Conditions: Hypogonadism Hypogonadism, Male Hypogonadotropic Hypogonadism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 673
Healthy volunteers: no

Brief summary:
Testosterone is the principal androgen produced by the male testes. Male Hypogonadism is the result of inadequate production of testosterone by the Leydig cells of the testes and is reflected by total serum concentrations of testosterone of \< 300 nanograms (ng)/deciliters (dL), with no discernible diurnal pattern. The etiology of hypogonadism may be primary or secondary. The treatment of males with primary, and in some cases, secondary hypogonadism includes administration of testosterone.

Testim® and Fortesta® are topical gels that when applied daily help to increase the total testosterone levels in the blood through skin absorption. Aveed® is an injectable form of testosterone treatment and participants randomized to this treatment arm will receive 3 injections over the course of 16 weeks.

This study is designed to evaluate the effect on blood pressure of approved testosterone products (Testim®, Fortesta®, and Aveed®) after 16 weeks of therapy using 24-hour ambulatory blood pressure to reveal shifts in blood pressure levels.

Detailed description:

Arms:
arm 1: Fixed dosage level of 750 milligrams (mg)/3 milliliters (mL) administered by intramuscular injections. arm 2: 40 mg once daily topical gel administration. arm 3: 50 mg once daily topical gel administration.

Interventions: intervention 1: Aveed Injectable Product intervention 2: Fortesta intervention 3: Testim
Intervention descriptions: intervention 1: Testosterone undecanoate administered by intramuscular injections. intervention 2: Testosterone gel administered topically. The daily dose of the study drug will be titrated for each participant, according to approved dosage and administration instructions, until the circulating testosterone concentrations of the participant reaches normal concentrations (300-1000 ng/dL). intervention 3: Testosterone gel administered topically. The daily dose of the study drug will be titrated for each participant, according to approved dosage and administration instructions, until the circulating testosterone concentrations of the participant reaches normal concentrations (300-1000 ng/dL).

Protocol document:
Prot_000.pdf: 
 
 
Endo Pharmaceuticals Inc. 
1400 Atwater Drive 
Malvern, PA 19355 USA 
PROTOCOL NUMBER: EN3000-101 
AN OPEN-LABEL, RANDOMIZED, PARALLEL-GROUP, 
THREE TREATMENT ARM, MULTICENTER STUDY ON 
HYPOGONADAL MALES TO EVALUATE THE EFFECT ON 
24-HOUR AMBULATORY BLOOD PRESSURE AFTER
16-WEEK CONTINUOUS TREATMENT WITH MARKETED
TESTOSTERONE PRODUCTS 
IND 072297: EN3331 (AVEED®) 
IND 076634: EN3350 (FORTESTA®) 
IND 061307*: EN3834 (TESTIM®) 
*Auxilium Pharmaceuticals, LLC (Auxilium; formerly Auxilium Pharmaceuticals, Inc.) was
acquired by Endo International plc in January 2015. The sponsor of the application remains
Auxilium; however, Endo Pharmaceuticals Inc. (Endo) is authorized to act and to communicate
on behalf of Auxilium. The sponsor is responsible for the conduct of the study, analysis of the
data, and preparation of the clinical study report.
Original Protocol: 17 November 2019 
Protocol Amendment 1: 19 March 2020 
Protocol Amendment 2: 15 September 2020 
Protocol Amendment 3: 28 September 2021 
Protocol Amendment 4: 28 February 2022 
.  
NCT #: NCT04456296 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Overall Rationale for the Amendment 4 
The inclusion of reserve samples was removed from Section 8.1.1 and the sample size was 
decreased.  
Minor changes throughout the protocol amendment included wording changes for clarity, 
correction of minor typographical errors and revision of abbreviations. 
Major changes are listed below. 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schedule of 
Activities, Table 1 - Testim 
and Fortesta 
Section 4.1.5.1 Testim and 
Fortesta Treatment Arm 
Added visit windows of ±3 days to the 
Days 113 and EOS Day 114 visits.  
Removed visit window from the 
EOS/ET heading and included the 
windows with visits as required. 
Section 1.2 Schedule of 
Activities, Table 2 - Aveed 
Section 4.1.5.2 Aveed 
Treatment Arm 
Added visit windows of ±3 days to the 
Days 106 and EOS Days 107 visits. 
Removed visit window from the 
EOS/ET heading and included the 
windows with visits as applicable. 
Section 1.2 Schedule of 
Activities, Table 1Testim 
and Fortesta 
Inserted footnote ‘c’ indicating that 
testosterone values collected at 
Screening will be used for evaluating 
study inclusion.  
To provide clarification that Day -1 
testosterone laboratory values are not 
available or needed for Day 1 eligiblity 
assessments.  
Section 1.2 Schedule of 
Acitivities, Table 2 Aveed 
Inserted footnote ‘d’ indicating that 
testosterone values collected at 
Screening will be used for evaluating 
study inclusion. 
To provide clarification that Day -1 
testosterone laboratory values are not 
available or needed for Day 1 eligiblity 
assessments. 
Section 4.1 Overall design 
and Synopsis 
Added that 618 subjects will be enrolled 
in 3 treatment groups. 
Consistency with modified sample size. 
Section 5.2 Subject 
Exclusion Criterion, #3 
Deleted > 5 years when defining stable 
disease. Removed reference to 
oncologic. 
Deletion of  > 5 years applied to clarify 
that stable disease is at the discretion of 
the investigator rather than for > 5 
years. Removed oncologic since this is 
detailed in exclusion criterion 8b. 
Section 5.2 Subject 
Exclusion Criterion, #8.b  
Clarified the exclusion criteria to 
include cancer or a previous history of 
cancer or relapse of cancer within the 
previous 5 years. 
Allows PI to determine appropriateness 
of subject for inclusion in study. The 
Prescribing Information  indicates that 
carcinoma of the prostate and breast are 
contraindicated, not testicular cancer 
and other types of malignancies. 
Section 5.2 Subject 
Exclusion Criterion, #23 
Section 8.1.6 
Electrocardiogram 
Revised QTc to QTcF 
Updated QTc to QTcF throughout the 
protocol for consistency with the 
method of calculation described in 
Section 7.1  


