical hypogonadism," data on TRT risks and benefits specifically in men without 
structural or genetic abnormalities that cause "classical hypogonadism" with very low 
circulating testosterone have only begun to emerge.32,33-35  In men with a variety of 
comorbid conditions that result in testosterone levels below the accepted normal range 
(e.g., obesity, diabetes or other chronic diseases), TRT has been shown to increase lean 
body mass and bone mineral density (theoretically reducing the risk of bone fractures), 
decrease fat mass and improve sexual desire in most studies, while improvements in mood 
and energy have been inconsistent.32,33-36  Low testosterone levels are implicated as one of 
the many factors causing anemia, which is more prevalent with advancing age,37 and 
 

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testosterone is known to increase hemoglobin (Hgb) levels, thereby presenting a potential 
benefit of TRT in hypogonadal men with anemia.34,38-41  Also, there is evidence to support 
a hypothesis that TRT may slow the progression to diabetes in hypogonadal men with pre-
diabetes.43-45  There are limited data in men with age-associated and/or comorbidity-
associated hypogonadism utilizing patient reported outcomes (PRO) tools created 
following the FDA guidance for PRO development.9,21,32  Given the opportunity that this 
protocol affords, the TRAVERSE study will analyze the effects of a testosterone gel 
(AndroGel 1.62%)1 in middle aged and older men with CV risk factors and/or CV disease 
on a number of efficacy endpoints that have demonstrated some level of responsiveness in 
previous TRT studies and that otherwise could not be studied in smaller studies of shorter 
duration.  Specifically, the TRAVERSE study will address the effect of TRT on 
improving the following efficacy variables versus placebo:  
●
sexual activity and function in subjects with low libido at Baseline
●
remission of persistent depressive disorder (PDD) in subjects with low-grade 
PDD at Baseline
●
adjudicated clinical bone fractures
●
correction of anemia in subjects with anemia at Baseline
●
progression to diabetes in subjects with pre-diabetes at Baseline
3.1
Differences Statement
This is the first placebo-controlled study that is adequately sized to characterize the 
impact of TRT or identical placebo on the incidence of MACE in hypogonadal men.
3.2
Benefits and Risks
The efficacy of AndroGel 1.62% is demonstrated by its ability to increase serum total 
testosterone (T) levels by the absorption of testosterone through the skin when applied 
topically.  The objective of TRT in hypogonadal men is to replace testosterone within the 
eugonadal range for healthy men (300 – 1000 ng/dL).  Replacement of testosterone levels 
into the eugonadal range in hypogonadal men should lead to restoration of androgenic 
 

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effects such as improvements in libido and mood, increased lean mass, decreased fat mass 
and increased BMD.2  The aforementioned endpoints have been examined in placebo-
controlled studies with various levels of supportive evidence depending on the cohorts 
(hypogonadal, eugonadal, mixed), and the endpoints examined.  
Potential risks of treatment with AndroGel 1.62% include secondary transfer of 
testosterone to others, increased PSA levels, mood swings, increased red blood cell (RBC) 
count, and skin irritation at the application site.1  
This study will evaluate the rate of MACE in hypogonadal men at risk for CV disease 
receiving TRT or placebo for up to approximately 5 years.  Additionally, the study will 
also evaluate as secondary outcomes a limited number of targeted safety (e.g., prostate) 
and efficacy endpoints, which are patient-important, consistent with symptom domains 
and/or target organ systems that have demonstrated responsiveness in previous TRT 
studies, and which will allow the testing of specific efficacy hypotheses in the 
five domains discussed earlier.
Considering the coronavirus (COVID-19) pandemic, the benefits and risks to subjects 
participating in this study have been re-evaluated.  Based on the limited information to 
date, no additional risks to study participants diagnosed with COVID-19 are anticipated 
with the use of Androgel 1.62%.  
4.0
Study Objective
The primary objective of this study is to compare the effect of TRT and placebo on the 
incidence of MACE in middle-aged and older hypogonadal men at risk for CV disease.  
The secondary CV safety endpoint is to compare the effect of TRT and placebo on an 
expanded list of CV outcomes including MACE plus coronary revascularization 
procedures/cardiac percutaneous coronary intervention (PCI) and coronary artery bypass 
graft (CABG) surgery.
An additional secondary safety objective is to determine the effect of TRT on the 
incidence of high-grade prostate cancer in this population.  Finally, this study will 
 

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evaluate a number of secondary and tertiary efficacy endpoints defined in the sub-studies 
(see Appendix O).
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 4, randomized, double-blind, placebo-controlled, multicenter study of 
topical TRT in symptomatic hypogonadal men with increased risk for CV disease.  
The initial planned study enrollment is approximately 6,000 subjects based on the 
projected timing when 256 MACE will occur under initial assumptions of the annual 
event rate, subject accrual rate, and study discontinuation rate.   
There will be approximately 400 sites in North America including Puerto Rico.
An Interactive Response Technology (IRT) system will randomize subjects to receive 
either topical testosterone or placebo in a 1:1 ratio.  Randomization will be stratified by 
pre-existing CV disease (Yes/No).  Titration of testosterone dose will occur in subjects 
receiving active testosterone, while sham dosage titrations will occur in subjects receiving 
placebo gel via the non-blinded central IRT system (Section 5.5.3).
The Screening Period is up to 60 days prior to first study drug dose.  Subjects may enroll 
an additional 30 days after the 60-day period due to COVID-19 related issues.  If the 
90-day screening period is required, sites should contact their monitor or refer to the 
90-day extension instructions on how to complete the process in IRT.
Once subjects meet all of the eligibility criteria during Screening, they will be randomized 
(1:1 ratio) to active study drug or placebo and will be followed until the study ends.  
Importantly, randomized subjects who elect to temporarily or permanently discontinue 
study drug (Section 5.4.1) will also be followed until the study ends unless the subject 
withdraws from the study completely (withdrawal of informed consent Section 5.4.1).  
Subjects who discontinue study drug will still be asked to follow their regularly scheduled 
protocol visits specified in Appendix C Study Activities.  Subjects who discontinue study 
 

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drug will be allowed to restart study drug at any time if medically appropriate 
(Section 5.4.1).
Periodic blinded overall MACE assessments, coupled with the sample size and duration 
of treatment to date, will be conducted (e.g., after 4,500 subjects have been enrolled or 
following 2.5 years of study conduct) to estimate whether or not the sample size and/or 
the study duration will need to be modified in order to observe at least 256 MACE.  
AbbVie or designee will make every effort to give sites advanced notice when the 
recruitment for the study is nearing completion to minimize the risk of a high number of 
subjects in Screening who may not be allowed to enroll in the study.
During telephone contacts and in-person visits throughout the study, subjects will be 
asked specific questions pertaining to the possible occurrence of MACE and adverse 
events of special interest (AESI), as well as the collection of additional information 
related to ongoing adverse events (AEs) (see Appendix C).
Randomized subjects will return for the Final Visit (FV) (Appendix C) once the Sponsor 
ends the study.  For randomized subjects who discontinue the study prematurely, 
Premature Discontinuation (PD) Visit case report forms (CRFs) should be completed at 
the time the subject withdraws consent (e.g., in-person preferably or via a phone visit) 
from the study or has a fatal outcome (if this information is available).  For lost to follow-
up subjects, every attempt should be made to contact the subjects to obtain study related 
information.  For these subjects, the FV CRFs should not be completed until the end of 
the study (Section 5.4.1) so that further study information can be obtained.
Subjects meeting the stopping criteria for study drug (Section 5.4 Removal of Subjects 
from Therapy or Assessment) will have study drug discontinued and will be followed for 
all safety events outlined in Appendix D for the duration of the study (Section 6.1.4).
The study is planned to end after at least 256 MACE have been positively adjudicated by 
Clinical Events Committee (CEC) for the principal sensitivity analysis of the primary 
 

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safety endpoint (see Section 8.1.4).  Enrolled subjects may be on study drug for the entire 
duration of the study, up to approximately 5 years.
It is expected that the number of MACE events will be higher in the subjects with pre-
existing CV disease.  To reach the intended event rate, the study is targeting at least 30%
of randomized subjects will satisfy inclusion criteria for pre-existing CV disease criteria 
(secondary prevention), and up to 70% of randomized subjects will satisfy CV risk factors 
criteria (primary prevention) combined; the proportions will be monitored and controlled 
via IRT throughout the study.  The Executive Steering Committee (ESC) and AbbVie 
may decide to cap the cohort of subjects with CV risk factors (i.e., no pre-existing CV 
disease) if that cohort is found to consistently exceed 70% of the total population enrolled 
or if the pooled primary event rate falls below projections.
AbbVie or its designee will make every effort to give sites advanced notice when 
recruitment for the study is nearing completion to minimize the risk of a high number of 
subjects in Screening who may not be allowed to enroll in the study.
Study data will be monitored by an independent Data Monitoring Committee (DMC) in 
accordance with standard conduct for clinical outcome studies.  Study oversight will occur 
through an ESC, which will advise AbbVie and the independent DMC.  The CEC will be 
utilized to adjudicate pre-specified CV, prostate and fracture event data during the study.  
See Appendix D and Appendix E for detailed event reporting and endpoint questionnaire, 
respectively.
Re-Screening
Subjects who fail to meet the selection criteria or who cannot return for Screening Visit 2 
(SV2) or Screening Visit 3 (SV3) within the visit window may be re-screened one time at 
the discretion of the Investigator once their clinical status changes provided they did not 
screen fail due to testosterone levels outside the entry criteria.
●
If the subject is re-screened within 3 months (90 days) of his initial Screening 
Visit, then only the necessary procedures to confirm eligibility need to be 
 

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performed with the exception of the SV2 PROs (Appendix C).  The SV2 PROs 
will be repeated for all re-screening subjects.  
●
If the subject has not been re-screened within 90 days of his initial Screening 
Visit, he is still permitted to re-screen but all of the Screening procedures must 
be repeated and he must be re-consented.
Men with a Screening Visit 1 (SV1) testosterone level between 300 and 333 ng/dL or men 
who did not have a confirmed testosterone level < 300 ng/dL at SV2 or SV3 can be re-
screened after 3 months following their last visit.  Men with two testosterone values 
< 100 ng/dL cannot be re-screened.  All of the Screening procedures must be repeated and 
the subjects must be re-consented.  Re-screened subjects will not receive a new subject 
number (Section 5.5.3).
5.2
Selection of Study Population
Adult male subjects who meet the inclusion criteria and do not meet any of the exclusion 
criteria will be eligible for enrollment (randomization) into the study.
5.2.1
Inclusion Criteria
1.
Men whose age is between 45 and 80 years, inclusive, at the time of Screening.
2.
Meet the study definition of clinical hypogonadism as evidenced by:
a)  Two serum testosterone levels < 300 ng/dL collected between 5 AM and 11 AM 
local time.  If SV1 level < 300 ng/dL, then proceed to SV2 or if needed, SV3:
●
SV1 level < 300 ng/dL; and SV2 level < 300 ng/dL
OR
●
SV1 level < 300 ng/dL; and SV2 level between 300 ng/dL and 333 ng/dL; and 
with a SV3 level < 300 ng/dL
●
If SV1 or SV2 level < 100 ng/dL, then additional SV3 confirmatory 
testosterone test is needed
Note:  Testosterone levels should be collected at least 48 hours apart.
 

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AND 
b)  Presence of at least one sign or symptom that may be related to low testosterone 
values and is/are consistent with hypogonadism such as the following:
●
Decreased sexual desire or libido
●
Decreased spontaneous erections (e.g., morning erections)
●
Decreased energy or fatigue/feeling tired
●
Low mood or depressed mood
●
Loss of body (axillary and pubic) hair or reduced shaving
●
Hot flashes
3.
Have pre-existing (historical) CV disease as evidenced by at least one disease in 
Table 1 OR at least three CV Risk Factors from Table 2.
Table 1.
Pre-Existing CV Disease
Coronary Artery 
Disease

Acute MI > 4 months before SV1 

Coronary artery disease (at least a 50% lesion in two of the major 
coronary artery distributions including their branches) as documented by 
angiogram (see Appendix Q for further details)

Coronary revascularization (coronary artery bypass grafting [CABG] or 
percutaneous coronary intervention [PCI]) > 4 months before SV1
Cerebrovascular 
Disease

Stroke excluding hemorrhagic > 4 months before SV1

TIA that required treatment > 4 months before SV1

Catheter-based or surgical revascularization of the carotid or middle 
cerebral arteries > 4 months before SV1

Extracranial carotid artery stenosis > 50%, excluding intracranial vessels
Peripheral Arterial 
Disease

Symptomatic peripheral arterial disease (i.e., lower extremity arterial 
disease documented by ankle/brachial index < 0.9 with claudication or 
resting limb ischemia obtained in the prior 12 months)

Peripheral arterial revascularization or amputation due to arterial 
obstructive disease > 4 months before SV1

Peripheral arterial stenosis > 50% 

Abdominal aortic aneurysm not due to connective tissue disorders
 

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Table 2.
Cardiovascular Risk Factors
Risk Factor
Definition
Hypertension
- Hypertensive and taking prescription anti-hypertensive medication
OR
- Systolic blood pressure (SBP) > 140 or diastolic blood pressure 
(DBP) > 90 mmHg during Screening Period
Dyslipidemia
- Dyslipidemic and taking prescription anti-dyslipidemic medication
OR
- Low-density lipoprotein corrected (LDL-C) > 160 mg/dL or high-
density lipoprotein cholesterol (HDL-C) < 40 mg/dL during Screening 
Period
Current Smoker
- Current daily cigarette/cigar smoker (e-cigarette smoking alone does 
not satisfy this criterion)
Stage 3 Chronic Kidney 
Disease (CKD) as defined by 
eGFR ranges
- Estimated Glomerular Filtration Rate (eGFR) > 30 and < 60 mL/min 
by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
creatinine equation during Screening Period
Diabetes
-Diabetic and currently taking prescription anti-diabetic medication
OR 
- Hemoglobin A1c (HbA1c) ≥ 6.5% or fasting glucose of 
≥126 mg/dL during Screening Period 
Elevated hsCRP
- History of high-sensitivity C-reactive protein (hsCRP) ≥2.0 mg/L 
(≥0.2 mg/dL) and confirmed at SV2
Documented Historical 
Agatston Coronary Calcium 
Score ≥ 75th percentile for age 
and race (supported by medical 
records)
- The Agatston coronary calcium score should not be obtained for the 
purposes of Screening (a link will be provided for calculation of the 
75th percentile calcium score)
≥ 65 Years of Age
4.
Naïve to testosterone replacement, clomiphene, compounded or over-the-counter 
(OTC) androgenic steroid derivatives and dehydroepiandrosterone (DHEA), 
including investigational products that may affect the reproductive hormonal 
system within the past 6 months.
5.
Willingness and the ability to apply topical testosterone gel as instructed by the 
study staff and comply with the requirements of this study protocol.
 

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6.
Intact skin surfaces on the upper arms and shoulders where the topical testosterone 
will be applied.
Rationale for the Inclusion Criteria
1 – 4
To select appropriate subject population with a disease status representative 
of the target population for evaluation
5
To select subjects who will comply with study procedures for adequate 
evaluation
6
To select subjects who would be expected to have reliable testosterone 
absorption from the application site
5.2.2
Exclusion Criteria
1.
Congenital or acquired hypogonadism for whom long-term therapy with placebo 
would not be medically appropriate.
2.
Two testosterone levels < 100 ng/dL during Screening.
3.
Current or recurrent ulcer, erosion, lichenification, inflammation psoriasis, eczema 
or use of topical cortiosteroids on the upper arms and shoulders.  Tattoo application 
or removal in the region of study drug application within 6 months of Screening.
4.
Known skin intolerance to alcohol or allergy to any of the ingredients of the study 
drug (see AndroGel 1.62% prescribing information).
5.
History of treatment with growth hormone, anti-estrogen or estrogen treatment 
within 90 days prior to Screening.
6.
Subjects taking acute course (> 5 days) of opioids or systemic glucocorticoids 
> 7.5 mg prednisone equivalent per day (e.g., hydrocortisone 30 mg, 
methylprednisolone 6 mg, or dexamethasone 1.2 mg) for a recent acute condition 
(e.g., surgery, trauma, or illness) 1 week before SV1 through Day 1 (Note:  Chronic 
daily therapy is allowable). 
7.
History of prostate (current or in the past) or breast cancer.
 

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8.
Severe lower urinary tract symptoms as indicated by an International Prostate 
Symptom Score (I-PSS) > 19.
9.
Prostate nodule or induration as determined by the Investigator on screening 
Digital Rectal Examination (DRE).  Men who have a documented normal DRE 
within 6 months of SV1 will not require a screening DRE.  Prostate enlargement 
consistent with benign prostatic hyperplasia (BPH) is not an exclusion criterion.  
Prostate abnormalities where prostate cancer has been ruled out through previous 
negative biopsies are also not exclusionary.
10.
PSA > 3.0 ng/mL; men treated with 5-alpha reductase inhibitors (e.g., dutasteride, 
finasteride) are eligible for participation as long as PSA levels are not > 1.5 ng/mL.
11.
Seeking fertility currently or for the duration of the study.
12.
History of untreated, severe obstructive sleep apnea.
13.
Body Mass Index (BMI) > 50 kg/m2.
14.
Documented MI, coronary revascularization (CABG, PCI), unstable angina, stroke, 
transient ischemic attack (TIA) requiring treatment, catheter-based or surgical 
revascularization of the carotid or middle cerebral arteries or procedures to 
treat/current evidence of critical limb ischemia < 4 months of SV1 or during the 
Screening period.
15.
New York Heart Association Class III or IV heart failure.
16.
Sitting SBP > 180 mmHg or < 80 mmHg or sitting DBP > 110 mmHg or 
< 50 mmHg at any point during the Screening period.
17.
HbA1c > 11% at Screening for diabetic subjects.
18.
History of unprovoked deep vein thrombosis (DVT), unprovoked pulmonary 
embolism (PE), or known thrombophilia.
19.
Known history of polycythemia vera or secondary polycythemia, such as 
polycythemia due to untreated sleep apnea or severe chronic obstructive pulmonary 
disease (COPD). 
 