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Section No. and Name 
Description of Change 
Brief Rationale 
Section 8.1.1 Serum 
Testosterone Assessment 
Removed the paragraph regarding blood 
reserve levels. 
Reserve samples will no longer be 
collected. Clarified that testosterone 
samples collected at Screening will be 
used for study inclusion. Testosterone 
samples collected at Day -1 will be used 
as a baseline for the study. 
Section 9.1 Sample Size 
Determination 
Sample size was recalculated from 243 
per group (total 729) to 206 per group 
(total 618).  
Change in sample size was derived 
from a study or oral testosterone 
decanoate (White 2021), demonstrating 
an increase in systolic blood pressure 
with standard deviation of 11. 
Section 10.1.8, Source 
Documentation 
Modified retention of source 
documentation from 2 years to 3 years. 
Align with Endo’s internal policies. 
Section 12, References 
Added reference to White 2021. 
Used to support the change in standard 
deviation from 12 to 11 referenced in  
Section 9.1  
Overall Rationale for the Amendment 3 
The inclusion of testosterone metabolites was removed from the description of laboratory testing. 
The projected date for trial completion was revised to December 2022 based on an anticipated 
enrollment of 50 subjects per month at 25 sites. 
Minor changes throughout the protocol amendment included wording changes for clarity, 
correction of minor typographical errors and revision of abbreviations. 
Major changes are listed below. 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, Study 
Period 
Date of trial completion revised to 
December 2022 
Reflects the delay in trial enrollment 
due to the Covid-19 pandemic.  
Section 7.2 Subject 
Discontinuation/Withdrawal 
from the Study 
Removed the phrase ‘except the 
collection of AE information’ from the 
last paragraph. 
Removed to reflect that once a subject 
withdraws consent, no further 
procedures can be done. 
Section 9.3.3 Serum 
Laboratory Testing 
The mention of testosterone metabolites 
was removed laboratory testing. 
Removed the mention of testosterone 
metabolites to reflect that metabolites 
were not planned to be analyzed as total 
testosterone level is being used to 
assess safety, study drug compliance 
and titration. 
Overall Rationale for the Amendment 2 
Rescreening language has been added to allow the assessments performed in the initial screen to 
be used if no more than 30 days have passed since the assessments were performed and the 
assessments are considered valid. The urine drug screen was removed as subjects were having 
positive urine drug screen results from the components of prescribed medications, (ie, Adderall 
for attention deficit disorder [ADD] showed positive for amphetamine). Exclusion criterion #21 
was modified for clarity. 


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Major changes are listed below. 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Date of first subject enrolled updated to 
June. 
 
Section 1.2 Schedule of 
Activities, Table 1 
footnote  ‘c’ 
The following text was added: 
Site personnel will ensure that the same 
arm and cuff size will be used. Vital 
signs taken will include SBP and DBP, 
pulse rate, respiratory rate, and body 
temperature. The results, date, and time 
for all vital sign assessments will be 
recorded. 
To clarify how vital signs are to be 
taken. 
Section 1.2 Schedule of 
Activities, Table 2 
footnote ‘a’ 
The following text was added: 
Subjects receiving the Aveed injection 
will have vital signs taken before 
administration of the study drug. Site 
personnel will ensure that the same arm 
and cuff size will be used. Vital signs 
taken will include SBP and DBP, pulse 
rate, respiratory rate, and body 
temperature. The results, date, and time 
for all vital sign assessments will be 
recorded. 
To clarify when vital signs are to be 
taken in relation to the study drug. 
Section 1.2 Schedule of 
Activities, Table 1 and 
Table 2  
Urine Drug Screen was removed from 
the SOA. 
Removed because some subjects had 
positive urine drug screen results from 
the components of prescribed 
medications. 
Section 1.2 Schedule of 
Activities, Table 2 
Serum testosterone footnote ‘d’ was 
moved from the Procedures column to 
the Screening Phase column. 
  
Section 1.2 Schedule of 
Activities, Table 2 
The first 24-hour ABPM was moved 
from the Return Visit – Day 2 column 
to the Visit 1 Day 1 column. 
The screening period was expanded 
from 14 days to 28 days to 
accommodate the time needed to obtain 
the results of the clinical laboratory 
testing performed.  
Section 1.2 Schedule of 
Activities, Table 1 and 
Table 2 
The heading for the Screening Phase 
was revised from ‘Day -14 to -2” to 
“Day -28 to -2.” 
Section 1.1 Synopsis 
The screening days were revised from 
“between Day -14 and -2” to “between 
Day -28 and -2.” 
Section 4.1.1 Screening  
Screening days were revised from 
“between Day -14 and -2” to “between 
Day -28 and -2.” 
Section 2.1 Study 
Rationale 
The following text was added: 
The COVID-19 public health 
emergency has disrupted the conduct of 
clinical research throughout the world. 
At Endo Pharmaceuticals Inc. (Endo), 
ensuring the safety of clinical study 
participants is our primary concern. In 
Language was developed to clarify how 
the Sponsor will proceed during the 
COVID-19 Public Health Emergency. 


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Section No. and Name 
Description of Change 
Brief Rationale 
addition, the integrity of data obtained 
from clinical trials must be ensured. 
In order to ensure subject safety and 
protect data integrity, Endo, in 
accordance with the FDA Guidance on 
Conduct of Clinical Trials of Medical 
Products during COVID-19 Public 
Health Emergency (March 2020, 
updated 02 July 2020), will allow 
virtual visits for safety assessments. 
During a potential travel 
restriction/lockdown due to COVID-19, 
subjects enrolled in the study may 
experience a delay or cancellation of 
important site visits that could impact 
serum testosterone levels and delay or 
affect the required testosterone 
replacement. To avoid any potential 
delay or disruption in the testosterone 
replacement therapy of those subjects, 
as our commitment toward every 
subject’s well-being, Endo may decide 
to temporarily delay the enrollment of 
the subjects into any of the arms of the 
protocol.  
In addition, any subjects affected by the 
health emergency will be allowed to 
continue in the study and complete 
remaining assessments when the 
investigational sites re-open as follows: 
• Subjects who started this study prior 
to a COVID-19 interruption will be 
allowed to continue in the study and 
complete all remaining assessments, if 
willing to do so in accordance with the 
scheduling outlined in Section 1.2. 
Section 5.2 Exclusion 
Criteria, Exclusion 
Criterion #21  
Was modified to:  
Has a history of substance abuse or is 
taking any substance of abuse (Note: 
subjects on a stable dose of any 
medications that have been prescribed 
by a healthcare practitioner for a 
properly documented medical condition 
are exempt). 
Subjects who were taking prescribed 
medication were having positive urine 
drug screen testing given the 
components of these medication, 
(ie, Adderall for ADD showed positive 
for amphetamine). 


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Section No. and Name 
Description of Change 
Brief Rationale 
Section 5.5 Screen Failures 
The last paragraph was deleted and 
replaced with: 
A subject who does not meet all of the 
eligibility criteria and is considered a 
screen failure may be rescreened once. 
If a subject rescreens within 30 days of 
their original screening date, 
assessments from the initial screening 
period may be used as long as they are 
considered to be valid and within 
protocol entry criteria. Any abnormal 
assessments must be repeated. The 
period from the start of rescreening 
related procedures to the study 
treatment must not exceed 28 days. 
Rescreening language has been added to 
allow the assessments performed in the 
initial screen to be used if no more than 
30 days have passed since the 
assessments were performed and the 
assessments are considered valid. 
Section 8.1 Safety 
Assessments 
The following paragraph was added: 
In order to ensure subject safety and 
protect data integrity, Endo, in 
accordance with the FDA Guidance on 
Conduct of Clinical Trials of Medical 
Products during COVID-19 Public 
Health Emergency (March 2020, 
updated 02 July 2020), will allow 
virtual visits for safety assessments. 
During a potential travel 
restriction/lockdown due to COVID-19, 
subjects enrolled in the study may 
experience a delay or cancellation of 
important site visits that could impact 
serum testosterone levels and delay or 
affect the required testosterone 
replacement. To avoid any potential 
delay or disruption in the testosterone 
replacement therapy of those subjects, 
as our commitment toward every 
subject’s well-being, Endo may decide 
to temporarily delay the enrollment of 
the subjects into any of the arms of the 
protocol. In addition, should subjects 
be affected by the health emergency, 
they will be allowed to continue in the 
study and complete remaining 
assessments when the investigational 
sites re-open. 
Language was developed to clarify how 
the Sponsor will proceed during the 
COVID-19 Public Health Emergency. 


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Section No. and Name 
Description of Change 
Brief Rationale 
Section 8.1.5 Vital Signs 
The highlighted text was added: 
Subjects receiving the Aveed 
injection will have vital signs taken 
before administration of the study 
drug. For all subjects, vital signs will 
be obtained after the subject has been 
seated for 5 minutes (minimum), with 
feet flat on the floor and back 
supported. Site personnel will ensure 
that the same arm and cuff size will be 
used. Vital signs taken will include 
SBP and DBP, pulse rate, respiratory 
rate, and body temperature. The results, 
date, and time for all vital sign 
assessments will be recorded. 
To clarify that vital signs must be taken 
before Aveed injection. 
Section 9.1 Sample Size 
Determination 
ABPM Population was changed to Full 
Analysis Set. 
Changed to clarify Sample Sets 
Section 9.2 Analysis 
Populations 
This section was updated to the 
following: 
Four analysis populations will be 
considered in the study: the Safety 
Population, the Intent-to-Treat 
Population (ITT), the Full Analysis Set 
(FAS), and the ABPM Population. 
• Safety Population: will include all 
subjects who receive at least 1 
dose/injection of study treatment. All 
safety analyses will be based on the 
Safety Population. 
• Intent-to-Treat Population: (ITT): will 
include all randomized subjects who 
have at least 1 dose/injection of study 
medication. Sensitivity analysis for 
primary and secondary efficacy 
analysis will be based on this 
population to assess the effect due to 
study discontinuation. 
• Full Analysis Set (FAS): will include 
all ITT subjects with valid baseline and 
EoS ABPM assessments, and. All 
primary and secondary efficacy 
analysis will be based on the ABPM 
Population. 
• ABPM Population: will include all 
FAS subjects with at least 85% 
compliance to treatment during the 
study. All primary and secondary 
efficacy analysis will be based on the 
ABPM Population. 
Two analysis sets were added to the 
analysis populations. 


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Section No. and Name 
Description of Change 
Brief Rationale 
Section 9.3.1.3 Sensitivity 
Analysis 
This section has been added: 
9.3.1.3. Sensitivity Analysis 
Two types of sensitivity analysis will 
be performed: 1) primary and 
secondary analysis based on ABPM 
population, 2) primary and secondary 
analysis based on ITT population to 
account for missing data due to study 
discontinuation. 
Added to clarify sensitivity analysis. 
Overall Rationale for the Amendment 1 
The primary purpose of this amendment was to separate descriptions of treatment with 
testosterone gel (Fortesta/Testim) from descriptions and procedures of treatment with 
testosterone solution for injection (Aveed). This change was to clarify both the schedule of 
treatment of study drugs and the procedures for each arm of the study. Amendment 1 was 
incorporated into the protocol on 19 March 2020.  
Minor changes throughout the protocol amendment included wording changes for clarity, 
correction of minor typographical errors and revision of abbreviations. 
Major changes are listed below. 
Section No. and Name 
Description of Change 
Brief Rationale 
Protocol Amendment 
Summary of Changes 
Summary of Changes Added 
Added with Amendment 1 
Abbreviations throughout 
Amendment 
Abbreviations updated and 
standardized 
 
Section 1.1 Synopsis 
Section 4.1.3 Treatment 
Key Inclusion Criteria added 
Added to clarify overall study design 
description 
Section 1.1 Synopsis 
Section 4.1.3 Treatment 
Treatment description for Aveed 
separated from treatment description 
for Fortesta/Testim 
Added to clarify the differences in 
treatment days and procedures between 
testosterone gel (Fortesta/Testim) and 
injection (Aveed) 
Timing of ABPM analysis for Aveed 
was revised to Day 100 to align with 
item 3 (Advice/ Information Request 
dated May 24, 2019) 
Section 1.1 Synopsis 
Section 4.1.5 Ambulatory 
Blood Pressure Monitoring 
(End of Study) 
Description of End of Study 
procedures for Fortesta/Testim 
separated from End of Study for 
Aveed 
Section 1.2 Schedule of 
Activities, Table 1 and 
Table 2  
The Schedule of Activities table has 
been separated into a table for 
Fortesta/Testim and a second table 
for Aveed 
Tables separated to clarify the 
differences in treatment days and 
procedures between testosterone gel 
(Fortesta/Testim) and injection (Aveed) 
Timing of ABPM analysis for Aveed 
was revised to Day 100 to align with 
item 3 (Advice/ Information Request 
dated May 24, 2019)  
Section 5.2 Subject Exclusion 
Criteria  
Reorganized for clarity  
 


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Section No. and Name 
Description of Change 
Brief Rationale 
Section 5.5 Screen Failures 
Reworded for clarity 
 
Section 6.1 Treatment 
Administration, Table 3  
Updated to clarify timing of 
treatment for each treatment 
 
Section 6.2 Study Treatment 
Preparation/Handling/Storage/ 
Accountability 
Section 6.4 Study Treatment 
Compliance 
Added information on study drug 
accountability monitoring – tubes 
and canisters must be returned at 
each visit. 
 