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20.
History of major non-cardiovascular surgical procedure (e.g., major abdominal or 
thoracic procedure) within the 3 months prior to Screening and/or at the time of 
Screening, a major surgery is scheduled.
21.
Any inpatient hospitalizations (duration of hospitalization > 24 hours) or major 
febrile illness (temperature > 101°F) within 4 weeks prior to Screening.
22.
Active malignancy or diagnosed with or treated for cancer within the past 2 years.  
Subjects with basal and squamous cell carcinoma of the skin that has been 
successfully treated will be allowed to participate.
23.
A current condition, therapy, lab abnormality, history of clinically significant 
medical or psychiatric conditions or other circumstance or reasons which, in the 
opinion of the Investigator or the study staff, might pose a risk to the subject, make 
participation not in the subject's best interest, confound the results of the study 
(e.g., if subject cannot comply with requirements of the study), make the subject an 
unsuitable candidate to receive study drug, or interfere with the subject's 
participation for the full duration of the study.
24.
History, suspicion, or evidence of significant drug or alcohol abuse or illicit steroid 
use within the previous 12 months prior to Screening (SV1), as determined by the 
Investigator.
25.
Clinical laboratory analysis shows any of the following abnormal results:
a.
Hematocrit (Hct) > 50%.
b. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) > 3 × upper 
limit of normal (ULN).
26.
Severe or end-stage CKD documented by eGFR < 30 mL/min.
27.
Has been treated with any unapproved investigational drug within 30 days or five 
half-lives of the drug (whichever is longer) prior to the first dose of study drug.  If 
the investigational product is known or thought to significantly affect the subject's 
CV risk profile, the washout period is 6 months prior to Screening (SV1).
 

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28.
Subject has a history of any of the following:
●
Major psychiatric disorder that is not controlled with a stable treatment 
regimen in the opinion of the Investigator. 
●
Any suicide attempts within the past year or a response greater than 0 on 
Question 9 from Patient Health Questionnaire-9 (PHQ-9) at Screening.
29.
Subjects who have undergone female to male gender reassignment.  
Rationale for the Exclusion Criteria
5, 6, 11, 12, 13
To avoid conditions which constitute a contraindication for 
testosterone therapy, to reduce the risk to subjects to exclude 
underlying conditions that would indicate an unstable medical 
condition, or increase the subject's chances of being discontinued 
shortly after starting study drug and/or compromise the subject's 
safety
1, 2, 7, 8, 9, 10, 
14 - 23, 25, 26, 
28, 29
To avoid medical conditions that may compromise the ability to 
identify subjects with the correct diagnosis or to interpret medical 
importance of clinical results
11, 24
To exclude subjects who may be at increased risk for protocol non-
adherence or PD
3, 4, 27
To avoid bias in the evaluation of efficacy and safety by 
concomitant use of other medications or treatments
5.2.3
Prior and Concomitant Therapy
Prescription medications and over the counter aspirin, iron, folate, B12, vitamin D and 
calcium that the subject is receiving at the time of enrollment, or receives during the 
study, must be recorded along with the reason for use, date(s) of administration including 
start and end dates, and dosage information including dose, route and frequency.  Other 
non-prescription medications may be collected in the case of AESI, AEs leading to study 
drug discontinuation and SAEs.  
 

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During each phone contact or in-person visits with subjects who discontinue study drug 
prematurely, subjects will be asked whether or not they have started on TRT since they 
discontinued study drug, and if so, the route of administration, frequency and dose will be 
obtained.
The Therapeutic Area Medical Director (TA MD) or designated personnel should be 
contacted if there are any questions regarding concomitant or prior therapy(ies). 
Prior to study drug initiation, Investigators and/or other study site personnel should 
inform all participating subjects with known or presumed coronary artery disease that 
administration of drug products for the treatment of erectile dysfunction (i.e., tadalafil; 
sildenafil citrate; vardenafil hydrochloride) is contraindicated in subjects using any form 
of organic nitrate/organic nitrite and may potentiate the hypotensive effect of nitrates.  
This discussion should be documented in the source document.  
COVID-19 Pandemic-Related Vaccination Guidance
The impact of M16-100 study drug on COVID-19 vaccination is unknown. However, 
given the ongoing COVID-19 pandemic, FDA authorized/approved vaccines may be 
administered during screening and/or treatment period to prevent SARS-CoV-2 infection.
The decision to receive a locally available FDA authorized/approved COVID-19 vaccine 
should be based on a local guidance and an individual discussion between the treating 
physician and the subject.
Note: The above guidance applies to all FDA authorized/approved SARS-CoV-2 vaccine 
doses given as part of the complete treatment course.
These recommendations may be subject to change based on the evolving knowledge 
around the use of FDA authorized/approved SARS-CoV-2 vaccines in patients, as more 
data are collected in real-world scenarios and clinical trials.
 

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Any FDA authorized/approved SARS-CoV-2 vaccine information must be documented 
on the Concomitant Medications eCRF page.  
Reactions associated with the FDA authorized/approved SARS-CoV-2 vaccine should be 
reported as AEs if they meet the protocol reportable AE criteria (See Section 6.1.1.1). If 
the event meets the criteria for an SAE, then follow the SAE reporting directions (See 
Section 6.1.5).  All protocol defined AEs, medications, permanent study drug or study 
discontinuation, etc. due to COVID-19 should be noted as such in EDC.
5.2.3.1
Prohibited Therapy
The eligibility criteria list medications that are prohibited prior to study entry (see 
Section 5.2.1 and Section 5.2.2).
Subjects must not take oral nitrates concomitantly with drug products used to treat erectile 
dysfunction (i.e., tadalafil, sildenafil citrate, vardenafil hydrochloride).
The following pertains to prohibited medications during the study.  
●
Compounded or OTC androgenic steroid preparations, supplements or 
testosterone derivatives
●
Topical corticosteroids on the upper arms and shoulders (e.g., hydrocortisone)
●
Clomiphene
●
TRT from a source outside the study
Subjects must not take any other form of testosterone other than the study drug during the 
study as stated above.  Subjects who receive TRT from a source outside the study after 
discontinuing study drug are eligible to re-start study drug based on the last study 
prescribed dose so long as the subjects are at the end of the labeled (package insert) 
dosing interval for non-study testosterone (Section 5.4.1).
 

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5.2.3.2
Rescue Therapy
Medications containing testosterone treatments or medications known to increase 
testosterone and used as rescue therapy for hypogonadal symptoms are not permitted 
during the study.
5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures are listed in the following section of this protocol and are summarized 
in tabular format in Appendix C.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits, excluding Screening, Day 1, Week 2,
Week 4, Months 60/Final and Premature Discontinuation Visits, may be conducted 
virtually via phone or video conference only if in-person visits are not possible.
5.3.1.1
Study Procedures
Informed Consent
The subject will sign and date a study-specific Institutional Review Board (IRB)/Ethics 
Committee (EC) approved informed consent form before any study procedures are 
performed at or prior to SV1.
Details regarding how informed consent will be obtained and documented are provided in 
Section 9.3. 
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.
 

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Cardiovascular (CV) Risk Assessment
Subjects will be assessed for pre-existing CV disease (Section 5.2.1) or at least 3 CV risk 
factors (Table 2).  CV risk should be assessed prior to SV2 testosterone testing.  
Medical and Surgical History/Alcohol and Nicotine Use 
For all subjects, a complete medical and surgical history will be obtained during the 
Screening Period.  In addition, history of alcohol and nicotine use will be obtained from 
each subject during the Screening Period.  The medical history will be updated on Day 1 
prior to dosing.  The updated medical history on Day 1 will serve as the Baseline for the 
clinical assessment.
Cancer History
Subject's cancer history will be obtained during the Screening Period, if applicable.  The 
cancer history will be updated on Day 1 prior to dosing.  If the subject is given a diagnosis 
of cancer post-Baseline, then additional information will be collected.  
CV Family History
The subjects will be asked if their father, mother, brother or sister have a history of heart 
attacks.    
Height, Body Mass Index (BMI), Weight 
Height will be measured only during the Screening Period (Appendix C) in order to 
calculate BMI (calculated during Screening Period only); the subject will not wear shoes.  
Body weight (visits specified in Appendix C) will be measured on a calibrated scale
shortly after the subject empties his bladder with the subject in light indoor clothing with 
pockets empty and without shoes, belts, jewelry or other accessories.  Weight may be 
recorded in kilograms to the nearest 0.1 kilogram or in pounds to the nearest 0.25 pound.  
If possible, the same scale should be used for all weight measurements.
 

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BMI is defined as the subject weight in kilograms divided by the subject height in meters 
squared (kg/m2) and should be calculated to the nearest one-tenth unit.  All calculations 
made for the purpose of establishing a subject's eligibility and to be randomized into the 
study should be recorded in the Screening Visit source documents and CRFs.  The 
following formulas will be used to convert to metric units for calculation of BMI:
Pound (lb) ÷ 2.2 = Kilogram (kg)
Inch (in) × 0.0254 = Meter (m)
BMI calculations will be made by the Investigator or designee during the Screening 
Period and at Baseline using the following formula:
BMI (kg/m2) = weight (kg) ÷ [height (m) at Screening Visit]2
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During virtual visits, weight measurement may be performed by subject or caregiver as 
needed and if possible.
Physical Examination
A complete physical examination will be performed at SV2.  The physical examination at 
SV2 will serve as the Baseline physical examination for clinical assessment.  All other 
physical examinations as indicated in Appendix C will be symptom-directed 
examinations.  
Any significant physical examination findings not present at Baseline and detected on 
subsequent examinations will be documented and any significant findings meeting the 
criteria in Section 6.1.1.1 will be reported.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the Investigator.
 

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Prostate-Specific Antigen (PSA)
A blood draw to measure PSA should occur prior to the DRE as prostate manipulation can 
falsely elevate PSA.  
Only men who have a testosterone < 300 ng/dL at SV1 will have a PSA evaluated from 
that same sample.  At Screening, the PSA must be ≤ 3.0 ng/mL (≤ 1.5 ng/mL in men 
receiving 5-alpha reductase inhibitors).
PSA tests will be collected as specified in Appendix C.  PSA values will remain blinded 
after randomization unless two consecutive PSA values are elevated as defined in 
Section 6.1.8.
Digital Rectal Examination (DRE)
A DRE will be performed as indicated in Appendix C and should be done after the PSA 
blood draw.
The Screening DRE will not be required if the subject had a previous normal DRE within 
6 months of SV1 and the written documentation of the DRE result is provided.  Written 
documentation of the DRE result for on treatment visits will be required for DREs not 
performed at the study site with the timing windows defined in the Appendix C.  An 
abnormal DRE during the Screening Period will exclude the subject from the study until 
any prostatic abnormalities have been evaluated and deemed not exclusionary.  Any 
abnormalities found on the DRE during either Screening or Treatment (except benign 
prostatic enlargement, or BPH) will be recorded and referred to a urologist for further 
evaluation.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position for 
approximately 5 minutes, pulse rate, respiratory rate, and body temperature will be 
obtained at visits specified in Appendix C.  
 

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12-Lead Electrocardiogram (ECG)
A resting (supine for approximately 5 minutes) 12-lead ECG will be performed at the 
designated study visits as specified in Appendix C.  A qualified physician will interpret 
the clinical significance of any abnormal finding, sign, and date each ECG.  
ECG with QT interval corrected for heart rate using Fridericia's correction formula 
(QTcF) should be reported (or calculated) and documented in the source documents and 
later transcribed on to the appropriate electronic CRF (eCRF), if QTcF prolongation is 
observed (> 430 msec).  In addition, any clinically significant findings will be 
documented in the source documents and later transcribed on to the appropriate eCRF.  
Each signed original ECG may be reviewed by the responsible site monitor and kept with 
subject's source documents onsite.
Subjects can have a repeat ECG at any time during the study as warranted, based on the 
opinion of the Investigator.
Serum Testosterone Testing
Blood samples will be collected as indicated in Appendix C to determine serum 
testosterone concentration.  For information on screening serum testosterone, refer to 
Inclusion Criterion 2.
The average of the Screening Period (SV1, SV2 and SV3 if necessary) testosterone values 
will be used as the subject's Baseline testosterone value.  
After study randomization, pre-dose serum testosterone samples will be collected 
24 hours (± 2 hours) of the last applied dose for the purpose of titration.  For example, if 
the last applied dose was at 12:00 pm the day prior to the study visit, the blood sample 
should be taken between 10:00 am to 2:00 pm.
●
Subjects should not apply their regularly scheduled study drug dose prior to 
the in-person study visits as defined in Appendix C.  
 

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●
Subjects should receive a reminder to apply the dose 24 hours before the study 
visit, even if that is not their usual study drug application time.  
●
The following subjects should be rescheduled within 1 week for a serum 
testosterone level if their serum testosterone cannot be drawn 24 hours 
(± 2 hours) from the last applied dose. 
○
Subjects who apply a dose less than 22 hours from the time of serum 
testosterone sample collection.  
○
Subjects who apply a dose greater than 26 hours from the time of serum 
testosterone sample collection. 
●
Subjects should bring their current study drug to the site.  Subjects who forget 
to bring the study drug to their study visit should make arrangements to return 
study drug to study site as soon as possible.  The dose applied during the study 
visit will come from the newly dispensed study drug.  
Consult Section 5.1 for information on re-screening.
Clinical Laboratory Tests
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests as indicated in Table 3 and collection time points can be found in 
Appendix C.  Unscheduled clinical labs may be obtained at any time during the study if 
deemed appropriate per Investigator's discretion.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing, and shipping of these samples.  For study visits when samples for 
plasma glucose, serum chemistry or testosterone tests are collected, subjects should be 
fasting (a minimum 8-hour fast) whenever possible.  If a subject is not able to fast when 
necessary, the non-fasting status will be recorded in subject's source document.
Urine samples will be obtained according to Appendix C.  The central laboratory will be 
responsible for performing a macroscopic urinalysis (urine dipstick) on the collected urine 
specimens.  Specified abnormal macroscopic urinalyses defined as leukocytes, nitrite, 
 

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protein, ketones, or blood greater than negative, or glucose greater than normal will be 
followed up with a microscopic analysis at the central laboratory.
The last clinical laboratory test values obtained prior to the first dose of study drug will 
serve as the Baseline laboratory test values.
Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistrya
Urinalysisb
Hematocrit (Hct)c
Hemoglobin (Hgb)c
Red Blood Cell (RBC)c
count
White Blood Cell 
(WBC) count
Platelet count (estimate 
not acceptable)
Mean Corpuscular 
Volume (MCV)c
Mean Corpuscular 
Hemoglobin 
(MCH)c
Mean Corpuscular 
Hemoglobin 
Concentration 
(MCHC)c
Neutrophils
Lymphocytes 
Monocytes 
Eosinophils
Basophils  
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Gamma-glutamyl transferase 
(GGT)
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
LDL-C
HDL-C
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Leukocytes
Nitrites
Other Laboratory Tests
hsCRPd
PSAc
Serum Creatininee
Fasting Plasma Glucosea
HbA1c
Sex Steroidsa
Testosteronec
Free Testosteronec,f
Dihydrotestosterone (DHT)c
Estradiolc
a.
Minimum 8-hour fast except for SV1.
b.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A 
microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, protein, ketones, 
or blood greater than negative or glucose greater than normal.
c.
Post-baseline results are blinded.
d.
hsCRP will only be collected during Screening.
e.
Serum creatinine obtained according to Appendix C and will be used to calculate eGFR (central laboratory 
performing calculations).  eGFR assessment (CKD-EPI Equation) will be performed in all men.
f.
Free Testosterone only collected at SV2 (or SV3 if necessary) and Month 12 (Year 1).
 

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Starting at Day 1, the Investigator will assess results of laboratory tests for clinical 
significance and will document the assessment in the source record.
Blinded Laboratory Results:
Starting at Day 1, the results for the following labs will be blinded to sites/Investigators in 
an effort to maintain the study blinding:
●
Sex Steroids (Testosterone, DHT, Estradiol, Free Testosterone)
●
PSA
●
Hgb
●
Hct
●
RBC, MCV, MCH, MCHC
The Investigator will be notified if a subject has a value for testosterone, PSA, or Hct that 
requires additional follow-up, repeat assessment of the lab of interest, and/or modification 
of the study drug dosing regimen.
Testosterone and other sex steroid levels should not be collected outside of the protocol.
Randomization/Drug Assignment
All Screening laboratory results must be reviewed, signed, and dated by the Principal 
Investigator or Sub-investigator prior to the Baseline Visit.  Subjects will not be enrolled 
into the study if laboratory or other Screening result abnormalities are deemed clinically 
significant by the Principal Investigator or Sub-investigator.
Subjects who meet the eligibility criteria may proceed to randomization via IRT at the 
Day 1 (Baseline) Visit.  Enrolled subjects will keep their unique subject number initially 
assigned at SV1 throughout the study.  An IRT system will randomize subjects to receive 
either topical testosterone or placebo in a 1:1 ratio.  Randomization will be stratified by 
pre-existing CV disease (Yes/No).
 