Section 8.1.5 Vital Signs 
The procedure for taking vital signs 
was expanded 
 
Section 8.2.5 Pregnancy 
Procedures regarding pregnancies in 
the partners of study participants 
were clarified 
 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................2 
1. 
PROTOCOL SUMMARY ..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Schedule of Activities .................................................................................................19 
2. 
INTRODUCTION ......................................................................................................23 
2.1. 
Study Rationale ...........................................................................................................23 
2.2. 
Background .................................................................................................................23 
2.3. 
Risk/Benefit Assessment ............................................................................................24 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................26 
3.1. 
Study Objective(s)/Endpoint(s) ..................................................................................26 
4. 
STUDY DESIGN .......................................................................................................26 
4.1. 
Overall Design ............................................................................................................26 
4.1.1. 
Screening ....................................................................................................................26 
4.1.2. 
Ambulatory Blood Pressure Monitoring (24 Hour) ....................................................27 
4.1.3. 
Treatment ....................................................................................................................27 
4.1.4. 
Interim Evaluation ......................................................................................................28 
4.1.5. 
Ambulatory Blood Pressure Monitoring (End of Study) ............................................28 
4.1.5.1. 
Testim and Fortesta Treatment Arm ...........................................................................28 
4.1.5.2. 
Aveed Treatment Arm ................................................................................................28 
4.1.6. 
Study Duration ............................................................................................................29 
4.2. 
Scientific Rationale for the Study Design ..................................................................29 
4.3. 
Justification for Dose ..................................................................................................29 
4.4. 
End-of-Study Definition .............................................................................................29 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
5.1. 
Subject Inclusion Criteria ...........................................................................................29 
5.2. 
Subject Exclusion Criteria ..........................................................................................30 
5.3. 
Randomization Criteria ...............................................................................................32 
5.4. 
Lifestyle Considerations .............................................................................................32 
5.5. 
Screen Failures ............................................................................................................32 
6. 
STUDY TREATMENT ..............................................................................................33 
6.1. 
Treatment Administration ...........................................................................................33 


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6.2. 
Study Treatment Preparation/Handling/Storage/Accountability ................................33 
6.3. 
Measures to Minimize Bias ........................................................................................34 
6.3.1. 
Interactive Response Technology ...............................................................................34 
6.4. 
Study Treatment Compliance .....................................................................................34 
6.5. 
Prior and Concomitant Medications and Procedures ..................................................34 
6.5.1. 
Prohibited Medications and Procedures .....................................................................35 
7. 
DISCONTINUATION FROM STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................35 
7.1. 
Discontinuation of Study Treatment ...........................................................................35 
7.2. 
Subject Discontinuation/Withdrawal From the Study ................................................36 
7.3. 
Lost to Follow-up .......................................................................................................36 
8. 
STUDY ASSESSMENTS AND PROCEDURES......................................................37 
8.1. 
Safety Assessments .....................................................................................................37 
8.1.1. 
Serum Testosterone Assessment .................................................................................38 
8.1.2. 
Medical and Surgical History .....................................................................................38 
8.1.3. 
Physical Examination .................................................................................................38 
8.1.4. 
Height and Weight ......................................................................................................38 
8.1.5. 
Vital Signs ..................................................................................................................38 
8.1.6. 
Electrocardiogram .......................................................................................................39 
8.1.7. 
Clinical Laboratory Determinations ...........................................................................39 
8.2. 
Adverse Events and Serious Adverse Events .............................................................39 
8.2.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................40 
8.2.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................40 
8.2.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................40 
8.2.4. 
Secondary Exposure to Testim and Fortesta...............................................................40 
8.2.5. 
Pregnancy ...................................................................................................................41 
8.3. 
Treatment Overdose ....................................................................................................41 
8.3.1. 
Treatment Abuse/Misuse ............................................................................................41 
8.4. 
Pharmacokinetics ........................................................................................................41 
8.5. 
Pharmacodynamics .....................................................................................................41 
8.6. 
Genetics ......................................................................................................................42 
8.7. 
Biomarkers ..................................................................................................................42 


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8.8. 
Medical Resource Utilization and Health Economics ................................................42 
9. 
STATISTICAL CONSIDERATIONS AND METHODS .........................................42 
9.1. 
Sample Size Determination ........................................................................................42 
9.2. 
Analysis Populations ..................................................................................................42 
9.3. 
Statistical Analyses .....................................................................................................43 
9.3.1. 
Efficacy Analysis ........................................................................................................43 
9.3.1.1. 
Primary Analysis ........................................................................................................43 
9.3.1.2. 
Secondary Analysis ....................................................................................................43 
9.3.1.3. 
Sensitivity Analysis ....................................................................................................43 
9.3.2. 
Safety Analyses ..........................................................................................................43 
9.3.2.1. 
Adverse Events ...........................................................................................................44 
9.3.3. 
Serum Laboratory Testing ..........................................................................................44 
9.4. 
Interim Analysis ..........................................................................................................44 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................45 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.....................45 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................45 
10.1.2. 
Financial Disclosure ...................................................................................................46 
10.1.3. 
Informed Consent Process ..........................................................................................46 
10.1.4. 
Data Protection ...........................................................................................................47 
10.1.5. 
Committee Structure ...................................................................................................47 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................47 
10.1.7. 
Data Quality Assurance ..............................................................................................47 
10.1.8. 
Source Documents ......................................................................................................48 
10.1.9. 
Study and Site Closure ................................................................................................48 
10.1.10. 
Publication Policy .......................................................................................................48 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................49 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................49 
10.3.1. 
Definitions ..................................................................................................................49 
10.3.2. 
Relationship to Study Drug ........................................................................................50 
10.3.3. 
Intensity Assessment ..................................................................................................51 
10.3.4. 
Reporting Adverse Events and Serious Adverse Events ............................................51 


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10.3.4.1. 
Reporting Adverse Events ..........................................................................................51 
10.3.4.2. 
Reporting Serious Adverse Events .............................................................................51 
10.3.4.3. 
Follow-up Procedures for Serious Adverse Events ....................................................52 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................52 
10.5. 
Appendix 5: Genetics .................................................................................................52 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ..............52 
10.7. 
Appendix 7: Medical Device Incidents ......................................................................52 
10.8. 
Appendix 8: Country-specific Requirements .............................................................52 
11. 
INVESTIGATOR’S STATEMENT ...........................................................................53 
12. 
REFERENCES ...........................................................................................................54 
 


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LIST OF TABLES 
Table 1: 
Schedule of Activities – Testim and Fortesta .............................................................19 
Table 2: 
Schedule of Activities – Aveed (Testosterone Undecanoate Injection) .....................21 
Table 3: 
Study Treatments ........................................................................................................33 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Special Term 
Explanation 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse event 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EoS 
End-of-study 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
IRT 
Interactive response technology 
LH 
Luteinizing hormone 
MAP 
Mean arterial pressure 
PI 
Prescribing information 
PP 
Pulse pressure 
REMS 
Risk evaluation and mitigation strategies 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SoA 
Schedule of activities 
TEAE 
Treatment-emergent adverse event 
TRT 
Testosterone replacement therapy 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Marketed Products: AVEED® (testosterone undecanoate) injection, TESTIM® (testosterone 
gel), FORTESTA® (testosterone) Gel 
Name of Active Ingredient: Testosterone 
Title of Study: An Open-Label, Randomized, Parallel-Group, Three Treatment Arm, Multicenter 
Study on Hypogonadal Males to Evaluate the Effect on 24-Hour Ambulatory Blood Pressure After 
16-Week Continuous Administration With Marketed Testosterone Products 
Principal Investigator: (To be determined) 
Study Period:  
Date first subject enrolled: June 2020 
Estimated date last subject completed: December 2022 
Phase of Development: 4 
Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
 
• To assess the change from baseline in 
mean 24-hour systolic blood pressure 
(SBP) after 16 weeks of continuous 
treatment with study drug as indicated by 
the prescribing information (PI). 
• Mean change from baseline to end-of-study 
(EoS) in 24-hour average systolic ambulatory 
blood pressure (BP). 
Secondary 
 
• To assess the safety of 16 weeks of 
continuous treatment with study drug as 
indicated by PI. 
• Mean change from baseline in 24-hour average 
and time windows of interest in mean arterial 
pressure (MAP), SBP, diastolic blood pressure 
(DBP), pulse pressure (PP), and heart rate 
obtained during treatment. 
• Change from baseline over time (hourly 
average) by nominal clock time and time after 
dose in MAP, SBP, DBP, PP, and heart rate. 
• Percent of subjects with new antihypertensive 
medications. 
• Percent of subjects with dose increases in 
antihypertensive medications. 
 