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Study Drug Dispensing, Dosing, and Compliance
Study drug will be dispensed to subjects beginning at Day 1 (Baseline) and at specified 
visits as shown in Appendix C.  The first dose of study drug will be administered after all 
other Day 1 (Baseline) procedures are completed.  
Site Endpoint Questionnaire and AESI, AEs Leading to Study Drug Discontinuation, 
SAEs, and Concomitant Medications
The site staff will ask the subjects several questions about safety endpoints including CV, 
prostate, and fracture events (example questions Appendix E) during both in-person and 
phone visits as indicated in Appendix C.  A positive response to any of the site endpoint 
questions will prompt the completion of a more detailed Endpoint Form.  The site staff 
will also collect any AESI, AEs leading to study drug discontinuation, SAEs and 
concomitant medications at these visits.  These questions will be asked of all subjects in 
the study, both subjects continuing on study drug as well as subjects who prematurely 
discontinue study drug.
Rating Scales
International Prostate Symptom Score-1 (I-PSS)
The I-PSS is a questionnaire (example Appendix F) used to help assess urination patterns 
and define the severity of BPH or lower urinary tract symptoms.46  The standardized 
I-PSS instrument will be administered to the subject at designated visits.  Subjects will 
complete the I-PSS as indicated in Appendix C.
Sexual Function Questionnaires DeRogatis Interview for Sexual Function – Male 
(DISF – SRII)©
The DISF-SRII47 is a brief inventory of questions about sexual thoughts and activity.  The 
questions are divided into 5 sections that ask about different aspects of the individual's 
sexual experiences.  Some questions request answers in terms of "how often" one engages 
in certain sexual activities.  Other questions ask "how intense" one's sexual experiences 
are.  A third type of question asks how much one "enjoyed" or was "satisfied" by different 
 

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aspects of sexual activities and relationship.  Each section has one or more scale definition 
boxes located alongside the questions.  For Section I of the instrument, the scales range 
from 0 – 7 or 0 – 5.  Results from Section I (Sexual Desire domain) will determine 
whether or not a subject is included in the sexual function sub-study analysis set.  
Section I of the DISF-SRII will only be asked at Baseline.  Subjects will complete the 
DISF-SRII Section I as indicated in Appendix C (Main Study) and Appendix O (Sub-
study).  The example DISF-SRII is provided in Appendix G.
Hypogonadism Impact of Symptoms Questionnaire (HIS – Q)
The HIS-Q is a validated patient-reported outcome measurement to evaluate the 
symptoms of hypogonadism and assess changes in symptoms among men with 
hypogonadism in response to treatment with TRT.  It includes 28 item questions assessing 
5 domains (sexual, energy, sleep, cognition and mood) and 2 sexual subdomains (libido 
and sexual function):  sexual domain (5 open ended questions and 7 items spread between 
the libido and sexual function subdomains), libido subdomain (3 items), sexual function 
subdomain (4 items), energy domain (3 items), sleep domain (3 items), cognition domain 
(3 items), and mood domain (7 items).48  Subjects will complete the HIS-Q as indicated in 
Appendix C.  The example HIS-Q is provided in Appendix H.
Patient Global Index of Improvement (PGI – I) 
The PGI-I is adapted from questions that assess two other conditions, severity and 
improvement questionnaires in the treatment of men with lower urinary tract symptoms 
secondary to BPH,49 and global impression questionnaires for incontinence.50  Subjects 
not participating in either the sexual function or the PDD sub-studies will be asked about 
their global impression of hypogonadism overall, while men participating in the sexual 
function sub-study and/or PDD sub-study will be asked about their impression of their 
libido and/or depression, respectively, since starting study drug.  The PGI-I will be 
completed as indicated in Appendix C (for all subjects in main study) and Appendix O
(for subjects who qualify for sexual function and/or PDD sub-studies only).  The example 
PGI-I questions are provided in Appendix I.
 

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International Index of Erectile Function (IIEF-5) – Sexual Function Sub-Study Only
The IIEF-5 is a 5-item self-administered questionnaire measurement of erectile 
dysfunction.51  Subjects will complete the IIEF-5 questions as indicated in Appendix O.  
The example IIEF-5 questions are provided in Appendix J.  
Psychosexual Daily Questionnaire (PDQ) Question 4 Only – Sexual Function 
Sub-Study Only
The PDQ52 is a self-reporting instrument designed for the assessment of sexual function 
and mood on a daily basis.  The subjects will be asked to complete Question 4 from the 
PDQ for 7 consecutive days before each study visit as indicated in Appendix O.  The 
example PDQ Question 4 is provided in Appendix K.  If subjects complete less than 4 of 
7 days (e.g., Day –7 to Day –1) for the Baseline (Day 1) PDQ assessments, then they will 
be discontinued from the Sexual Function Sub-Study.
Patient Health Questionnaire-9 (PHQ-9)
The PHQ-9 is a validated self-administered questionnaire that is used to evaluate severity 
of depression.  Each of the 9 items in the questionnaire is scored from zero (not at all) to 3 
(nearly every day); thus the total score can range from 0 – 27 with higher number 
denoting greater severity of depression.53  Subjects will complete the PHQ-9 
questionnaire as indicated in Appendix C (SV2) and Appendix O.  The example PHQ-9 
questions are provided in Appendix L.
Geriatric Depression Scale (GDS)-15 – PDD Sub-Study Only
The GDS-15 is a widely used instrument to assess depressive symptoms in older adults.  
While the instrument was developed and validated for use in older patients, the literature 
also supports GDS-15 performance characteristics in younger patients.54  Subjects will 
complete the GDS-15 questionnaire as indicated in Appendix O.  The example GDS-15 
questions are provided in Appendix M.
 

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Additional Depression Questions – PDD Sub-Study Only
Additional questions will be asked of participants at Baseline to assess their eligibility for 
the PDD sub-study.  Subjects enrolled in the PDD sub-study will complete additional 
question at the same time points as the GDS-15.  The example additional questions are 
provided in Appendix N.
Modified Rankin Scale (mRS)55
The mRS is a commonly used scale for measuring the degree of disability or dependence 
in the daily activities of subjects who have suffered a stroke or transient ischemic attack 
(TIA) (See Appendix P).
The mRS score will be obtained by interviewing the subject or subject representative 
when the event is initially reported as well as approximately 90 days following a reported 
TIA or stroke event to ascertain the level of disability as suggested by the scale.  This may 
be done in person or via the telephone.
Phone Call
The subjects will be contacted by phone as indicated in Appendix C.  The subjects will be 
queried about endpoints and AEs following the guidance provided in Section 6.0.  
30-Day Follow-Up Call After Final Visit (FV)
A 30-day phone call will be performed on all subjects who complete Week 260/FV on 
study drug.  The phone call will check on the status of any AEs (Section 6.1.1) that were 
ongoing and to determine whether any new AEs have occurred.  All events meeting the 
criteria in Section 6.1.1.1 will be collected.  Consult Table 7 for other end-of-study 
scenarios.  
Final Visit (FV)
The FV occurs when the subject completes 260 weeks of active treatment or until the 
primary endpoint is achieved in the study (i.e., the study is stopped).  At the FV, all AEs 
 

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will be reviewed to determine if the event is resolved, resolved with sequelae, ongoing or 
fatal.  
Premature Discontinuation (PD) Visit
The PD Visit (Appendix C) will be conducted when the subject prematurely discontinues 
from study drug and elects Option 3 or Option 4 (Section 5.4.1).  The visit will be 
scheduled/conducted as close as is feasible to when the subject decides to prematurely 
discontinue study drug.  Subjects requiring PD visits will be followed for safety events 
outlined in Appendix D and end of study vitality status.
End of Study (EOS)/Study Completion
The last contact (e.g., office visit or phone call) with the subject will serve as the EOS for 
each subject.  For subjects completing 260 weeks of treatment on study drug, there will be 
the 30-day phone call.  For subjects prematurely discontinuing study drug less than 30 
days before Week 260/FV, then a 30-day phone call will be the EOS.  For subjects 
prematurely discontinuing study drug but continuing study visits greater than 30 days 
before Week 260/FV, the Week 260/FV will serve as the EOS.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
The following modifications are allowed during the COVID-19 pandemic:
Study visits and/or activities should be performed as scheduled whenever possible.  
Virtual visits are allowed if in-person site visit is not possible due to pandemic related 
reasons. Screening (SV1, SV2 and SV3), Day 1, Week 2, Week 4, M60/Final and 
Premature Discontinuation Visits cannot be performed virtually.
During virtual visits, the following activities may be performed:
●
Vital signs if able by the subject, weight if able by the subject, 
AEs/SAEs/AESI and Endpoints collection as well as collection of additional 
information related to ongoing adverse events.
 

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If a subject missed a visit or had a virtual visit prior to Month 6/Week 26 visit: he should 
continue using the most recent dose of study drug as per protocol and/or IRT titration 
notification and complete any missed visits as soon as possible.
If a subject missed or had a virtual Month 3/Week 12 visit: a PSA must be performed at 
the next in-person visit per protocol, in addition to other laboratory tests. 
Subjects who cannot complete an in-person Month 6/Week 26 visit should discontinue 
study drug temporarily until an in-person visit can occur.
If a subject had a Month 6/Week 26 in-person visit and associated lab tests resulted: he 
should continue using the most recent dose of study drug as per protocol and/or IRT 
titration notification and complete any missed visits as soon as possible.
If a subject missed a visit or had a virtual visit after Month 6/Week 26 visit: he should 
continue using the most recent dose of study drug as per protocol and/or IRT titration 
notification and complete any missed visits as soon as possible. The physical exam and 
other missed assessments should be completed at the next in-person visit.
Subjects who did not complete an in-person visit for 12 months should discontinue study 
drug temporarily until an in-person visit can occur.
5.3.2
Safety Variables
5.3.2.1
Primary Outcome Variables
Primary Safety Endpoint:  Time to MACE, is defined as time from randomization to 
first component event occurrence of the composite MACE endpoint.  MACE is defined as 
a composite endpoint consisting of any of the following: 
●
Nonfatal MI
●
Nonfatal stroke
●
Death due to CV causes
 

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5.3.2.2
Secondary Safety Variables
This study will examine the effect of testosterone on a number of additional safety 
endpoints as specified below.
Secondary CV safety endpoint is defined as time from randomization to first component 
event occurrence of the composite endpoint consisting of the following:
●
Nonfatal MI
●
Nonfatal stroke
●
Death due to CV causes
●
Cardiac revascularization procedures/cardiac PCI and CABG
Secondary Prostate Safety Endpoints:
●
High grade prostate cancer (Gleason score of 4 + 3 or higher)
5.3.2.3
Tertiary Safety Endpoints and Tertiary Prostate Endpoints
Tertiary Safety Endpoints:
●
All-cause mortality 
●
Heart failure events (hospitalization or urgent visit)
●
Venous thromboembolic events to include DVT/PE/venous thromboembolism 
(excluding superficial thrombophlebitis)
●
Peripheral arterial revascularization
Tertiary Prostate Safety Endpoints:
●
Prostate biopsy
●
Any prostate cancer
●
Acute urinary retention
●
Starting pharmacologic treatment for lower urinary tract symptoms
 

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●
Invasive prostate surgical procedures (e.g., prostatectomy, transurethral 
prostate resection, brachytherapy or other prostate surgical procedure) for 
benign prostatic hyperplasia
5.3.2.4
Adjudicated Events
The CEC will adjudicate pre-specified CV, prostate and fracture events during the study, 
as described in Appendix D.  The CEC will have separate charters for each of the 
three event categories governing the adjudication progress.
Many of the endpoint events from this study will be reviewed by experts serving on the 
adjudication committees to ensure the accuracy of the data.  Adjudication results for these 
endpoint events will be for research purposes only and will not be used for the clinical 
management of subjects.  Therefore, adjudication results will not be shared with the 
Investigators.
5.3.3
Efficacy Variables
A limited number of pre-specified efficacy endpoints have been included as secondary 
outcomes in five efficacy domains.  
The following efficacy endpoints will be evaluated in sub-studies or analyses of 
subpopulations:
1.
Improvement in sexual activity in hypogonadal men with low libido
2.
Remission of depression in hypogonadal men with late-onset, low grade PDD 
(dysthymia)
3.
Reduction in incidence of clinical fractures
4.
Correction of anemia in subset of subjects with Baseline anemia
5.
Reduction in progression from pre-diabetes to diabetes in subset of subjects with 
pre-diabetes at Baseline
 

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For additional efficacy sub-study information, refer to Appendix O.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to discontinue from the study or the study drug at any time.  In 
addition, the Investigator may discontinue a subject from the study drug at any time.  
Subjects who discontinue study drug after they have been randomized will not be 
replaced.
Temporary Discontinuation of Study Drug
Subjects who have received marketed testosterone replacement therapy should be 
managed per Section 5.2.3.1.
If a subject temporarily discontinues study drug, every attempt should be made to restart 
study drug as soon as possible when medically appropriate based on the Investigator's 
judgment, provided the subject does not meet any of the reasons for permanent 
discontinuation of study drug as listed below.  There will be no minimum or maximum 
allowed duration of study drug discontinuation, and the regularly scheduled visits and/or 
phone calls should continue while the subject is not on study drug.  Subjects eligible to 
restart study drug should restart study drug based on their last study prescribed dose.  
If study drug is discontinued for ≤ 4 weeks, no further action is necessary.  If study drug is 
discontinued for > 4 weeks, subject should return for an unscheduled visit 4 ± 1 weeks 
after restarting study drug to assess his testosterone level.    
The dates of study drug discontinuation and when drug is restarted, and the reason for 
temporary discontinuation should be documented in the source document and eCRF.  
Once study drug is restarted, the subject should return for the next closest scheduled visit 
(if study visit(s) were missed) and complete all study visit assessments.
 

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COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it is necessary to employ mitigation strategies to enable 
the Investigator to ensure subject safety and continuity of care.
The Investigator should contact the Retention Hotline before discontinuing a subject from 
the study drug or study for any reason to ensure all acceptable mitigation steps have been 
explored.
Permanent Discontinuation of Study Drug
In rare instances, it may be necessary for a subject to permanently discontinue study drug.  
Permanent study drug discontinuation is clearly justified by meeting the protocol criteria 
for permanent discontinuation as described below.  Once the subject discontinues study 
drug, the appropriate study visits and/or phone calls should still be continued until the 
study ends.
Reasons for Permanent Study Drug Discontinuation
Subjects should discontinue study drug for any of the following:
●
Confirmed serum testosterone levels > 750 ng/dL even after down-titration to 
the lowest dose (see Section 6.1.9)
●
Confirmed prostate cancer diagnosis during the study (see Section 6.1.8)
●
Confirmed repeat Hct value > 54% even after down titration to the lowest dose 
(see Section 6.1.9)
●
PDD sub-study: Subjects at risk of suicide as determined by the Investigator 
and/or a non-zero response to Question 9 on post-Baseline PHQ-9 
(Appendix L)
Discontinuing the Study Entirely (Withdrawal of Informed Consent)
In order to minimize missing data for safety and efficacy assessments, subjects who 
discontinue study drug treatment should continue to be followed for all regularly 
scheduled visits, unless they have decided to discontinue their study participation entirely 
 

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(withdrawal of informed consent).  If a subject discontinues the study prematurely, the 
subject should undergo a PD Visit at the time he discontinues from the study regardless of 
when he discontinued study drug.  Subjects should be advised on the continued scientific 
importance of their data even if they discontinue treatment with study drug.  The subjects 
should also be informed of their options for continued study visits and/or follow-up phone 
calls.
Discontinuation of study drug should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for indirect follow-up, e.g., medical 
records checks.  If the subjects decide to discontinue the study entirely, the subjects
should be asked if other means of follow-up are possible, e.g., medical records check.  
Subjects requesting withdrawal should be advised that withdrawal of informed consent to 
continue in the study will diminish the public health value of the study.  Withdrawal of 
informed consent for follow-up should be accompanied by documentation of the reason 
for withdrawal.
Subjects who withdraw should be explicitly asked about the contribution of possible AEs 
to their decision to withdraw consent, and any AE information elicited should be 
documented.
Preferably, the subject should withdraw consent in writing and, if the subject or the 
subject's representative refuses or is physically unavailable, the site should document the 
reason for the subject's failure to withdraw consent in writing.  While subjects have the 
right to discontinue study drug and leave the study at any time, Investigators and site staff 
will ask the subjects to remain in the study, if they are able, for follow-up evaluations.
Retention Hotline and Continued Participation Options  
Investigator(s) or designee should contact the Retention Hotline prior to the subject 
permanently discontinuing from the study drug or the study entirely (withdrawal of 
informed consent) in order to discuss the subject's status and ensure continued follow-up 
in the study.  For all subjects who inform the site that they want to discontinue the study 
 

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permanently (withdrawal of informed consent), the study site must discuss with the 
subject the options available for continued participation.
As a last resort, in an effort to optimize subject retention, the following four options 
should be offered to the subject regarding continued participation; however, every effort 
should be made to keep subjects who discontinue study drug under participation Option 1, 
matching the same study visits and procedures as subjects who remain on study drug.
Option 1:  Subject discontinues study drug temporarily or permanently but continues to 
participate in study site visits and procedures following the protocol specified visit 
schedule until the end of the study.
Option 2:  Subject discontinues study drug and study procedures permanently but 
continues telephone (or other communication, i.e., email or text messages as allowed 
according to institutional guidelines) contact following the protocol specified visit 
schedule until the end of the study.  Date of the contact, the identity of the contact, update 
contact information, concomitant medications, and SAE assessments including but not 
limited to identification of AESI and MACE should be collected at each telephone visit 
(or other communication).  All events meeting the criteria in Section 6.1.1.1 will be 
collected.
Option 3:  Subject discontinues study drug and study procedures permanently and does 
not allow site to contact him but allows the site to review the subject's medical records 
and/or contact their Primary Care Physician and/or Designated Contact following the 
protocol specified visit schedule or at least every 6 months until the end of the study, to 
ensure his safety, and to check if the subject had any AESI, SAEs, and identification of 
MACE.  At the time that the subject discontinues from the study, the subject should 
undergo a FV.  The reason for discontinuation should be collected and recorded on the 
CRF.  Date of the contact or review of the records, the identity of the contact or source, 
and any updates to concomitant medications and SAE assessments including but not 
limited to identification of AESI and MACE (if available) should be collected at each 
 

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contact/review of medical records.  All events meeting the criteria in Section 6.1.1.1 will 
be collected.  
Option 4:  Subject discontinues study drug and study procedures permanently and 
chooses no further contact from the site and withdraws informed consent.  Subject 
revokes consent to contact him directly or his Primary Care Physician and/or Designated 
Contact or review of his medical records.  Vital status will be checked at the end of study 
using appropriate available public information sources, if allowed according to 
institutional guidelines.  Whenever possible, all events meeting the criteria in 
Section 6.1.1.1 will be collected.
NOTE:  Options 2 – 4 should not be explored if the subject is willing to continue 
participation under Option 1.  Site should make every effort to maintain in-person visits 
wherever and whenever possible as defined in Appendix C.  
The subject's continued level of participation should be clearly documented and updated 
in the subject's source documents and eCRFs.  If a subject no longer wishes any further 
contact, the primary criterion for withdrawal of consent must also be recorded.  In 
addition, efforts should be made to perform all assessments for the PD Visit.
Lost to Follow-Up (LTFU)
Subjects may become potentially LTFU at any time during the study, especially after 
missed study visits.  The status of LTFU is defined by the inability to gather vital status at 
the end of the study and only when instructed to do so by the study team.  Every effort 
will be made to ensure that the subject continues to return to the clinic for study visits and 
avoid LTFU during the conduct of the study.  After the first missed visit, subjects that are 
potentially LTFU should receive a minimum of three documented phone calls, faxes, 
and/or emails as well as one registered/certified mail letter.  Additional attempts to contact 
the subject should be performed following the study specified visit schedule until the 
study is completed.  All reasonable efforts must be made to locate subject to determine 
 

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and report his ongoing status.  This includes follow up with persons authorized by the 
subject.  All attempts should be documented in the subject's source documents.
The Investigator must attempt to document assessments of study endpoints and 
occurrence of events through the end of the study.  If it is determined that the subject has 
died, the site will use permissible local methods to obtain the date and cause of death as 
well as obtain records to support this through the subject's next of kin.  If the subject died 
at a medical facility or hospice, records should be obtained from the facility or the 
provider that referred the subject to hospice.  If the subject died at home, the site should 
document the known circumstances that preceded the death.  If medical records are not 
available, the site will be asked to provide a written narrative.  Per the adjudication 
charter, undetermined deaths will be adjudicated as CV deaths through the adjudication 
process.
If the use of a third-party representative (a patient locator service) to assist in the 
treatment portion of the study has been included in the subject's informed consent, then 
the third-party representative may work with the site staff to obtain the subject's contact 
information or other public vital status data necessary to complete the treatment portion of 
the study.  The site staff and representative will consult publicly available sources, such as 
public health registries and databases, in order to obtain updated contact information.  If 
after all attempts, the subject remains LTFU at the end of the study, then the last known 
alive date, as determined by the Investigator, should be reported and documented in the 
subject's source documents.
Vital Status Assessment at EOS
At the end of the study, the Investigator should attempt to obtain vital status and primary 
CV safety endpoint information (CV death, non-fatal MI, non-fatal stroke) for those 
subjects not completing all study required visits (e.g., LTFU or withdraw consent if 
agreed to by the subject).
 

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5.4.2
Discontinuation of Entire Study
The Sponsor may terminate this study prematurely in its entirety or AbbVie may 
terminate this study prematurely at any study site, for reasonable cause provided that 
written notice is submitted in advance of the intended termination.  The Investigator may 
also terminate the study at his/her site for reasonable cause, after providing written notice 
to AbbVie in advance of the intended termination.  Advance notice is not required if the 
study is stopped due to safety concerns.  If the Sponsor terminates the study for safety 
reasons, AbbVie, or its designee, will immediately notify the Investigator by telephone 
and subsequently provide written instructions for study termination.
When the study ends or is terminated, all randomized subjects continuing in the study will 
return for the FV procedures as specified in Appendix C Study Activities.  For subjects 
remaining on study drug, the post-therapy SAE collection period will continue for 30 days 
following the termination of study drug therapy.
5.5
Treatments
5.5.1
Treatments Administered
Though all subjects will start on the 40.5 mg dose (2 pump actuations) of the study drug
once daily, they may receive a dose in the range of 20.25 mg (1 actuation) to 101.25 mg 
(5 actuations) in 20.25 mg increments during the course of the study if titrations are 
necessary.  
Before using a new pump of study drug, the pump will need to be primed by pushing the 
actuator all the way down 3 times.  Do not use any study drug that came out while 
priming the pump.  Wash it down the sink to avoid accidental exposure to others.  The 
pump only needs to be primed when using a new pump for the first time.  For the first 
study drug administration at Baseline, the subject should administer the study drug at the 
site so that the site staff can observe the administration of study drug.
The subject will self-administer study drug once daily in the morning to the shoulder(s) 
and upper arm(s).  On subsequent study visit days, subjects should not apply their daily 
 

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dose until after a sample is collected to measure serum testosterone (See Appendix C for 
titration study visits).  Following sample collection, subjects are to apply study drug at the 
site.  Subjects should be rescheduled within 1 week for a serum testosterone level if their 
serum testosterone cannot be drawn 24 hours (± 2 hours) from last applied dose.
The study drug should not be administered to other parts of the body, including abdomen, 
genitals, chest, armpits (axillae), or knees.  
Figure 1.
Application Sites
Following study drug administration, the subjects should wash their hands with soap and 
water.  After the study drug has completely dried, the subject should cover up the 
application site with a t-shirt.  
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 4.
 

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Table 4.
Identity of Investigational Product
Investigational 
Product
Mode of 
Administration
Formulation
Strength per 
Actuation
Manufacturer
AndroGel 1.62%
Topical
Gel
20.25 mg of 
testosterone per 
1.25 g of gel
Laboratoires Besins-
International
AndroGel 1.62% 
matching placebo
Topical
Gel
NA
Laboratoires Besins-
International
5.5.2.1
Packaging and Labeling
The study drug will be provided in metered dose pumps containing AndroGel 1.62% or 
matching placebo.  Each pump will be labeled as required per US requirement.  Labels 
must remain affixed to the containers.  The approximate dosage and duration for 
one bottle are depicted in Table 5.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject is unable to come to the study site to pick up his study drug due to COVID-19, 
a direct-to-patient (DTP) study drug shipment can be made from the study site to the 
subject and/or return of study drug to study site by courier if allowed by local regulations.  
Each study site is responsible for obtaining any necessary approval for providing DTP 
study drug shipment from any applicable state or federal agency.
Study drug may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:
●
DTP shipment of study drug is allowed by local regulations and the relevant 
IRB/IEC.
●
Subject agrees to have the study drug shipped directly to his home.
Instructions will be provided by AbbVie as to how a study site can initiate a DTP 
shipment using Marken, a global vendor selected by AbbVie to provide this service when 
necessary.  Shipments of study drugs from the study site to a subject's home will be 
 

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appropriately temperature controlled (qualified shipper or temperature monitoring) within 
the labeled storage conditions.  Signature is required upon delivery; however, due to 
COVID-19 related social distancing, this may be provided by the courier after delivery.  
Documentation of the shipment is to be retained by the study site.  Also, Marken is able to 
pick-up study drug from a study subject's home and return it to the study site.
●
If study sites are not able to use Marken, then another courier may be 
acceptable. Any study site that uses another such courier must follow the 
controlled substance courier requirements and be responsible for complying 
with any applicable laws and regulations related to the shipping to and from 
the site of a controlled substance.
In each instance, the study site will work directly with Marken or another courier to 
facilitate the DTP shipment.  As such, AbbVie should not receive subject identifying 
information related to these shipments.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
Table 5.
Approximate Dosage and Duration of Use for 1 Bottle of Study 
Drug
Dosage 
Duration of Use for 1 Bottle
20.25 mg (1 actuation)
60 days
40.5 mg (2 actuations)
30 days
60.75 mg (3 actuations)
20 days
81.0 mg (4 actuations)
15 days
101.25 mg (5 actuations)
12 days
5.5.2.2
Storage and Disposition of Study Drugs
All clinical drug supplies are to be stored in a secure, monitored, limited-access area in 
accordance with labeled storage conditions.  The study drug should be stored between 15° 
 

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to 25°C (59° to 77°F).  The Investigator will maintain accurate records of the disposition 
of all clinical drug supplies received during the study.  The controlled storage area should 
have a temperature recording device capable of recording the high and low temperatures 
in a 24-hour period.  A storage temperature log is to be maintained to document proper 
storage conditions.  The temperature must be recorded on a temperature log every 
business day.  Malfunctions or any temperature excursions must be reported to AbbVie 
immediately.  In case of a temperature excursion, study drug should be quarantined and 
not dispensed until AbbVie deems the study drug as acceptable.
AndroGel 1.62% is listed as Drug Enforcement Administration (DEA) CIII drugs in the 
US and must be handled according to applicable federal and local regulations.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to AbbVie.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be randomized using IRT.  Before the study is initiated, IRT directions 
will be provided to each site.  
For subjects that re-screen, the Screening number assigned by IRT at the initial Screening 
visit should be used; a new Screening number should not be requested.  Subjects will keep 
the same subject number assigned to them at Screening.  
Subjects who are eligible (Section 5.2) will be randomized in a 1:1 ratio to one of 
two treatment groups (Table 4) and stratified by pre-existing CV disease (Section 8.3).
Blinded study drug will be dispensed on Day 1 (Baseline) and at regular intervals 
thereafter during the treatment period according to Appendix C.  At the designated 
scheduled study visits, subjects will return to the site to obtain new supply of study drug 
and return used/unused study drug packaging supply.  The unused study drug returned by 
 

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the subject will not be re-dispensed.  The Investigator or designee will access the IRT 
system at each study visit prior to dispensing study drug to the subject.  Study drug cannot 
be dispensed without using the IRT system.  Study containers will be labeled with their 
unique module number.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose for this study is discussed in Section 5.6.4.
All eligible subjects will be started at 40.5 mg of study drug, either active drug or placebo, 
on Study Day 1 (Baseline).  Titration will be based on pre-dose morning total serum 
testosterone concentrations and will be communicated to the sites via an IRT system, 
while maintaining blinding of the actual testosterone values.  
Subjects will return for pre-dose serum testosterone assessment 24 hours (± 2 hours) after 
the last applied dose according to the titration study visit schedule in Appendix C.
Subjects will be asked when they last applied study drug.  Subjects should be rescheduled 
within 1 week for a serum testosterone level if their serum testosterone cannot be drawn 
24 hours (± 2 hours) from the last applied dose. 
Within approximately 7 days of these titration study visits, the subject's dose may be 
titrated up or down in 20.25 mg increments or remain on the previously assigned dose, 
based on pre-specified criteria (Table 6).
No dose can be titrated below 20.25 mg or above 101.25 mg during the course of the 
study.
The pre-specified titration criteria to be applied during the study are based on testosterone 
serum concentrations as shown in Table 6.
 

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Table 6.
Dose Titrations
Pre-Dose (Preferably Morning) Sample Collection for 
Serum Testosterone Concentrations to Occur Within 
24 Hours (± 2 hours) Following the Last Applied Dose
Dose Titration
Greater than 750 ng/dL 
Decrease daily dose by 20.25 mg 
(one pump actuation)
Between 350 ng/dL and 750 ng/dL, inclusive
No change:  continue on current dose
Less than 350 ng/dL 
Increase daily dose by 20.25 mg (one pump 
actuation)
Irrespective of testosterone levels, subjects randomized to 
placebo will receive sham titrations
Dose titrations will be performed at 
periodic intervals for subjects randomized 
to placebo
Subjects may also have study drug titrated for elevated Hct (Section 6.1.9).
If subjects are asked to titrate following a titration visit, they will be asked to cross out the 
previous instructions specifying their previous number(s) of pumps/actuations per day or 
dose and fill in their updated number of pumps/actuations per day or dose.
Should a subject's dose require titration, site personnel will communicate this to the 
subjects within approximately 3 days from the receipt of IRT notification to titrate.  
Serum testosterone levels for visits after Screening will remain blinded to the subjects and 
site personnel.
If subjects are not taking their prescribed dose (e.g., titration was required but subjects did 
not titrate and continued on the non-titrated dose from the previous visit/testosterone 
blood draw), the site should not draw a serum testosterone.  The subject should be 
instructed to start their prescribed dose and return to the site for an unscheduled visit in 
4 ± 1 weeks for a testosterone blood draw in order to determine if titration is needed.  
5.5.5
Blinding
Study drug (active and placebo) will be supplied in a blinded fashion.
 

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Throughout the course of the study, the subject, all study site personnel and the Sponsor 
will be blinded to each subject's treatment.
Central third party vendors (IRT and central laboratory) will be unblinded to serum 
testosterone levels and will coordinate titrations for active treatment and placebo, as well 
as any actions necessary as a result of sustained high testosterone levels despite down-
titration or as a result of increased Hct.
The blind for an individual subject may be broken using IRT system if, in the opinion of 
the Investigator, it is in the subject's best interest to do so.  The Investigator must make 
every effort to contact AbbVie or designee before breaking the blind.  AbbVie or designee 
must be notified within 24 hours of the blind being broken.  The date, time, and reason the 
blind was broken must be recorded on the appropriate eCRF.  In the highly unlikely event 
that unblinding is necessary for a subject, only a designated AbbVie staff member outside 
of the study team will be unblinded.  All other personnel involved with the conduct of the 
study, including the CEC, will remain blinded.  Once the blind has been broken for an
individual subject, the subject will discontinue study drug but the subject may remain in 
the study for regularly scheduled visits.
5.5.5.1
Blinding of Data for Independent Data Monitoring 
Committee (DMC)
An external independent DMC comprised of persons, independent of the Sponsor, the 
Clinical Research Organization (CRO), and the Academic Research Organization (ARO), 
with relevant expertise in their field will review unblinded safety data from the ongoing 
study.  The primary responsibility of the independent DMC will be to protect the safety of 
subjects participating in this study.
A separate independent DMC charter will be prepared outside of the protocol and will 
describe the roles and responsibilities of the independent DMC members, frequency of 
data reviews, and relevant safety data to be assessed.
 

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5.5.5.2
Blinding of Data for Executive Steering Committee (ESC)
A separate charter will be prepared for other governance body (ESC) outside of the 
protocol to define the roles and responsibilities.
The CECs will not be responsible for any safety assessment of the study.  The 
responsibility for safety assessment will remain with the DMC, which will act 
independently from the Sponsor, ESC, and CECs.
5.5.6
Treatment Compliance
Subjects will be instructed to return all used or unused bottles at each visit to determine 
compliance via bottle weight. 
At each of the visits, the study coordinator will question the subject regarding adherence 
to the assigned regimens.  A weight measurement of the study drug pump bottle will be 
conducted.  Study drug lot number, the date that the study drug bottle(s) were 
dispensed/returned and the weight of the returned study drug bottles will be recorded. 
The bottle weight of the returned study drug bottles will be compared to an average bottle 
weight to determine compliance.  The number of doses that should have occurred between 
visits will be calculated.
Subjects with compliance values below 80% or above 120% compliance will be 
re-instructed on proper use and informed of the importance of compliance to continue in 
the study.
An overall accountability of study drug will be performed and verified by 
AbbVie/designee.
5.5.7
Study Drug Accountability
The Investigator must agree to comply with all applicable DEA laws and regulations 
regarding controlled substances as outlined in 21 CFR 1300.  Additionally, the 
Investigator must agree to limit access to the study drug only to the named 
 

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Sub-investigators or to other appropriately designated study personnel or monitoring 
personnel.  Study drug will only be dispensed to subjects enrolled in the study by the 
Investigator or his/her designated representatives.
Study drug will only be shipped once the DEA License has been received from each site.  
The study drug must be shipped to the address listed on the Form DEA-223.  Study drug 
must be securely stored at the same location according to DEA guidelines for CIII 
controlled substances.  Upon receipt of a shipment, the Investigator or site representative 
at the site will 1) open and inspect the shipment; 2) verify that the study drug supplies 
have been received intact, in the correct amounts and at the correct address; 3) 
acknowledge receipt of study drug consignment via the IRT system.
The IRT system will maintain a current and accurate inventory of all study drug, 
accountability, reconciliation, returns and destruction for each site.  The investigational 
site will weigh returned opened study drug and enter the weight into the IRT system.  
Study drug bottles that are returned unopened at a visit will not be weighted but they must 
be reconciled.  
Subjects should return all used and unused study drug at each visit.  Study drug 
accountability will be recorded in IRT and compliance will be performed by the site staff 
in a timely manner so that the subject can be counseled if compliance is outside of the 
accepted range (i.e., below 80% or above 120%).  The monitor will confirm and verify 
ongoing study drug accountability.
Upon completion of the study, the investigational site must complete a final inventory of 
supplies.  All original study drug bottles supplied by AbbVie, whether empty or 
containing unused drug, must be inventoried and returned to AbbVie or an AbbVie 
designated site for destruction.  Return shipping labels must be attached to the containers.  
The monitor will generate and prepare a shipment for destruction within the IRT system.
 