Overall Design: 
This is a Phase 4, open-label, randomized, parallel-group, 3 treatment-arm, multicenter study on 
hypogonadal males to evaluate the effect on 24-hour ambulatory BP after 16 weeks of continuous 
treatment with marketed testosterone products. 


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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Marketed Products: AVEED® (testosterone undecanoate) injection, TESTIM® (testosterone 
gel), FORTESTA® (testosterone) Gel 
Name of Active Ingredient: Testosterone 
A total of approximately 618 hypogonadal males will be enrolled across the 3 treatment arms of this 
study. Subjects currently with controlled hypertension and without hypertension will be enrolled. The 
study will consist of a screening phase, followed by a 24-hour ambulatory blood pressure monitoring 
(ABPM) phase (baseline). After baseline BP has been monitored, subjects will be randomly assigned 
to 1 of 3 treatment arms. 
In order to be eligible to participate in the study, at the Screening Visit and on Study Day 1, subjects 
must: 
1. Be male and ≥ 18 years of age at the time of consent. 
2. Have a diagnosis of primary hypogonadism (congenital or acquired) OR hypogonadotropic 
hypogonadism (congenital or acquired). 
3. Have a total serum testosterone at screening < 300 ng/dL based on 2 blood samples obtained at 
10:00 am (± 2 hours) on 2 separate occasions at least 48 hours apart. 
4. Be naïve to androgen replacement or washout of 12 weeks following intramuscular androgen 
injections; 4 weeks following topical, buccal, nasal, or oral androgens. Washout should be 
completed by Study Day -2. 
5. Have a screening BP at rest of less than 140 mm Hg for SBP and less than 90 mm Hg for 
DBP. 
Screening will take place between Day -28 and Day -2. Screening assessments will include (but are not 
limited to) informed consent, serum testosterone levels, physical examination, 12-lead 
electrocardiogram (ECG), vital signs, and clinical laboratory tests. After all assessments are 
completed, each subject’s eligibility will be evaluated. Subjects found eligible will be instructed to 
return to the study center on Day -1 for the activities described in the Schedule of Activities (SoA). 
Blood samples will be collected on Day -1 for baseline serum testosterone assessment (day before 
ABPM). All eligible subjects will come to the study center on Day 1 for ABPM. A 24-hour ambulatory 
blood pressure recorder machine will be attached to the subject’s arm, at bicep level. The machine will 
be set to measure BP every 30 minutes for the next 24 hours. Baseline BP will be analyzed (systolic 
and diastolic means) for the overall 24 hour period, daytime (from waking up to bedtime) and night 
time (from retiring to bed until waking) for each subject. The 24-hour ambulatory blood pressure 
recorder machine must be returned to the study site by the subject on the following day (Day 2). 
After the 24-hour ABPM is read and determined to be valid (Day 2), each subject will be randomly 
assigned to 1 of the 3 treatment arms: 
• 
Testosterone undecanoate injection (AVEED) 
• 
Testosterone gel (FORTESTA) 
• 
Testosterone gel (TESTIM) 
Fortesta and Testim subjects will be administered the allotted study drug and start application of the 
study drug on Day 2. Subjects will be instructed not to shower, wash, and/or swim within two hours 
after daily study drug application and will be provided with instructions to continue applying/ 
administering topically the Fortesta or Testim study drug according to the approved PI. Aveed subjects 
will receive an intramuscular injection on Day 2, Day 30 (± 3 days), and Day 100 (± 3 days). For more 
information on study treatments, see the Study Operations Manual. 


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Name of Sponsor/Company: Endo Pharmaceuticals Inc. 
Name of Marketed Products: AVEED® (testosterone undecanoate) injection, TESTIM® (testosterone 
gel), FORTESTA® (testosterone) Gel 
Name of Active Ingredient: Testosterone 
Fortesta and Testim subjects will be instructed to visit the clinic during the Treatment Follow-up Phase 
on Day 16, Day 37, Day 67, and Day 97 (± 3 days). During each of these visits, serum testosterone 
levels will be taken at the designated times (2 hours prior to Testim application and 2 hours after 
Fortesta application) followed by instructions for titrating dose accordingly if applicable. For subjects 
on the Fortesta arm, if further titration is required after the Follow-up Visit on Day 37, the investigator 
should refer to the PI for information on when to schedule subsequent follow up visits. The daily dose 
of the study drug will be titrated for each subject, according to approved dosage and administration 
instructions, until the circulating testosterone concentrations of the subject reaches normal 
concentrations (300-1000 ng/dL). The appropriate amount of study drug will be dispensed to subjects 
to last until the next follow-up visit. However, if titration is needed, subjects may need to return to the 
clinic in between scheduled follow-up visits for additional drug supply. If additional visits are required 
during the Treatment Follow-up Phase, they may occur as Unscheduled Visits. Subjects will follow the 
same instructions as previously outlined for any Unscheduled Visits as were followed during the 
Treatment Follow-up Phase. 
Laboratory evaluations should be performed as needed during unscheduled visits. Unscheduled visits 
may occur as necessary for the Aveed subjects. 
Fortesta and Testim subjects will be instructed to visit the study center on Day 113 (± 3 days) for blood 
collection for serum testosterone determination and again on Day 114 to be fitted with the ABPM 
device in addition to the other EoS assessments as described in the Testim and Fortesta SoA. 
A 24-hour ambulatory blood pressure recorder machine will be attached to the subject’s arm (using the 
same arm as for baseline), at bicep level. The machine will be set to measure BP every 30 minutes for 
the next 24 hours. The 24-hour ambulatory blood pressure recorder machine must be returned to the 
study site by the subject on the following day (Day 115). 
Aveed subjects will be instructed to visit the study center on Day 30 (± 3 days), and Day 100 
(± 3 days) for intramuscular injections and on Day 106 (± 3 days) for a serum testosterone draw. 
Subjects will return to the study center on Day 107 to be fitted with the ABPM device in addition to 
completing the other assessments as listed in the Aveed SoA. A 24-hour ambulatory blood pressure 
recorder machine will be attached to the subject’s arm (using the same arm as the baseline), at bicep 
level. The machine will be set to measure BP every 30 minutes for the next 24 hours. On Day 108 the 
24-hour ambulatory blood pressure recorder machine must be returned to the study site by the subject. 
If a subject is terminated early, an early termination visit will be scheduled and efforts will be taken to 
collect his 12-lead ECG, blood samples for clinical laboratory tests (including serum testosterone on 
the day prior to ABPM) and 24-hour ABPM data. EoS activities/assessments are listed in the SoA. 
Disclosure Statement: This is an open-label 3 treatment-arm study in 3 different marketed 
testosterone treatments.  
Number of Subjects (planned): Approximately 618 subjects will be enrolled across the 3 treatment 
arms. 
Treatment Groups and Duration: All subjects will receive 1 of 3 testosterone treatments. Each 
treatment will be administered according to the applicable PI. 
Data Monitoring Committee: No monitoring committees will be used for this study. 
 