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5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
A placebo-controlled study is one way to assess whether or not TRT significantly impacts 
the risk of CV events.  Use of CECs and a DMC, both composed of independent experts, 
to maximize the unbiased and consistent adjudication of events, and for ongoing 
evaluation of safety are well-established components of ethical, well-run clinical studies 
designed to assess CV outcomes.
5.6.2
Appropriateness of Measurements
In this CVOT, the incidence of MACE in symptomatic, hypogonadal men at increased 
CV risk will be ascertained.  Specifically, the incidence of nonfatal MI, nonfatal stroke 
and CV death (including fatal MI and fatal stroke) will be measured in both the active and 
placebo groups as the primary endpoint of study.
Additionally, efficacy endpoints based on pre-specified hypotheses will be assessed as 
secondary outcomes in several efficacy domains.  These secondary endpoints are 
consistent with symptom domains and/or target organ systems that have demonstrated 
some level of responsiveness in past TRT studies and will allow the testing of specific 
efficacy hypotheses in five efficacy domains:  improved sexual activity and function in 
middle-aged and older hypogonadal men with low libido; remission of depression in men 
with low grade PDD (dysthymia); slowing progression to diabetes in men with 
pre-diabetes; correction of anemia in men with anemia; and reduction of clinical bone 
fracture.
Specified laboratory serum testosterone assessments will be used as a measure of 
adequate titration of study drug; standard clinical and laboratory procedures will be 
utilized in this study.
 

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5.6.3
Suitability of Subject Population
This study will enroll hypogonadal men at increased risk for CV events.  Eligible subjects 
are men between the ages of 45 and 80 years who have low serum testosterone, signs or 
symptoms that are associated with hypogonadism, and who may benefit from therapeutic 
intervention by raising and maintaining their testosterone concentrations within the 
normal range.  Confirmation of testosterone values below normal limits will be conducted 
during Screening.  Subjects who are not suitable for long-term placebo therapy, such as 
men with clear organic and/or genetic etiology, or hypogonadal men with two screening 
testosterone levels < 100 ng/dL, for whom long-term therapy with placebo might not be 
medically appropriate, will be excluded.  Subjects will either be naïve to testosterone 
therapy or have not been treated with testosterone in the past 6 months.  Men for whom 
there are a relative or a concrete contraindication for testosterone therapy such as those 
with history of prostate or breast cancer, severe lower urinary tract symptoms, 
erythrocytosis, and those seeking fertility will be excluded.
The eligibility criteria will ensure the enrollment of subjects who are experiencing 
signs/symptoms that may be associated with low testosterone and are at risk of 
experiencing a CV outcome event during the study.  The study will also allow for the 
evaluation of the effect of TRT on the incidence of MACE in hypogonadal men with 
increased risk for CV events within a reasonable time period.  Likewise, the study will 
assess whether testosterone replacement beneficially impacts a pre-specified set of 
efficacy outcomes.
5.6.4
Selection of Doses in the Study
With the exception of the 101.25 mg dose, all doses utilized in the study are per the 
product label of AndroGel 1.62%.  The maximum dose of 101.25 mg dose was selected to 
ensure that men not achieving normal testosterone levels at the highest labeled dose have 
the opportunity to optimize their testosterone levels.  Though not pursued in the 
development program for AndroGel 1.62%, AbbVie does have data characterizing the 
pharmacokinetics of the 101.25 mg dose (data on file).
 

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6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The study drug contains:
●
AndroGel 1.62% or matching placebo
●
Pre-filled bottle with actuator
Complaints associated with any component of study drug must be reported to AbbVie.  
For AEs related to any component of study drug, please refer to Sections 6.1 through 
6.1.5.  For Product Complaints, please refer to Section 6.2.
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of AESI, 
AEs leading to study drug discontinuation, and SAEs, on a routine basis throughout the 
study.  The Investigator will assess and record these events in detail including the date of 
onset, event diagnosis (if known) or sign/symptom, severity, time course (end date, 
ongoing, intermittent), relationship of the AE to study drug, and any action(s) taken 
(e.g., interruption of study drug).  For SAEs considered as having "no reasonable 
possibility" of being associated with study drug, the Investigator will provide an "other"
cause of the event.  For AEs to be considered intermittent, the events must be of similar 
nature and severity.  AEs as defined above, whether in response to a query, observed by 
site personnel, or reported spontaneously by the subject will be recorded.
All AESI, AEs leading to study drug discontinuation and SAEs should be followed until 
resolution or marked as ongoing if the study is completed and the event is still pending 
resolution.
 

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6.1.1
Definitions
6.1.1.1
Adverse Event
AEs will not be collected in the study unless they meet the definition of an AESI, they 
resulted in study drug discontinuation or they met regulatory criteria for SAEs as outlined 
in Section 6.1.1.3.
Adverse events of cancers should be reported per protocol defined criteria and recorded 
on the AE/SAE form along with Cancer Diagnosis Study form in EDC.
Primary and secondary endpoints that are SAEs will be collected but will be considered 
expected for the purposes of FDA Investigational New Drug (IND) safety expedited 
reporting.  Therefore, they will be exempt from FDA IND individual case safety 
reporting.  See Appendix D for the list of these endpoints.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an AE if the surgery/procedure is being performed for a pre-existing condition.  However, 
if the pre-existing condition deteriorates unexpectedly during the study (e.g., surgery 
performed earlier than planned), then the deterioration of the condition for which the 
elective surgery/procedure is being done will be considered an SAE.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as an SAE 
within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the Investigator, would 
have resulted in immediate fatality if medical 
intervention had not been taken.  This does not include 
an event that would have been fatal if it had occurred 
in a more severe form.
 

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Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital 
for any length of time or prolongs the subject's hospital 
stay.  This does not include an emergency room visit 
or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include 
experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug 
dependency or drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate CRF.
 

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6.1.1.3
Adverse Events of Special Interest (AESI), AEs Leading to 
Study Drug Discontinuation and Serious Adverse Events 
(SAEs)
Along with any AEs leading to study drug discontinuation and SAEs, the Investigator will 
monitor each subject for pre-defined AESI throughout the study.  See Appendix D for a 
detailed list of AESI.
6.1.2
Adverse Event Severity
The Investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The AE causes considerable interference with the subject's usual 
activities and may be incapacitating or life-threatening.
6.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is insufficient evidence (information) to suggest a causal 
relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
 

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In addition, when the Investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an alternative etiology or cause of event must be provided by the Investigator for 
the SAE.
6.1.4
Adverse Event Collection Period
All defined AEs (Section 6.1.1.1 through Section 6.1.1.3) will be recorded from the time 
of study drug administration until the end of the study/study completion.  
All AESI, AEs leading to study drug discontinuation and SAEs will be followed until 
resolution or achievement of a new stable state, or until the subject withdraws consent for 
study participation, or until the final study-related communication (e.g., phone call at the 
end of the study or 30 days after last dose as define above or final study communication in 
subjects truly LTFU), whichever occurs first.
In addition, SAEs will be collected from the time the subject signed the study-specific 
informed consent.
Subjects who discontinue the study drug without withdrawing consent will be followed 
for AEs for the duration of the study.  Subjects discontinuing study drug at or near the end 
of the FV will be contacted up to or including 30 days later.
Regardless of the below scenarios, every effort will be made to obtain vital status and 
complete Endpoint information prior to database lock as described in Appendix E.
 

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Table 7.
End of Study (EOS) Scenarios 
Scenario
Last Visit Type
30-Day Follow-Up Phone Call
Completes Week 260/FV on 
study drug
Final Visit
Yes
Option 1 (Section 5.4.1):  
Discontinues study drug but 
follows protocol specified visits 
and procedures
Final Visit
No*
Option 2 (Section 5.4.1):  
Discontinues study drug but 
allows phone contact
Phone call as Final Visit if in
person visit is not possible
No*
Option 3 (Section 5.4.1):  
Discontinues study drug/study 
procedures but allows medical 
record review 
Premature Discontinuation Visit
N/A**
Option 4 (Section 5.4.1):  
Withdraws informed consent
Premature Discontinuation Visit
N/A***
*
If subject discontinues study drug within 30 days of Week 260/FV, subject should receive a 30-day phone call. 
**
This scenario assumes that the subject does not want further phone contact.  If there is access to medical records, 
every attempt should be made to obtain primary safety endpoint information (i.e., CV death, nonfatal MI, nonfatal 
stroke).  Any updates to concomitant medications and SAE assessments including but not limited to identification 
of AESI and MACE (if available) should be collected.
*** This scenario assumes that the subject does not want further phone contact.  Will attempt to obtain vital status at 
EOS.
AE information will be collected as shown in Figure 2.
 

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Figure 2.
Adverse Event Collection
Throughout treatment, AESI, AEs leading to study drug discontinuation and SAEs will be 
collected utilizing standard eCRFs and will be reported via the electronic data capture 
(EDC) system.
COVID-19 Pandemic-Related AE/Discontinuations Reporting Requirements
'COVID-19 infection' should be documented for all COVID-19 related AEs on the AE 
eCRF page in EDC.
Discontinuation due to COVID-19 related AE should be documented if subject 
permanently discontinues study drug (or study) or has a study drug interruption,
COVID-19 AE should be noted as the reason on the applicable eCRF form.
●
On the Endpoint form/documentation for MACE, indicate if the event is due to 
COVID-19 by adding in 'COVID-19 infection.'
●
If subject permanently discontinues study drug (or study) or has a study drug 
interruption due to risk of COVID-19 that is not considered an AE, document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Phone:  +1 (973) 784-6402
6.1.6
Pregnancy
Pregnancy of the subject's female partner will be reported to AbbVie within 
1 working day of the site becoming aware of the pregnancy.  Information regarding 
pregnancies in the partners of study subjects will be collected from the date of first dose 
through 30 days following the last dose of study drug.  
Information regarding a pregnancy occurrence in a study subject's partner and the 
outcome of the pregnancy will be collected.  In the event of pregnancy occurring in a 
subject's partner during the study, written informed consent from the partner must be 
obtained prior to collection of any such information.
The medical outcome for either mother or infant, meeting any serious criteria including an 
elective or spontaneous abortion, is considered an SAE and must be reported to AbbVie 
within 24 hours of the site becoming aware of the event.
6.1.7
Management of Abnormal Laboratory Results (PSA, Hct, 
and Testosterone)
Testosterone, PSA and Hct values remain blinded throughout the study starting at Day 1.  
Elevated PSA, Hct and serum testosterone values meeting the criteria in Section 6.1.8 and 
Section 6.1.9, respectively, will require additional action.  For elevated PSA values, the 
central laboratory will communicate to the site via lab report the need for further action; 
for elevated Hct and serum testosterone, the IRT system will communicate to the site via 
IRT notification the need for further action.
6.1.8
Elevated Prostate Specific Antigen Management
All PSA values will be blinded starting at Day 1.  As referenced in Section 6.1.7, for 
elevated values, the central laboratory will notify the site via lab report.  The site should 
schedule a repeat PSA approximately 4 – 6 weeks after the initial test.  
 

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Subjects should also be made aware that long plane or car rides, ejaculation, bike riding, 
urinary tract infections (UTIs), recent catheterizations, prostatitis are examples of factors 
that can affect PSA levels.  Subjects who need a repeat PSA should be encouraged to 
abstain from activities that are known or suspected to increase PSA for the 48 hours prior 
to the repeat PSA.
The Investigator will be notified of the elevation and will refer the subject to a urologist 
for further evaluation.  It is recommended to continue study drug in these subjects while 
being evaluated by a urologist.  Subjects with non-confirmatory findings (e.g., negative 
biopsy, decision on the urologist's part not to do additional investigations) following the 
evaluation may continue on study drug.  Subjects with biopsies positive for prostate 
cancer should have study drug discontinued (Section 5.4.1).
A subject will be referred for urological evaluation for consideration of further work-up, 
which may include a prostate biopsy, if a new prostate nodule or induration is detected, or 
if he meets any of the following criteria:
Elevated PSA criteria
Subjects NOT taking 5-ARI
Subjects TAKING 5-ARI
Confirmed PSA increase above 
Baseline value during the first year
PSA > 1.4 ng/mL above 
baseline
PSA > 0.7 ng/mL above baseline
Confirmed absolute PSA value at 
any time during the study
PSA > 4.0 ng/mL
PSA > 2.0 ng/mL
Men 45 – 54 years of age 
Baseline PSA was < 1.5 ng/mL 
and whose PSA increases to 
> 3.0 ng/mL
Baseline PSA was < 0.75 ng/mL 
and whose PSA increases to 
> 1.5 ng/mL
For men age 55 or older whose repeat PSA confirms the 1.4 ng/mL (0.7 ng/mL in men on 
5-ARI) increase or a level > 4.0 ng/mL (> 2.0 ng/mL in men on 5-ARI), their risk 
variables will be entered into the PCPT Risk Calculator Version 2.0.56  The three resulting 
estimates will be provided:  Risk of no cancer, risk of low-grade cancer, risk of high-grade 
cancer.  These results will be calculated and provided to the subject.  With the subject's 
own risk estimates, he may then be shown an IRB approved video that provides extensive 
 

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and updated information about pros and cons of a prostate biopsy.  Along with the video, 
the subject will be provided with a urology referral.
6.1.9
Testosterone and Hematocrit/Hemoglobin Management
All testosterone, Hct, and Hgb values will be blinded starting at Day 1.  
If the serum total testosterone is > 750 ng/dL or Hct is > 54%, the IRT system will notify 
the site via an IRT notification to decrease dose by 1 actuation.  The site will contact 
(e.g., by phone, via email, etc.) the subject and instruct the subject to reduce by one study 
drug actuation.  After Week 26, the site will also ask the subject to return for a repeat 
blood draw 4 ± 1 weeks after dose reduction for both a serum total testosterone and Hct.  
Dose reductions and repeat blood draws may occur every 4 ± 1 weeks until the level 
decreases.  If the serum total testosterone is > 750 ng/dL or Hct is > 54% even after dose 
titration to the lowest possible dose, the subject will be discontinued from study drug 
(Section 5.4.1).  For Hgb value that is < 8.0 g/dL or > 18.9 g/dL, the unblinded medical 
monitor will review the lab value and notify the site for further action as appropriate.
If the subject does not return for a repeat blood draw, then the site should contact the 
subject (e.g., by phone, via email, etc.) at least twice to schedule a blood draw visit.  If the 
subject is unwilling or unable to repeat the blood draw(s) as described above, then he may 
need to be discontinued from study drug.  
Once a subject has down titrated a cumulative of 3 times for elevated Hct management, he 
will not have the opportunity to up titrate even if his testosterone results would dictate an 
up titration.  
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
 

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For a product, this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues.
Any information available to help in the determination of causality by the device to the 
Product Complaints outlined directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the study drug and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event via the Product Complaint 
form in EDC.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to AbbVie (or an 
authorized representative) and documented in source as required by AbbVie.  Product 
Complaints associated with AEs will be reported in the study summary.  All other 
complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (bottle).  In instances where a return is requested, every effort should be made 
by the Investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
The Sponsor does not allow intentional/prospective deviations from the protocol unless 
when necessary to eliminate an immediate hazard to study subjects.  The Principal 
Investigator is responsible for complying with all protocol requirements, and applicable 
global and local laws regarding protocol deviations.  If a protocol deviation occurs (or is 
 

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must be documented in the subject's source documents and denoted that they were related 
to COVID-19.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Unless noted otherwise, all analyses will be performed using SAS® version 9.3 (SAS 
Institute Inc., Cary, NC 27513) under the UNIX operating system.
8.1.1
Analysis Sets
The following data sets will be used for the analyses of safety and efficacy endpoints for 
this study:
The Full Analysis Set (FAS) comprising all randomized subjects.  Subjects will be 
categorized according to treatment assigned at randomization.  The FAS will be mainly 
used for the summary of subjects' disposition and summary of subjects' demographics and 
Baseline characteristics for the study.
The Safety Set comprising all randomized subjects who receive at least one dose of study 
drug (TRT or placebo).  Subjects will be categorized according to treatment received.  
Unless otherwise specified, the Safety Set will be used for the analysis of all safety 
endpoints of the study.
The Efficacy Analysis Sets (EAS) are pre-specified subgroups of the FAS comprising of 
eligible subjects from the main study who satisfy the criteria for sub-studies for sexual 
function, PDD, bone fracture, anemia and diabetes.  The EAS will be used for the 
analyses of these sub-studies (Section 5.3.3 and Appendix O).  For instance, the EAS for 
the analysis of sexual function sub-study will include subjects with Baseline DISF-SRII 
Section I:  Sexual Desire domain score ≤ 20 (Section 5.3.3 and Appendix O).
 

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8.1.2
Demographics, Other Baseline Characteristics, Subject 
Disposition and Concomitant Medication
Demographics and other Baseline data (including disease characteristics) will be 
summarized descriptively by treatment arm using the FAS. 
Continuous data summaries, including at minimum the mean, standard deviation, median, 
minimum, and maximum, will be presented for age, height, weight, BMI, vital signs and 
laboratory assessments at Baseline.
Categorical data summaries will be presented as frequencies and percentages for race, 
ethnicity, age, pre-existing CV disease, prior use of testosterone (yes/no), and nicotine use 
(yes/no), alcohol use and physical exam data including vital signs.
For treatment comparisons and summaries, a Baseline value in general is defined as the 
last non-missing value obtained prior to or at the time of randomization unless specified 
otherwise in the analysis plan.
The number and percentage of subjects enrolled by investigator/institution will be 
provided.  The number and percentage of subjects who are randomized, receive study 
drug, discontinue study drug, or discontinue the study will be summarized.
Prior and concomitant medications taken will be summarized.
8.1.3
Analysis of Treatment 
Continuous summaries of subjects' total duration of treatment with study drug will be 
provided.  Treatment duration will be computed as follows:
Treatment duration = Date of last dose of study drug – date of first dose of study drug 
+ 1.
Total patient-years of exposure will be calculated by summing the duration of treatment 
for all subjects in the Safety Set and dividing this sum by 365.25 (= 1 year).  In addition, 
the number and percentage of subjects exposed to study drug will be summarized for the 
 

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following categories of exposure duration:  ≤ 1 month, > 1 to 2 months, > 2 to 3 months, 
> 3 to 6 months, > 6 months to 1 year, > 1 to 2 years, > 2 to 3 years, etc.
8.1.4
Analysis of Safety
8.1.4.1
Primary Safety Endpoint
The primary endpoint of the study, time to MACE, is defined as time from randomization 
to the first occurrence of any component event of the composite MACE endpoint 
consisting of CV death, non-fatal MI and non-fatal stroke.  Time to MACE for subjects 
who do not experience an event on study will be right-censored at the time of their last 
available follow-up observation.
A Cox proportional-hazards regression model will be used to estimate the hazard ratio of 
TRT to placebo and its two-sided 95% confidence interval (CI).  The model will have the 
prior CV disease/risk as a covariate.  The non-inferiority of TRT to placebo will be 
claimed if the upper limit of the 95% CI for hazard ratio rule out the margin of 1.5 
following 256 events.  Median time to event (TTE) and its 95% CI, as well as Kaplan-
Meier (KM) estimates of the incidence function (cumulative event rates over time) will be 
calculated.  
The primary analyses will include all MACE (i.e., time to the first occurrence of MACE 
for each subject with an event) reported in the study using the Safety Set and will be 
repeated using the FAS as supportive analyses.
Principal Sensitivity Analyses for Primary Endpoint
The principal sensitivity analyses will be performed based on 'on-exposure' period.  In this 
analysis, MACE that occurs during the period from randomization to 365 days post last 
dose will be included.  Events occurring after 365 days post last dose will be censored.
Other Sensitivity/Supportive Analyses for Primary Endpoint
Two other sensitivity analyses will be performed.
 

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●
Analysis only includes MACE that occurs during the period from 
randomization to 30-days-post last dose.  Events occurring after 30-days-post 
last dose will be censored.
●
For subjects with drug interruption(s) that was 3 months or longer, events 
occurring after 30-days-post the start date of the first interruption of 3 months 
or longer will be censored.  For all other subjects, events occurring after 
30-days-post last dose will be censored.
Additional sensitivity analyses may be performed where appropriate.  
In addition, the restricted mean survival time (RMST) at 3-year based on the KM estimate 
will be obtained.  When assumptions of constant hazards hold, the three measures of 
treatment difference, namely, hazard ratio (HR), risk difference, and RMST may be 
obtained as simple transformations of each other.  Thus, assuming a background event 
rate of 1.5%, the decision threshold (non-inferiority margin) for absolute risk difference at 
3 years and RMST at 3 years proportional to a HR of 1.5 under the constant hazards 
condition, respectively, is set to be 2.14% and –12 days as supportive analyses.
Component events of MACE will also be analyzed using similar methods.  Categorical 
summaries of incidence of these events will also be provided.
8.1.4.2
Secondary CV Safety Endpoints 
Secondary CV safety endpoint is defined as time from randomization to first component 
event occurrence of the composite endpoint consisting of any of the following:
●
Nonfatal MI
●
Nonfatal stroke
●
Death due to CV causes
●
Coronary revascularization procedures/cardiac PCI and CABG
Time to secondary CV composite endpoint will be analyzed using similar methods as 
described in Section 8.1.4.1.
 

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8.1.4.3
Secondary Prostate Safety Endpoints
The incidence of high grade prostate cancer (Gleason score of 4 + 3 or higher) will be 
summarized and will serve as a secondary safety endpoint and an event of special interest 
for prostate safety.
8.1.4.4
Other Safety Endpoints
Tertiary Safety Endpoints
The incidence of the following events will be summarized. 
●
All-cause mortality 
●
Heart failure events (hospitalization or urgent visit)
●
Thromboembolic Events to include DVT/PE/venous thromboembolism 
(excluding superficial thrombophlebitis)
●
Peripheral arterial revascularization
Tertiary Prostate Safety Endpoints:
●
Prostate biopsy
●
Any prostate cancer
●
Acute urinary retention
●
Starting pharmacologic treatment for lower urinary tract symptoms
●
Invasive prostate surgical procedures (e.g., prostatectomy, transurethral 
prostate resection, brachytherapy or other prostate surgical procedure) for 
benign prostatic hyperplasia
Adverse Events
Treatment emergent AESI, AEs leading to study drug discontinuation and SAEs will be 
summarized by treatment group and overall in descending order of overall frequency by 
Medical Dictionary for Regulatory Activities (MedDRA) preferred term, as well as in a 
lexicographic order by system organ class (SOC) and MedDRA preferred term (PT).  
 

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Treatment emergent events are those that are reported from the time of study drug 
administration until 30 days following discontinuation of study drug.  Treatment emergent 
AESI and SAEs will also be summarized according to their relationship to study drug and 
their maximum severity.  In addition, treatment emergent AEs/SAEs that lead to study 
drug discontinuation will also be summarized.
Clinical Laboratory Data
Continuous summaries of mean changes from Baseline for items such as PSA, lipids, Hct 
and Hgb will be summarized and treatment group differences in change from Baseline to 
each post-Baseline Visit will be assessed.
Vital Signs
Continuous summaries of the mean change from Baseline to each visit in vital signs, 
including weight, will be provided.  Vital sign variables include, but are not limited to, 
SBP, DBP, pulse rate, temperature, and weight.
8.1.5
Efficacy
The analysis of the efficacy endpoints will be detailed in the statistical analysis plan 
(SAP).  For each of the five efficacy domains, the condition, the study population and the 
primary hypotheses have been pre-specified in Section 5.3.3 and Appendix O.  The 
sample size for each efficacy endpoint (Table 8) is based on estimation of the defined 
relevant disease population and this study should be well powered to answer the efficacy 
endpoints and the sample size rationalized based on consideration of the hypothesized 
treatment effect and statistical power.
 

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Table 8.
Sample Size for Efficacy Endpoints
Efficacy 
Domain
Condition/Study Population
Efficacy Endpoint
Estimated 
Sample 
Size
Power
Sexual 
function
Middle-aged and older 
hypogonadal men with low libido
Change from Baseline in 
overall sexual activity per 
PDQ Question 4
810
91%
Low grade, 
PDD 
(Dysthymia)
Middle-aged and older men with 
late-onset, low grade, PDD 
(dysthymia)
Proportion of men whose 
PDD remits during 
intervention per remission 
definition
780
90%
Fracture
All men enrolled in the 
TRAVERSE Study
Proportion of men with 
adjudicated clinical bone 
fractures
6000
90%
Diabetes
Middle-aged and older 
hypogonadal men with pre-
diabetes at Baseline
Proportion of men, who had 
pre-diabetes at Baseline, and 
who progress to diabetes
2430
90%
Anemia
Middle-aged and older 
hypogonadal men with 
unexplained anemia
Proportion of anemic men 
whose anemia is corrected 
during the intervention 
period
576
90%
Note:
The sample sizes were based on 6,000 from the parent study and may be modified if sample size changes.
For serum testosterone, point-in-time testosterone levels will be evaluated to assess the 
percentage of men with serum testosterone levels in the normal range at different visits.  
Other exploratory analyses may be conducted as well, such as the relationship between 
changes in testosterone with changes in the selected efficacy endpoints during the study.
8.1.6
Interim Analyses
No interim analysis is planned for the study.
8.1.7
Type 1 Error Adjustment
Type I error adjustments for multiple comparisons are not planned for safety or efficacy 
endpoints, subgroup analyses, supportive analyses or sensitivity analyses for this study.
 

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8.2
Determination of Sample Size
This non-inferiority study plans to observe a total of 256 primary composite events 
(i.e., MACE) to rule out a HR of 1.5 at the 95% (2-sided) upper confidence limit 
(i.e., 1-sided alpha = 2.5%) with 90% power on the estimated annual placebo event rate of 
1.5%, an accrual period of 3.5 years, and an annualized LTFU rate of 2%, a total of 
approximately 5,400 subjects (2,700 per treatment arm) are needed to observe the 
256 required events for the primary analysis.
However, in order to achieve similar power for the principal sensitivity analysis  
(i.e., analysis to censor subjects after 365 days post last dose), approximately 6,000 
subjects (in 3.5 year accrual period) will be needed assuming the treatment 
discontinuation rate is 20% in the first year, and 10% in the second year and thereafter. 
Therefore, the study is planned to enroll approximately 6,000 subjects (3,000 per 
treatment arm), and the study will be stopped and analysis will be conducted after 
256 MACE are observed for the principal sensitivity analysis.  The study duration is 
projected to be 5.2 years under the alternative hypothesis (True HR = 1.0, i.e., no 
increased risk with TRT) and 4.4 years under the null hypothesis (True HR = 1.5). 
8.2.1
Blinded Sample Size Re-Estimation (BSSR)
We note that certain design parameters may be different over the course of the study, most 
notably the assumed accrual rate, the annualized placebo event rate, and LTFU rate.  
Therefore, a periodic blinded review of the pooled study data will occur during the course 
of the study (e.g., after 4,500 subjects have been randomized or at approximately 2.5 years 
from the first subject enrolled). 
The accrual rate and pooled event LTFU and treatment discontinuation rates will be 
evaluated against the original estimates used in the study design.  The total number of 
subjects that will be enrolled for the study may be adjusted according to the observed 
pooled event rate, LTFU rate, as well as the accrual rate (the accrual period may need to 
be adjusted too) in order to obtain the target 256 events within the planned study duration 
 

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(i.e., approximately 5 years assuming no increased risk with TRT).  The aforementioned 
adjustments and final sample size determinations will take this consideration into account.
Detailed Methodology of the BSSR
In general, for time-to-event analysis, sample size needed to achieve a certain number of 
events is a function of event rate (p), LTFU rate (d), accrual period (r), total study 
duration (t), and total required number of events (e).  Thus, we can write the below 
formula for the sample size calculation, assuming constant hazard.
 = (, 
, , , )
In the study design, we assumed
 = 1.5%    , 1.5%    ℎ  = 1.0 

 = 2%  
 = 4 "
 = 5.2 " ℎ  = 1.0
 = 256 $"
Assume the BSSR is conducted at time % from the first subject enrolled, and the 
following notations:
%: '  "'(" 
  % 
%: '  $" "$
  %
%: 
 $  "$
  % 

%: 
 )*+   %
 

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For those subjects among % who haven't had events yet, we can predict the additional 
number of events (%
,) that will occur in the remaining of the study (i.e., in the interval 
from % to ) based on observed event rate (%) and LTFU rate (
%).
The additional sample size needed for the remaining of the study can be estimated as
- = (%, 
%, -, -, -)
Where - = 256 −% −%
,; - =  −%; and - (accrual duration in the remaining of the 
study) can be adjusted if necessary.
Therefore, the total sample size will be  = % + -.
8.3
Randomization Methods
Subject will be randomized via IRT system, using 1:1 randomization ratio and permuted 
block randomization, to receive either topical testosterone or placebo.  Randomization 
will be stratified by pre-existing CV disease (Yes/No).  Since the study is targeting at least 
30% of randomized subjects enrolled in pre-existing CV disease cohort, and up to 70% of 
randomized subjects in CV Risk Factors cohort (i.e., no pre-existing CV disease); the 
proportions will be monitored and controlled via IRT system throughout the study.  The 
ESC and Sponsor may decide to cap the CV risk factors cohort if that cohort is found to 
consistently exceed 70% of the total population enrolled or if the pooled primary event 
rate falls below projections.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the current package insert, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
 

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ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the Investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
Screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
 

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the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Due to COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The Investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, CEC, and regulatory inspection(s), providing direct access to source data 
documents.  The specific rules that apply to adjudicating events will be outlined within 
their respective charters (e.g., non-fatal MI adjudication criteria can be found in the CV 
events CEC charter).
 

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10.2
Case Report Forms
The eCRF must be completed for each subject screened/enrolled in this study.  These 
forms will be used to transmit information collected during the study to AbbVie and 
regulatory authorities, as applicable.  The CRF data for this study are being collected with 
an EDC system called Rave® provided by the technology vendor Medidata Solutions 
Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will comply with 
Title 21 CFR Part 11.  The documentation related to the validation of the EDC system is 
available through the vendor, Medidata, while the validation of the study-specific eCRFs 
will be conducted by AbbVie or designee and will be maintained in the Trial Master File 
at AbbVie or the CRO.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the study through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
 

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Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmax, provided by the technology vendor Signant Health of 
Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, Signant Health.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by Signant Health.
Internet access to the ePRO data will be provided by Signant Health for the duration of 
the study.  This access will be available for the duration of the study to the site 
investigator, as well as delegated personnel.  Such access will be removed from 
investigator sites following the receipt of the study archive.  Data from the ePRO system 
will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's ePRO data.  It will be possible for 
the Investigator to make paper print-outs from that media.
The ePRO data will be collected by the following methods:
Tablet Based
The (instrument/scale) will be collected electronically via a tablet/laptop device into 
which the subject will directly enter the required pieces of information.  The electronic 
device will be programmed to allow data entry for only the visits specified in the protocol 
and will not allow for subjects to complete more than one of the same assessments at any 
one visit.  All data entered on the device will be immediately stored to the device itself 
and (manually/automatically) uploaded to a central server administrated by (ePRO 
Vendor).  The Investigator and delegated staff will be able to access all uploaded subject 
 

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entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Subjects may be brought in for an unscheduled visit to complete any questionnaires that 
were not done at the previous visits. These questionnaires will be recorded in the ePRO 
device under the previous visit name that was missed.  They should be completed prior to 
the next scheduled on-site visit.
Phone/Web Based
The PDQ Question 4 (Appendix K) data for the sexual function sub-study (Appendix O) 
will be collected via the phone or through a web-based system.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to Investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.
 

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13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The Investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements.  If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
The EOS is defined as the date of the last subject last visit.
 

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14.0
Investigator's Agreement
1.
I have received and reviewed the product labeling for AndroGel 1.62%.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
Testosterone Replacement therapy for Assessment of long-term 
Vascular Events and efficacy ResponSE in hypogonadal men 
(TRAVERSE) Study
Protocol Date:
06 May 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 

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15.0
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71.
Benito M, Vasilic B, Wehrli FW, et al.  Effect of testosterone replacement on 
trabecular architecture in hypogonadal men.  J Bone Miner Res.  
2005;20(10):1785-91.
72.
Al Mukaddam M, Rajapakse CS, Bhagat YA, et al.  Effects of testosterone and 
growth hormone on the structural and mechanical properties of bone by micro-MRI 
in the distal tibia of men with hypopituitarism.  J Clin Endocrinol Metab.  
2014;99(4):1236-44.
73.
Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al.  Effect of testosterone 
treatment on volumetric bone density and strength in older men with low 
testosterone a controlled clinical trial.  JAMA Intern Med.  2017;177(4):471-9.  
doi:  10.1001/jamainternmed.2016.9539.
 

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74.
Ania BJ, Suman VJ, Fairbanks VF, et al.  Incidence of anemia in older people:  an 
epidemiologic study in a well defined population.  J Am Geriatr Soc.  
1997;45(7):825-31.
75.
Artz AS, Fergusson D, Drinka PJ, et al.  Mechanisms of unexplained anemia in the 
nursing home.  J Am Geriatr Soc.  2004;52(3):423-7.
76.
Ble A, Fink JC, Woodman RC, et al.  Renal function, erythropoietin, and anemia of 
older persons:  the InCHIANTI study.  Arch Intern Med.  2005;165(19):2222-7.
77.
Joosten E, Pelemans W, Hiele M, et al.  Prevalence and causes of anemia in a 
geriatric hospitalized population.  Gerontology.  1992;38(1-2):111-7. 
78.
Nilsson-Ehle H, Jagenburg R, Landahl S, et al.  Hematological abnormalities and 
reference intervals in the elderly.  A cross-sectional comparative study of 
three urban Swedish population samples aged 70, 75 and 81 years.  Acta Med 
Scand.  1988;224:595-604. 
79.
Robinson B, Artz AS, Culleton B, et al.  Prevalence of anemia in the nursing home:  
contribution of chronic kidney disease.  J Am Geriatr Soc.  2007;55(10):1566-70.
80.
Steensma DP, Tefferi A.  Anemia in the elderly:  how should we define it, when 
does it matter, and what can be done?  Mayo Clin Proc.  2007;82(8):958-66.
81.
Beutler E, Waalen J.  The definition of anemia:  what is the lower limit of normal 
of the blood hemoglobin concentration?  Blood.  2006;107(5):1747-50.
82.
Izaks GJ, Westendorp RG, Knook DL.  The definition of anemia in older persons.  
JAMA.  1999;281(18):1714-7.
83.
Merchant AA, Roy CN.  Not so benign haematology:  anaemia of the elderly.  Br J 
Haematol.  2012;156(2):173-85.
84.
Salive ME, Cornoni-Huntley J, Guralnik JM, et al.  Anemia and hemoglobin levels 
in older persons:  relationship with age, gender, and health status.  J Am Geriatr 
Soc.  1992;40(5):489-96.
 