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1.2. 
Schedule of Activities 
Table 1: 
Schedule of Activities – Testim and Fortesta 
Procedures 
Screening 
Phase 
Day -28 to -2 
Baseline 
Treatment Follow-up Visitsa 
End-of-Study/Early Termination 
Day -1 
Visit 1  
Day 1 
Return 
Visit 
Day 2 
Visits 2a to 2db 
Days 16, 37, 67, and 97  
Day 113  
(± 3 days) 
EoS Visit  
Day 114 
(± 3 days) 
Return 
Visit 
Day 115 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
Xc 
 
X 
 
 
 
 
 
Medical history including 
previous treatments 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
 
X 
 
Vital signs (temperature, 
HR, BP & RR) d 
X 
 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
X 
 
International Prostate 
Symptom Score (IPSS)e  
X 
 
 
 
 
 
 
 
Digital rectal examination 
of the prostate 
X 
 
 
 
 
 
 
 
Alcohol and tobacco 
screen 
X 
 
 
 
 
 
 
 
Clinical laboratoryf 
X 
 
 
 
 
 
 
 
Serum testosterone 
Xg 
X 
 
 
Xh 
Xh 
 
 
24-hour ABPM 
 
 
Xi 
 
 
 
Xi 
 
Confirm valid ABPM 
sessionj 
 
 
 
X 
 
 
 
X 


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Table 1: 
Schedule of Activities – Testim and Fortesta (Continued) 
Procedures 
Screening 
Phase 
Day -28 to -2 
Baseline 
Treatment Follow-up Visitsa  
End-of-Study/Early Termination 
Day -1 
Visit 1  
Day 1 
Return 
Visit 
Day 2 
Visits 2a to 2db 
Days 16, 37, 67, and 97 
Day 113 
(± 3 days) 
EoS Visit 
Day 114 
(± 3 days) 
Return 
Visit 
Day 115 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
TREATMENT 
Randomizationk 
 
 
 
X 
 
 
 
 
Dispense Study Drugl 
 
 
 
X 
X 
 
 
 
Collect Study Drug 
 
 
 
 
X 
 
 
X 
Study Drug Compliance 
Check and Discussion 
 
 
 
 
X 
 
 
X 
a Treatment follow-up visits are for checking serum testosterone levels and titrating dose accordingly. For subjects receiving Fortesta, if further titration is 
required after Follow-up Visit on Day 37, the investigator should refer to the PI for information on subsequent follow-up visits. However, in the event 
additional visits are necessary, they may occur as Unscheduled Visits. 
b Window of ± 3 days are allowed. 
c  Testosterone samples collected at Screening will be used for evaluating study inclusion. 
d Temperature, heart rate (HR) and respiratory rate (RR) will be captured. BP will be measured, using a sphygmomanometer, at all office visits. Subjects will be 
seated on a chair with back rest, resting the flexed dominant arm on a flat surface so that the upper arm is at heart level. Subjects with BP > 140/90 mm Hg 
should be excluded from the study. Site personnel will ensure that the same arm and cuff size will be used. Vital signs taken will include SBP and DBP, pulse 
rate, respiratory rate, and body temperature. The results, date, and time for all vital sign assessments will be recorded. 
e International Prostate Symptom Score (IPSS) ≥ 19. 
f Includes tests for hematology, biochemistry, serum prostate-specific antigen (PSA), and urine analysis. 
g. Two blood samples will be obtained for serum testosterone, at 10 AM (± 2 hours) on 2 separate occasions spaced at least 48 hours apart (± 1 hour).  
h On the Testim treatment arm a blood sample will be collected from subjects 2 hours predose, and on the Fortesta treatment arm a blood sample will be 
collected from subjects 2 hours postdose. 
i Onsite device activation. 
j If a subject does not have a valid ABPM session (defined as ≥ 70% of expected measurements including 20 valid awake [0900-2100 h] and 7 valid sleep 
[0100-0600 h] measurements) at baseline or at the end of study visit the ABPM session can be re-done.  
k A valid ABPM must be confirmed prior to a subject being randomized.  
l The appropriate amount of study drug will be dispensed to each subject to last until the next follow-up visit, with instructions for administration. However, if 
up titration is needed, subjects may need to return to the clinic between scheduled follow-up visits for additional drug supply. 


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Table 2: 
Schedule of Activities – Aveed (Testosterone Undecanoate Injection) 
Procedures 
Screening 
Phase 
Day -28 to -2 
Baseline 
Treatment Visits 
(± 3 days) 
End-of-Study/Early Termination 
Day -1 
Visit 1  
Day 1 
Return 
Visit 
Day 2 
Study Visit  
Day 30 
Study Visit  
Day 100 
Day 106 
(± 3 days) 
EoS Visit 
Day 107 
(± 3 days) 
Return 
Visit 
Day 108 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
Xd 
 
X 
 
 
 
 
 
 
Medical history including 
previous treatments 
X 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
Vital signs (temperature, 
HR, BP & RR)a 
X 
 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
International Prostate 
Symptom Score (IPSS)b 
X 
 
 
 
 
 
 
 
 
Digital rectal examination 
of the prostate 
X 
 
 
 
 
 
 
 
 
Alcohol and tobacco 
screen  
X 
 
 
 
 
 
 
 
 
Clinical laboratoryc 
X 
 
 
 
 
 
 
 
 
Serum testosterone 
Xe 
X 
 
 
 
 
X 
 
 
24-hour ABPM 
 
 
Xf 
 
 
 
 
Xf 
 


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Table 2: 
Schedule of Activities – Aveed (Testosterone Undecanoate Injection) (Continued) 
Procedures 
Screening 
Phase 
Day -28 to -2 
Baseline 
Treatment Visits 
(± 3 days) 
End-of-Study/Early Termination 
Day -1 
Visit 1 
Day 1 
Return 
Visit 
Day 2 
Study Visit 
Day 30 
Study Visit 
Day 100 
Day 106  
(± 3 days) 
EoS Visit 
Day 107 
(± 3 days) 
Return 
Visit 
Day 108 
Confirm valid ABPM 
sessiong 
 
 
 
X 
 
 
 
 
X 
Randomizationh 
 
 
 