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85.
Svartberg J, Jenssen T, Sundsfjord J, et al.  The associations of endogenous 
testosterone and sex hormone-binding globulin with glycosylated hemoglobin 
levels, in community dwelling men.  The Tromso Study.  Diabetes Metab.  
2004;30(1):29-34.
86.
Laaksonen DE, Niskanen L, Punnonen K, et al.  Testosterone and sex hormone-
binding globulin predict the metabolic syndrome and diabetes in middle-aged men.  
Diabetes Care.  2004;27(5):1036-41.
87.
Selvin E, Feinleib M, Zhang L, et al.  Androgens and diabetes in men:  results from 
the Third National Health and Nutrition Examination Survey (NHANES III).  
Diabetes Care.  2007;30(2):234-8.
88.
Ding EL, Song Y, Malik VS, et al.  Sex differences of endogenous sex hormones 
and risk of type 2 diabetes:  a systematic review and meta-analysis.  JAMA.  
2006;295(11):1288-99.
89.
Kapoor D, Aldred H, Clark S, Channer KS, et al.  Clinical and biochemical 
assessment of hypogonadism in men with type 2 diabetes:  correlations with 
bioavailable testosterone and visceral adiposity.  Diabetes Care.  2007;30(4):911-7.
90.
Lakshman, KM, Bhasin S, Araujo AB.  Sex hormone-binding globulin as an 
independent predictor of incident type 2 diabetes mellitus in men.  J Gerontol A 
Biol Sci Med Sci.  2010;65(5):503-9.
91.
Woodhouse LJ, Gupta N, Bhasin M, et al.  Dose-dependent effects of testosterone 
on regional adipose tissue distribution in healthy young men.  J Clin Endocrinol 
Metab.  2004;89(2):718-26.
92.
Allan CA, Strauss BJ, Burger HG, et al.  Testosterone therapy prevents gain in 
visceral adipose tissue and loss of skeletal muscle in nonobese aging men.  J. Clin 
Endocrinol Metab.  2008;93(1):139-46.
93.
Mårin P, Oden B, Bjorntorp P.  Assimilation and mobilization of triglycerides in 
subcutaneous abdominal and femoral adipose tissue in vivo in men:  effects of 
androgens.  J Clin Endocrinol Metab.  1995;80(1):239-43.
 

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94.
Mauras N, Hayes V, Welch S, et al.  Testosterone deficiency in young men:  
marked alterations in whole body protein kinetics, strength, and adiposity.  J Clin 
Endocrinol Metab.  1998;83(6):1886-92.
95.
Haffner SM, Shaten J, Stern MP, et al.  Low levels of sex hormone-binding 
globulin and testosterone predict the development of non-insulin-dependent 
diabetes mellitus in men.  MRFIT Research Group.  Multiple Risk Factor 
Intervention Trial.  Am J Epidemiol.  1996;143(9):889-97.
96.
Keating NL, O'Malley AJ, Smith, et al.  Diabetes and cardiovascular disease during
androgen deprivation for prostate cancer.  J Clin Oncol.  2006;24(27):4448-56.
97.
Dhindsa S, Ghanim H, Batra M, et al.  Insulin resistance and inflammation in 
hypogonadotropic hypogonadism and their reduction after testosterone replacement 
in men with type 2 diabetes.  Diabetes Care.  2016;39(1):82-91.
 

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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by the Testosterone Replacement Therapy (TRT) 
Manufacturers Consortium are subject to the Good Clinical Practices (GCP) and local 
regulations and guidelines governing the study at the site location.  In signing the 
Investigator Agreement in Section 14.0 of this protocol, the investigator is agreeing to the 
following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie or their designee, except when 
necessary to protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie or their 
designee and/or the appropriate regulatory agency, and retaining all study-related 
documents until notification from AbbVie.
 

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8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 

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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Data and Statistical Sciences
Clinical Program Development
 

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Appendix C.
Study Activities
Months (Weeks) 
Visit Windows
Week 2 ± 4 Days, Month 1, 
Month 3 ± 7 Days
Month 6 ± 14 Days
All Subsequent Visits 
± 21 Days
Visits Timing Based on Time 
Elapsed from Baseline
SV1
SV2
SV3
D1 (Baseline)
W 2
M 1 W 4*
M 3 W 12 
M 6 W 26
M 9 W 39 (phone)
M 12 W 52 (year 1)
M 15 W 65 (phone)
M 18 W 78
M 21 W 90 (phone)
M 24 W 104 (year 2)
M 27 W 116 (phone)
M 30 W 130
M 33 W 142 (phone)
M 36 W 156 (year 3)
M 39 W 168 (phone)
M 42 W 182
M 45 W 194 (phone)
M 48 W 208 (year 4)
M 51 W 220 (phone)
M 54 W 234
M 57 W 246 (phone)
M 60 W 260/FV 
(Year 5)
PD
Unscheduled
30-Day Call
INTERVIEWS & QUESTIONNAIRES
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
X
CV Risk Assessmenta
X
Medical/Surgical 
History/Cancer History/CV 
Family History
X
X
Alcohol and Nicotine Use
X
AE Recordingb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior/Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Site Endpoint Questionnaire 
Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
X
X
X
X
X
Modified Rankin Scalec
X
 

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Months (Weeks) 
Visit Windows
Week 2 ± 4 Days, Month 1, 
Month 3 ± 7 Days
Month 6 ± 14 Days
All Subsequent Visits 
± 21 Days
Visits Timing Based on Time 
Elapsed from Baseline
SV1
SV2
SV3
D1 (Baseline)
W 2
M 1 W 4*
M 3 W 12 
M 6 W 26
M 9 W 39 (phone)
M 12 W 52 (year 1)
M 15 W 65 (phone)
M 18 W 78
M 21 W 90 (phone)
M 24 W 104 (year 2)
M 27 W 116 (phone)
M 30 W 130
M 33 W 142 (phone)
M 36 W 156 (year 3)
M 39 W 168 (phone)
M 42 W 182
M 45 W 194 (phone)
M 48 W 208 (year 4)
M 51 W 220 (phone)
M 54 W 234
M 57 W 246 (phone)
M 60 W 260/FV 
(Year 5)
PD
Unscheduled
30-Day Call
PRO
I-PSSd
X
X
X
X
X
X
X
DISF – SRII Section Ie
X
HIS-Q 
X
X
X
X
X
X
PHQ-9
X
PGI-I Hypogonadism
X
X
X
X
EXAM
Height & BMI, Weight 
Xf
X
X
X
X
X
X
X
X
Physical Examination
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg Xg
DRE
Xh
Xi
Xi
Xi
Xi
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
CENTRAL LABS
Testosteronej
X
X
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
X
X
X
Free Testosterone 
Xl
Xl
X
DHT, Estradiol
X
X
X
X
X
PSA
Xm
X
Xn
X
Xn
X
Xn
Xn
X
 

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Months (Weeks) 
Visit Windows
Week 2 ± 4 Days, Month 1, 
Month 3 ± 7 Days
Month 6 ± 14 Days
All Subsequent Visits 
± 21 Days
Visits Timing Based on Time 
Elapsed from Baseline
SV1
SV2
SV3
D1 (Baseline)
W 2
M 1 W 4*
M 3 W 12 
M 6 W 26
M 9 W 39 (phone)
M 12 W 52 (year 1)
M 15 W 65 (phone)
M 18 W 78
M 21 W 90 (phone)
M 24 W 104 (year 2)
M 27 W 116 (phone)
M 30 W 130
M 33 W 142 (phone)
M 36 W 156 (year 3)
M 39 W 168 (phone)
M 42 W 182
M 45 W 194 (phone)
M 48 W 208 (year 4)
M 51 W 220 (phone)
M 54 W 234
M 57 W 246 (phone)
M 60 W 260/FV 
(Year 5)
PD
Unscheduled
30-Day Call
Hematology
X
X
X
X
X
X
X
X
X
X
X
HbA1c 
X
X
X
X
X
X
X
X
Fasting Glucose
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
Urinalysis
X
X
X
X
hsCRP
X
Serum Creatinine (eGFR 
assessment) (CKP-EPI 
equation)
X
X
X
TREATMENT
Randomizationo
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Compliance Check 
& Discussion
X
X
X
X
X
X
X
X
X
X
X
X
X
X
*
Week 4/Month 1 Visit should be scheduled to occur about 10 days after the Week 2 visit to allow for testosterone to be resulted for titration.  If the subject has not been on the 
Week 2 titrated dose prior to his scheduled Week 4/Month 1 Visit, the visit should be rescheduled.
a.
CV risk should be initially assessed at SV1 and confirmed at SV2.  It will be necessary to ask the subject about nicotine use to fully assess his CV risk (see Table 2).
b.
Record AEs as described in Section 6.0. 
 

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c.
The Modified Rankin Scale (Appendix P) will be administered to subject or subject representative at initial report of event and approximately 90 days following a reported 
stroke or TIA.  This may be administered via telephone or in-person.  
d.
I-PSS greater than 19 is ONLY exclusionary at SV2.
e.
Subjects with a DISF – SRII Section I ≤ 20 at SV2 (Appendix G) and consented to participation in the sexual function sub-study (Appendix O) need to complete the 7-day 
PDQ Question 4 (Appendix K) prior to Baseline (Day 1) Visit.
f.
Height is only collected during the Screening Period to calculate BMI.  BMI is only calculated during the Screening Period for the purpose of establishing a subject's 
eligibility (Section 5.2.2).  Weight is collected at all visits as indicated.
g.
All physical exams following Screening will be problem-focused/directed rather than full physical exams.
h.
DREs performed outside the site within 6 months of SV1 are permitted as long as written documentation of the DRE result is provided.
i.
DREs performed outside the site within ± 2 months of a protocol scheduled DRE are permitted as long as written documentation of the DRE result is provided.  
j.
Starting at SV2, serum testosterone samples should be drawn fasting.  All screening serum testosterone samples will be collected between the hours of 5 AM and 11 AM.   
k.
Visits where study drug dose may be titrated.
l.
Free testosterone will only be resulted from either SV2 or SV3 in subjects who are eligible for the study.
m.
PSA will only be evaluated in subjects with testosterone levels < 300 ng/dL at SV1.
n.
Blood draws assessing PSA should always be made prior to DRE, as prostate manipulation can falsely elevate PSA.
o.
Only if all eligibility criteria are met.
 

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Appendix E.
Site Endpoint Questionnaire Form Example
These forms represent content only.  This form will be completed by the site.
Visit Form (Subject to Be Queried at Each Phone and In-Person Visit)
If any question is answered yes, the associated event should be entered on the AE CRF 
using the diagnosis, if known.
Since the Last Visit…
Yes
No
Visit Not Done
Did Subject Die? 
Did Subject experience a Myocardial Infarction or Hospitalized for 
Unstable Angina?
Did Subject have a Coronary Revascularization procedure attempted?
Did Subject have a Peripheral Revascularization Procedure attempted?
Did Subject have unplanned Urgent Visit or Hospitalization for Heart 
Failure?
Did Subject experience a TIA or Stroke?
Did Subject experience a Thromboembolic event (to include deep vein 
thrombosis, pulmonary embolus and other thromboembolic events)?  
Note:  Does not include superficial thrombophlebitis
Has the Subject had a PSA (Outside of the study)?
Has the Subject had a DRE (Outside of the study)?
Did the Subject have a Prostate Biopsy?
Has the Subject been diagnosed with Prostate Cancer?
Has the Subject been diagnosed with any other cancer besides Prostate 
Cancer?
Did the Subject have an episode of inability to Pass Urine?*
If so, was a catheter placed in the urinary bladder?
Did this episode require a visit to the emergency room or a hospital?
Was any prostate procedure done?
Has Subject been started on new medication for Prostate Enlargement or 
Lower Urinary Tract symptoms?
Has the Subject been diagnosed by a doctor or medical professional with 
a Fracture or Broken Bone?
Has the Subject been diagnosed by a doctor or medical professional with 
Diabetes (new or worsening)?
*
If one of these questions is answered 'YES,' the event should be reported on the endpoint form of Acute Urinary 
Retention/Invasive Prostate Procedure for BPH.
 

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Appendix F.
International Prostate Symptom Score (I-PSS) Example
INTERNATIONAL-PROSTATE SYMPTOM SCORE (I-PSS)
Not at all
Less 
Than 
1 Time 
in 5
Less 
Than 
Half the 
Time
About Half 
the Time
More Than 
Half the 
Time
Almost 
Always
1.  Over the past 
month, how often 
have you had a 
sensation of not 
emptying your 
bladder 
completely after 
you finished 
urinating?
0
1
2
3
4
5
2.  Over the past 
month, how often 
have you had to 
urinate again less 
than 2 hours after 
you finished 
urinating?
0
1
2
3
4
5
3.  Over the past 
month, how often 
have you found 
you stopped and 
started again 
several times 
when you 
urinated?
0
1
2
3
4
5
4.  Over the past 
month, how often 
have you found it 
difficult to 
postpone 
urination?
0
1
2
3
4
5
5.  Over the past 
month, how often 
have you had a 
weak urinary 
stream?
0
1
2
3
4
5
6.  Over the past 
month, how often 
have you had to 
push or strain to 
begin urination?
0
1
2
3
4
5
 

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INTERNATIONAL-PROSTATE SYMPTOM SCORE (I-PSS)
Not at all
Less 
Than 
1 Time 
in 5
Less 
Than 
Half the 
Time
About Half 
the Time
More Than 
Half the 
Time
Almost 
Always
None
1 time
2 times
3 times
4 times
5 or more 
times
7.  Over the past 
month, how many 
times did you 
most typically get 
up to urinate from 
the time you went 
to bed at night 
until the time you 
got up in the 
morning?
0
1
2
3
4
5
Total I-PSS Score S =
QUALITY OF LIFE DUE TO URINARY SYMPTOMS
Delighted
Pleased
Mostly 
Satisfied
Mixed 
About 
Equally 
Satisfied and 
Dissatisfied
Mostly 
Dissatisfied
Unhappy
Terrible
1.  If you were to 
spend the rest of 
your life with 
your urinary 
condition just the 
way it is now, 
how would you 
feel about that?
0
1
2
3
4
5
6
Quality of life assessment index L =
 

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Appendix G.
DeRogatis Interview for Sexual Function – Male (DISF – SR II)©
Example
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
  
  
 
  
  
  
 
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix H.
Hypogonadism Impact of Symptoms Questionnaire (HIS – Q) 
Example
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix I.
Patient Global Index of Improvement (PGI – I) Example
All Subjects (PGI-Hypogonadism)
Hypogonadism/overall global impression "Since the start of this study, I feel ______"
[very much better, much better, a little better, no change, a little worse, much worse, very 
much worse]
Sexual Function Sub-Study Only (PGI-Libido)
Libido – "Since the start of this study, my libido (sexual desire) is _______"
[very much improved; much improved; a little improved; unchanged; a little worse; much 
worse; very much worse]
Persistent Depressive Disorder (PDD) Sub-Study Only (PGI-Mood)
Depression – "Since the start of this study, my mood is _______"
[very much improved; much improved; a little improved; unchanged; a little worse; much 
worse; very much worse]
 

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Appendix J.
International Index of Erectile Function (IIEF-5) Example
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix K.
Psychosexual Daily Questionnaire (PDQ) Question 4 Example
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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Appendix L.
Patient Health Questionnaire-9 (PHQ-9) Example
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix M.
Geriatric Depression Scale (GDS-15) Example
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 

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Appendix N.
Additional Persistent Depressive Disorder (PDD) Sub-Study 
Questions – Example
Baseline Questions administered only to men meeting PHQ-9 criteria for further PDD 
sub-study eligibility consideration outlined in Appendix O:
●
Do you have any history of a major depressive episode?  Must be NO for 
enrollment in PDD sub-study
●
Have you had any mood disorder prior to age 40?  Must be NO for enrollment 
in PDD sub-study
●
Have you been treated for a mood disorder for longer than 6 months 
(e.g., antidepressant medication, psychotherapy)?  Must be NO for enrollment 
in PDD sub-study
Q1:  Given your best guess: over the past 2 years, have you been feeling sad or depressed 
more days than not even if you felt ok sometimes?  Must be YES for enrollment in PDD 
sub-study
Q2:  Again, given your best guess, over the past 2 years can you remember a period of 
time lasting 2 months or more when you were not feeling depressed much of the time?  
Must be NO for enrollment in PDD sub-study
Q3:  Again, given your best guess, how old were you when you were last feeling okay, 
that is, not feeling depressed most days?  Must be ≥ 40 years of age for enrollment in 
PDD sub-study
Q4:  Have you ever been diagnosed by a doctor or mental health professional with a major 
depressive disorder or with bipolar disorder?  Must be NO for enrollment in PDD sub-
study
Q5:  Have you ever felt so bad that you sought help from a mental health professional and 
had psychotherapy for more than 6 months?  Must be NO for enrollment in PDD sub-
study
 

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Q6:  Have you ever been prescribed an antidepressant for a mood problem, and took it for 
more than 6 months?  Must be NO for enrollment in PDD sub-study
Q7:  Have you ever felt so bad that you attempted suicide?  Must be NO for enrollment in 
PDD sub-study
After Baseline, the following question will be asked of men enrolled in the PDD 
sub-study in addition to the questionnaires that subjects answer as part of the study
"Give your best guess:  Over the past 6 months, have you been feeling sad or depressed 
more days than not even if you felt okay sometimes?"
 