X 
 
 
 
 
 
Study drug administration 
 
 
 
X 
X 
X 
 
 
 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Temperature, heart rate (HR) and respiratory rate (RR) will be captured. BP will be measured, using a sphygmomanometer, at all office visits. Subjects will be 
seated on a chair with back rest, resting his flexed dominant arm on a flat surface so that his upper arm is at heart level. Subjects with BP > 140/90 mm Hg 
should be excluded from the study. Subjects receiving the Aveed injection will have vital signs taken before administration of the study drug. Site personnel 
will ensure that the same arm and cuff size will be used. Vital signs taken will include SBP and DBP, pulse rate, respiratory rate, and body temperature. The 
results, date, and time for all vital sign assessments will be recorded. 
b International Prostate Symptom Score (IPSS) ≥ 19. 
c Includes tests for hematology, biochemistry, serum prostate-specific antigen (PSA), and urine analysis. 
d Testosterone samples collected at Screening will be used for evaluating study inclusion. 
e Two blood samples will be obtained for serum testosterone, at 10 AM (± 2 hours) on 2 separate occasions spaced at least 48 hours apart (± 1 hour).  
f Onsite device activation. 
g If a subject does not have a valid ABPM session (defined as ≥ 70% of expected measurements including 20 valid awake [0900-2100 h] and 7 valid sleep 
[0100-0600 h] measurements) at baseline or at the end of study visit the ABPM session can be re-done.  
h A valid ABPM must be confirmed prior to a subject being randomized.  
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This study will allow for a comparison of the safety profiles of 3 different marketed drugs over 
16 weeks of treatment. 
The COVID-19 public health emergency has disrupted the conduct of clinical research 
throughout the world. At Endo Pharmaceuticals Inc. (Endo), ensuring the safety of clinical study 
participants is our primary concern. In addition, the integrity of data obtained from clinical trials 
must be ensured. 
In order to ensure subject safety and protect data integrity, Endo, in accordance with the FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency (March 2020, updated 02 July 2020), will allow virtual visits for safety assessments. 
During a potential travel restriction/lockdown due to COVID-19, subjects enrolled in the study 
may experience a delay or cancellation of important site visits that could impact serum 
testosterone levels and delay or affect the required testosterone replacement. To avoid any 
potential delay or disruption in the testosterone replacement therapy of those subjects, as our 
commitment toward every subject’s well-being, Endo may decide to temporarily delay the 
enrollment of the subjects into any of the arms of the protocol.  
In addition, any subjects affected by the health emergency will be allowed to continue in the 
study and complete remaining assessments when the investigational sites re-open as follows: 
• Subjects who started this study prior to a COVID-19 interruption will be allowed to 
continue in the study and complete all remaining assessments, if willing to do so in 
accordance with the scheduling outlined in Section 1.2. 
2.2. 
Background 
Testosterone is the principal androgen produced by the male testes (Rommerts, 2004). It is 
involved in several developmental and physiological processes, including virilization of the male 
reproductive tract, skeletal muscle development, growth in stature, male pattern hair growth at 
the onset of puberty, spermatogenesis in adults and control of the gonadotropic functions of the 
pituitary by down-regulating the synthesis of luteinizing hormone (LH). It also plays a major role 
in male sexual behavior. 
Male hypogonadism is the result of inadequate production of testosterone by the Leydig cells of 
the testes (Odell and Swerdloff, 1978). Hypogonadism is reflected by serum concentrations of 
testosterone of < 300 ng/dL, with no discernible diurnal pattern (Surampudi et al, 2014). The 
etiology of hypogonadism may be primary or secondary. Primary hypogonadism is associated 
with dysfunction in the testes. Idiopathic primary testicular failure affects approximately 5% of 
the male population. Secondary hypogonadism is due to inadequate hormonal stimulation of 
functionally normal testes. The causes may be of hypothalamic or pituitary origin, including 
gonadotropin-releasing hormone deficiencies, isolated follicle-stimulating hormone or LH 
deficiencies, acquired gonadotropin deficiencies, prolactin secreting tumors, severe systemic 
illness, uremia, and hemochromatosis. 


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The treatment of males with primary, and in some cases, secondary hypogonadism includes 
administration of testosterone. Numerous clinical studies have confirmed the efficacy of 
testosterone in the treatment of hypogonadism (Thirumalai et al, 2017). The safety of 
testosterone administration is well established (Lawrence et al, 2017; Reaven, 1995; Malkin et al, 
2003). Clinical studies and literature reports have established the physiological and 
pharmacological effects and safety, even of large doses, of testosterone in both hypogonadal and 
eugonadal men (Ruige et al, 2001).  
Recently, however, there has been growing concern over the use of testosterone therapy and the 
increased risk of cardiovascular disease (Clavell-Hernandez and Wang, 2018). In a cohort study 
performed by Loo (Loo et al, 2019),evidence suggested that during the first 2 years of 
testosterone treatment, men with low testosterone levels were more likely to experience 
cardiovascular events such as ischemic stroke, transient ischemic attacks (TIAs), and myocardial 
infarction. Other studies, however, have found that testosterone replacement therapy (TRT) used 
to return testosterone to normal levels in hypogonadal males may actually have a beneficial 
effect on the cardiovascular system (Elagizi et al, 2018). Given the conflicting nature of this 
evidence, the increasing use of testosterone therapy has necessitated a re-evaluation of the safety 
of testosterone products. One avenue for the evaluation of cardiovascular safety during 
testosterone therapy is ambulatory blood pressure monitoring (ABPM) in subjects receiving 
testosterone treatment.  
ABPM is used to monitor BP over 24-hours in order to reveal shifts in BP levels that occur at 
various times during the day. According to the European Society of Hypertension (O’Brien et al, 
2013), some of the benefits of frequent BP measurements during the day include the ability to 
monitor BP during sleep, identification of ‘white-coat’ and masked hypertension, and the 
variation of subject BP during a 24-hour cycle. Of particular importance, ABPM, using a 
validated device coupled with subject training, allows BP monitoring in the home with 
measurements every 30 minutes, thereby providing a much more accurate picture of the subject’s 
BP at different time points. 
This study is designed to evaluate the effects of 3 different approved testosterone products on the 
ambulatory BP of hypogonadal males after 16 weeks of therapy. 
2.3. 
Risk/Benefit Assessment 
Adverse events (AEs) associated with TRT include gynecomastia, fatigue, priapism, weight gain, 
decreased high density lipoprotein (HDL) cholesterol, increased prostate size, difficulty in 
urination, and erythrocytosis (increased hemoglobin and/or hematocrit). Androgens are 
contraindicated in men with carcinoma of the breast or a history of primary hepatic carcinoma, 
known or suspected carcinoma of the prostate, nephrotic syndrome, hypercalcemia, and must be 
used cautiously in men with prostatic hypertrophy.  
Hypogonadism has been treated with administration of exogenous testosterone since it was 
synthesized some 60 years ago. Testosterone is approved by the US Food and Drug 
Administration (FDA) as replacement therapy in men for conditions associated with a deficiency 
or absence of endogenous testosterone. Testosterone is currently available in oral formulation, 
injectable depot solution, pellet implants, transdermal patches, topical gels, and buccal tablets. 
High dose oral formulations (testosterone esters) given for prolonged periods are associated with 
an increased incidence of liver disease, including cancer. Depot solutions are administered 