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Appendix O.
Sub-Studies and Sub-Population Analyses for Sexual Function, 
Persistent Depressive Disorder (PDD), Bone Fracture, Anemia and 
Diabetes
This section details the sub-studies, including the method of sub-population analyses, of 
five conditions in hypogonadal men that may benefit from TRT.  As the impact of 
testosterone treatment on the incidence of fracture will be tested, all subjects participating 
in TRAVERSE will be asked if they experience a fracture throughout the study, and will 
be asked to supply source documents of the fracture for adjudication.  Subjects with 
anemia or pre-diabetes at Baseline constitute sub-populations, which will be analyzed for 
resolution of anemia or slowing the progression to diabetes, respectively, based on 
analyses of laboratory data performed during the main study (e.g., Hgb, HbA1C, fasting 
glucose).  The sexual function and PDD sub-studies of qualified participants will include 
additional ePRO questionnaires to be completed by the subjects during the study.  To 
participate in one or more sub-studies, subjects must meet the eligibility criteria for that 
particular sub-study (detailed below).  Subjects may participate in any or all of the sub-
studies for which they are eligible.  Subjects who are eligible for the main study but do 
not meet the eligibility criteria for a sub-study will only participate in the main study.
1. Sexual Function Sub-Study
The sexual function sub-study will require additional ePRO questionnaires to be 
completed by the subjects who meet the eligibility criteria as shown below.  If subjects 
complete less than 4 of 7 days (e.g., Day –7 to Day –1) for the Baseline (Day 1) PDQ 
assessment, then they will be discontinued from the Sexual Function Sub-Study.
Background
Sexual symptoms are the most common reason that motivates men to seek testosterone 
treatment.  Yet, there are limited data on the efficacy of TRT in improving sexual function 
in men with age-related decline in circulating testosterone.  A recent randomized study 
reported greater improvements in sex drive and energy with 12 weeks of TRT versus 
placebo in hypogonadal men ages 19 to 80 years.32  The sexual function study of the 
 

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T-Trials reported improvements in sexual desire, erectile function and sexual activity in 
men 65 years or older with low libido and low serum testosterone.32,57  Since the T-Trials 
did not study men less than 65 years of age, it is important to determine the benefits on 
sexual function of TRT in middle-aged men, and whether the benefits in older men 
observed previously are durable over time and whether these benefits can be seen in men 
with CV disease and CV risk who are at higher risk of having sexual symptoms.  
Accordingly, the sexual function sub-study will determine the efficacy of TRT in 
improving sexual activity and function in middle-aged and older hypogonadal men with 
low libido who have increased CV risk and will determine the durability of treatment 
effect beyond the first year of intervention.
Objective
This sub-study will examine whether TRT (relative to placebo) improves overall sexual 
activity, sexual desire, and erectile function (change from Baseline in ePRO).
Eligibility
Inclusion Criteria
●
Low libido ascertained by DeRogatis Interview for Sexual Function-Male 
(DISF-SRII)47 Section I score ≤ 20 at SV2
●
Willingness to participate in the sexual function sub-study
Efficacy Variables
Sexual function sub-study will include subjects who have low libido, as indicated by 
DISF-SRII Section I score ≤ 20 at Baseline (collected SV2).
Endpoints all pertain to middle-aged and older men with low libido, and include:
●
Determine whether TRT for 1 year improves overall sexual activity, using 
Question 4 of the PDQ, more than placebo (Main analysis variable).
●
Determine whether TRT for 1 year improves sexual desire, using the libido 
domain of HIS-Q instrument, more than placebo.
 

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●
Determine whether TRT for 1 year improves erectile function, using the 
erectile function domain of the IIEF, more than placebo.
●
Determine whether improvements in sexual activity, sexual desire, and erectile 
function over 1 year are maintained after 2 years of TRT versus placebo.
●
Exploratory endpoint:  Compare the effect of TRT versus placebo therapy on 
patient global impression of change in sexual function using a patient global 
impression of change (PGI-I Libido) question.
Additional Sexual Function Sub-Study Activities
Months (Weeks)
Visit Windows
Day 1 ± 4 Days,
Month 6 ± 14 Days
All Subsequent Visits 
± 21 Days
Visits Timing Based 
on Time Elapsed from 
Baseline
7 Consecutive Days 
Prior to 
Day 1
D1
M 6 
W 26
M 12 
W 52
M 24 
W 104
M 60 W 
260/FV 
(Year 5)
PD
IIEF-5 
X
X
X
PDQ Question 4a
X
X
X
X
PGI-I Libido
X
X
X
X
a.
Subjects meeting the inclusion criteria for sexual function sub-study following SV2 (above) need to complete the 
7-day PDQ Question 4 (Appendix K) prior to Day 1 Visit (Baseline).
2. Persistent Depressive Disorder (PDD) Sub-Study
The PDD sub-study will require additional ePRO questionnaires to be completed by the 
subjects who meet the eligibility criteria as shown below.
Background
Epidemiologic evidence shows that,58,59 mid-life, low grade depression (dysthymia or 
PDD) is associated with low testosterone in men.  Studies investigating the impact of 
testosterone therapy have not observed improvement in men with major depressive 
disorder (MDD),60 but other studies have observed that testosterone therapy can improve 
 

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depressive (dysthymia or PDD) symptoms in men with low-grade, mid-life-onset 
PDD.61-63  
This sub-study will examine whether TRT (relative to placebo) improves depressive 
symptoms in men with low-grade, mid-life-onset PDD.
Eligibility
Inclusion Criteria
●
Willingness to participate in the PDD sub-study
Inclusion criteria for the PDD ("depression") sub-study include men who meet any of the 
below PHQ-9 criteria from SV2:
●
Total PHQ-9 score > 4
●
PHQ-9 Item 2 score of 1 or 2
●
PHQ-9 Item 10 score of > 0
Additionally, men must not meet any of the below PHQ-9 criteria from SV2:
●
Total PHQ-9 score > 15
●
PHQ-9 Items 1 or 2 score of 3
●
PHQ-9 Item 9 score of > 0
If subjects do not complete (i.e., partially or not at all) the PHQ-9 at Screening and/or 
GDS questionnaires with related depressive questions at Baseline, then they will be 
discontinued from the PDD Sub-study.
ePRO tablet programming will identify men that meet the above preliminary PHQ-9 
depression sub-study eligibility criteria from SV2. At the Baseline Visit, these men will 
then be asked additional eligibility questions (Appendix N) to assess their eligibility for 
the PDD sub-study via the PRO tablet based on questions (Appendix N) adapted from the 
 

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diagnosis of PDD as described in Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5)64 criteria for PDD with low-grade symptoms.
Finally, men who are still eligible via the above criteria will be asked to take the GDS-15 
questionnaire.  Men with GDS-15 (Appendix M) scores between 5 – 9 will then be 
entered into the PDD sub-study.
If subjects respond to any of the above questions in a way that makes them ineligible for 
the PDD sub-study, the tablet will skip the remainder of the questions related to PDD sub-
study eligibility.
Exclusion Criteria 
●
Lifetime history of any major depressive episode  
●
Onset of any mood disorder prior to age 40 years
●
History of treatment for a mood disorder longer than 6 months 
(e.g., antidepressant medication, psychotherapy) 
●
History of a suicide attempt
Efficacy Variables
The remission of low-grade, late-onset PDD will be defined by both of the following 
criteria: (Main analysis variable)
a.
GDS-15 < 5
AND
b. Response to the question:  "Over the past 6 months, have you been feeling sad or 
depressed more days than not even if you felt okay sometimes?" = no
The primary analyses will compare the proportion of men with low grade PDD at 
Baseline who go into remission in the placebo and testosterone arms.
●
Other analyses will include: 
 

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○
Changes in depression symptom scores using PHQ-9, GDS-15 and HIS-Q 
(Mood domain)
○
Proportion of men achieving remission at 12 months who remain in 
remission at 24 months
Additional PDD Sub-Study Activities
Months (Weeks)
Visit Windows
Day 1 ± 4 Days
Month 6 ± 14 Days
All Subsequent Visits ± 21 Days
Visits Timing Based on Time 
Elapsed from Baseline
D1
M 6 
W26
M 12 
W 52
M 18 
W 78
M 24 
W 104
M 60 W 
260/FV 
(Year 5)
PD
PHQ-9
X
X
X
X
Additional Persistent Depressive 
Disorder (PDD) Questions
X
X
X
X
GDS
X
X
X
X
PGI-I Mood
X
X
X
X
Discontinuation from Study 
Subjects at risk of suicide as indicated by a response greater than 0 on Question 9 of any 
post Baseline PHQ-9 and/or determined by the Investigator to be at risk of suicide should 
be discontinued from participation in the study and referred for appropriate follow-up care 
(Section 5.4.1).
3. Bone Fracture Sub-Study (Analysis Only)
Subjects will be asked whether or not they experienced a fracture since their last visit at 
every in-person and telephone study visit.  The subjects who report fractures during the 
study will be asked to provide all documentation of the fractures so that the events can be 
adjudicated.  The adjudicated events will be analyzed to compare the incidences of 
fracture in subjects on TRT versus placebo.
 

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Background
Approximately 30% of fractures occur in men, and mortality after a fracture is higher in 
men than in women.65-67  Although, age alone is likely an important cause of fractures in 
men, evidence suggests that hypogonadism associated with age is also an important 
cause.68  Testosterone treatment improves bone structure and strength of severely 
hypogonadal men,69-73 but testosterone treatment also improves bone structure and 
strength in older men with low testosterone due to aging alone.73  In the T-Trial bone sub-
study, testosterone treatment for 1 year improved volumetric BMD of whole bone in the 
spine by 4.2% more than placebo (P < 0.001) and in the hip by 1.3% more than placebo 
(P < 0.001).  This treatment also improved whole bone strength, as estimated by finite 
element analysis, by 7.1% (P < 0.001) in the spine and 1.8% (P < 0.001) in the hip more 
than placebo.73  In the TRAVERSE study, we will assess the impact of testosterone on the 
incidence of clinical fractures in men with CV disease and men with CV risk factors.
Objective
This sub-study will examine the effect of TRT (relative to placebo) on incidence rate of 
adjudicated clinical bone fractures.
Efficacy Variable
Determine if the incidence of clinical fracture, confirmed by adjudication, is reduced in 
subjects treated with TRT versus placebo.  Secondary fracture outcomes will be non-spine 
clinical fractures and hip fractures.
4. Anemia Sub-Study (Analysis Only)
Subjects must meet the eligibility criteria as described below in order to qualify for this 
sub-study. 
Background
The prevalence of anemia rises with advancing age, affecting approximately 10 – 12% of 
men > 65 years old and 20 – 30% in men > 85 years old, and is often associated with 
 

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diminished physical function.37,74-83  Unexplained anemia of aging is characterized by a 
decrease in circulating hemoglobin (usually between 10.0 to 12.7 g/dL) with normocytic 
red cell indices.  The pathophysiology is multifactorial, with low testosterone levels being 
implicated81,84 along with other factors.  Testosterone is known to increase Hgb and Hct 
through various mechanisms, including stimulation of erythropoietin secretion, increased 
sensitivity to erythropoietin, and increased iron availability through suppression of 
hepcidin.  Therefore, this large prospective study aims to determine the efficacy of 
testosterone therapy in correcting anemia in hypogonadal men with Hgb values below 
12.7 g/dL at Baseline.
Objective
This sub-study will examine the efficacy of TRT (relative to placebo) in correcting 
anemia in middle-aged and older hypogonadal men.
Eligibility
Inclusion Criterion
●
Hgb level ≥ 10 g/dL and < 12.7 g/dL
Exclusion Criterion
●
The use of any other erythropoietic stimulating agents, such as erythropoietin 
Efficacy Variables
Randomized subjects with a Hgb of < 12.7 g/dL at Baseline will be evaluated for 
outcomes of interest, including:
●
The proportion of men who have anemia at Baseline but who are no longer 
anemic (Main analysis variable)
●
The proportion of men with anemia at Baseline whose Hgb increases by more 
than 1 g/dL
 

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●
Exploration of possible relationship between improvement in anemia and 
change in energy domain score and the cognition domain score of HIS-Q 
[complete blood count (CBC) and HIS-Q are obtained throughout the parent 
study]
5. Diabetes Sub-Study (Analysis Only)
Subjects must meet the eligibility criteria as described below in order to qualify for this 
sub-study.  
Background
TRT may retard progression from pre-diabetes to diabetes with studies showing that 
testosterone supplementation in middle-aged men with truncal obesity and low-normal 
testosterone levels is associated with a reduction in visceral fat volume, serum glucose 
concentration, and an improvement in insulin sensitivity.42-45, 85-95  Use of long acting 
gonadotropin-releasing hormone (GnRH) agonists which inhibit testosterone to castrate 
levels increase fat mass in young men94 and increase the risk of diabetes and CV disease 
when given to men for prostate cancer.96  While the effects of testosterone on insulin 
sensitivity are mostly clear,97 the effects of testosterone on improving HbA1c in diabetes 
are inconsistant.36  The TRAVERSE study provides a clear opportunity to determine the 
effects of TRT on progression from pre-diabetes to diabetes given its extended duration 
and large sample size.
Objective
This sub-study will examine whether TRT (relative to placebo) is associated with a lower 
rate of progression to Type 2 diabetes mellitus in middle-aged and older hypogonadal men 
with pre-diabetes.
 

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Eligibility
Inclusion Criterion
●
A diagnosis of pre-diabetes, based on HbA1C level between 5.7 and 6.4%, 
inclusive or two fasting glucose levels between 100 and 125 g/dL, inclusive
Exclusion Criterion
●
A diagnosis of diabetes or use of diabetes medication at Baseline
●
HbA1c ≥ 6.5% at Screening 
●
Fasting glucose > 125 g/dL at Screening or Baseline Visit
Efficacy Variable
The proportion of enrolled subjects in each arm with pre-diabetes at Baseline who 
progress to diabetes, defined as HbA1c ≥ 6.5%, initiation of diabetes medication, or 
two fasting glucose levels > 125 mg/dL.
 

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Appendix P.
Modified Rankin Scale
Scale
Disability
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and activities
2
Slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6
Dead
 

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Appendix Q.
Coronary Artery Disease Definition
This appendix is to clarify for study investigators and study coordinators the entry 
criterion of coronary disease through evidence of percentage stenosis by angiogram from 
Table 1 (Pre-Existing CV Disease).
Coronary artery-specific considerations:
●
The typical coronary anatomy consists of the left main artery (LM) arising 
from the left coronary sinus and the right coronary artery (RCA) arising 
separately from the right coronary sinus.  The left main gives rise to the left 
anterior descending (LAD) and left circumflex (LCX) arteries.  Because the 
LM supplies the LCX and LAD, a stenosis (blockage) in the LM will count as 
the two artery distributions required for the criteria.  
●
The LAD and LCX also have branches.  The branches from the LCX are 
termed obtuse marginal (OM) or lateral (including "posterolateral") branches 
and the ramus intermedius.  The branches from the LAD are termed diagonal 
and septal branches.  Obstruction of one of these branch vessels will be 
considered as qualifying as a stenosis in that coronary distribution.  
●
"Right dominance" – The RCA, courses around the right side of the heart and 
usually gives off a posterior descending artery (PDA) that runs down the back 
of the heart between the ventricles.  In most patients, the PDA arises from the 
RCA (termed "right dominance").  
●
"Left dominance" – In approximately 10% of patients, the PDA arises from the 
LCX artery (termed "left dominance").  (Thus, stenosis of the proximal LCX in 
a left-dominant system affects two arterial distributions).  In a left dominant 
circulation, the RCA is small and supplies blood to the right ventricle only, 
and is not considered a major coronary distribution. 
In order to meet this eligibility criterion, "Evidence of coronary disease (at least a 50% 
lesion in two of the major coronary artery distributions including their branches) as 
documented by angiogram" one of the following must be present:
●
stenosis in the LM coronary artery
 

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●
in a right dominant system (see above), stenoses in any two of the three major 
arteries (LCX, LAD, or RCA) including branches of those arteries
●
in a left dominant system (see above):  any one of the following:
○
stenoses in the LAD (or branches) AND LCX (or branches)
○
stenosis in the proximal LCX
○
stenoses in the ramus intermedius or an OM branch AND in the distal LCX 
or PDA
 

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Figure 3.
Right-Dominant and Left-Dominant Circulations 
Key
D:  Diagonal
LAD:  Left Anterior Descending
LCX:  Left Circumflex Artery
LM:  Left Main
OM:  Obtuse Marginal
PDA:  Posterior Descending Artery
RCA:  Right Coronary Artery
RI:  Ramus Intermedius
S:  Septal