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relatively frequently and are considered painful injections. Another issue associated with the 
depot formulation is the mood swings that are produced as a result of the sustained 
supraphysiologic concentrations of testosterone that occur immediately after injection and lower 
than normal concentrations during the time period (a few days) prior to the next scheduled 
injection. Transdermal patches are often associated with a high incidence of inflammation at the 
site of application and pellet implants can result in rejection and infection. Since marked first 
pass metabolic inactivation of testosterone occurs in the liver after oral administration, 
testosterone esters by intramuscular administration have until recently been the mainstay of 
replacement therapy. However, significant amounts of testosterone are absorbed and enter the 
systemic circulation when applied to the skin in an appropriate vehicle. This observation was the 
basis for developing testosterone patches to deliver the hormone to scrotal and non-scrotal skin, 
and most recently by a topical testosterone gel (1%). Testosterone 2% gel is currently approved 
in 20 European countries. 
More detailed information about the known and expected benefit, risks, and reasonably expected 
AEs can be found in the Package Inserts for each treatment in this study. Additional information 
will be provided to subjects receiving Aveed in accordance with the approved risk evaluation and 
mitigation strategies. 
 


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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objective(s)/Endpoint(s) 
Objectives 
Endpoints 
Primary 
 
• To assess the change from baseline in mean 
24-hour systolic blood pressure (SBP) after 
16 weeks of continuous treatment with study 
drug as indicated by the prescribing 
information (PI). 
• Mean change from baseline to end-of-study 
(EoS) in 24-hour average systolic ambulatory 
blood pressure (BP). 
Secondary 
 
• To assess the safety of 16 weeks of 
continuous treatment with study drug as 
indicated by PI. 
• Mean change from baseline in 24-hour average 
and time windows of interest in mean arterial 
pressure (MAP), SBP, diastolic blood pressure 
(DBP), pulse pressure (PP), and heart rate 
obtained during treatment. 
• Change from baseline over time (hourly average) 
by nominal clock time and time after dose in 
MAP, SBP, DBP, PP, and heart rate. 
• Percent of subjects with new antihypertensive 
medications. 
• Percent of subjects with dose increases in 
antihypertensive medications. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 4, open-label, randomized, parallel-group, 3 treatment-arm, multicenter study on 
hypogonadal males to evaluate the effect on 24-hour ambulatory BP after 16 weeks of 
continuous treatment with marketed testosterone products. 
A total of approximately 618 hypogonadal males will be enrolled across the 3 treatment arms in 
this study. Subjects currently with and without hypertension will be enrolled. The study will 
consist of a screening phase, followed by a 24-hour ABPM phase (baseline). After a valid 
24-hour ABPM has been confirmed, subjects will be randomly assigned to 1 of 3 treatment arms. 
4.1.1. 
Screening 
Screening will take place on multiple days between Day -28 and Day -2. Informed consent will 
be obtained from all subjects prior to any screening assessments. Screening assessments will 
include (but are not limited to) informed consent, serum testosterone levels, physical 
examination, 12-lead electrocardiogram (ECG), vital signs, and clinical laboratory tests. After all 
assessments are completed, each subject’s eligibility will be evaluated. Subjects found eligible 


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will be instructed to return to the study center on Day -1 for the activities described in the 
Schedule of Activities (SoA).  
4.1.2. 
Ambulatory Blood Pressure Monitoring (24 Hour) 
Blood samples will be collected on Day -1 for baseline serum testosterone assessment (day 
before ABPM). All eligible subjects will come to the study center on Day 1 for ABPM. A 
24-hour ambulatory blood pressure recorder machine will be attached to the subject’s arm, at 
bicep level. The machine will be set to measure BP every 30 minutes for the next 24 hours. 
Baseline BP will be analyzed (systolic and diastolic means) for the overall 24 hour period, 
daytime (from waking up to bedtime) and night time (from retiring to bed until waking) for each 
subject. The 24-hour ambulatory blood pressure recorder machine must be returned to the study 
site by the subject on the following day (Day 2). 
In this clinical trial, an FDA cleared ABPM device will be used that meets the latest Association 
for the Advancement of Medical Instrumentation, European Society of Hypertension standards 
and also will have a British Hypertension Society A/A rating. The same brand of ABPM device 
will be used for every subject enrolled into the trial and each subject will use the same device at 
both the Day 1 Visit and as applicable, the EoS or Early Termination visit. 
In order to receive study drug on Day 2, the baseline 24-hour ABPM reading must be reviewed 
by the investigator (or qualified designee) in real time and considered valid. If a subject does not 
have a valid ABPM session (defined as ≥ 70% of expected measurements including 20 valid 
awake [0900-2100 h] and 7 valid sleep [0100-0600 h] measurements) at baseline or at the end of 
study visit the ABPM session may be repeated once in order to obtain a valid ABPM session. 
4.1.3. 
Treatment 
After ABPM is complete (Day 2) and determined by the investigator to be valid, each subject 
will be randomly assigned to 1 of the 3 treatment arms: 
• Testosterone undecanoate injection (AVEED) 
• Testosterone gel (FORTESTA) 
• Testosterone gel (TESTIM) 
Fortesta and Testim subjects will be administered the allotted study drug and start application of 
the study drug on Day 2. Subjects will be instructed not to shower, wash, and/or swim within two 
hours after daily study drug application and will be provided with instructions to continue 
applying/administering topically the Fortesta or Testim study drug according to the approved PI. 
Aveed subjects will receive an intramuscular injection on Day 2, Day 30 (± 3 days), and Day 100 
(± 3 days). For more information on study treatments, see the Study Operations Manual and 
Table 3. 
Fortesta and Testim subjects will be instructed to visit the clinic during the Treatment Follow-up 
Phase on Day 16, Day 37, Day 67, and Day 97 (± 3 days). During each of these visits, serum 
testosterone levels will be taken at the designated times (2 hours prior to Testim application and 
2 hours after Fortesta application) followed by instructions for titrating dose accordingly if 
applicable. For subjects on the Fortesta arm, if further titration is required after the Follow-up 
Visit on Day 37, the investigator should refer to the PI for information on when subsequent 


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follow-up visits should be scheduled. The daily dose of the study drug will be titrated for each 
subject, according to approved dosage and administration instructions, until the circulating 
testosterone concentrations of the subject reaches normal concentrations (300-1000 ng/dL). The 
appropriate amount of study drug will be dispensed to each subject to last until the next follow-up 
visit. However, if titration is needed, subjects may need to return to the clinic in between 
scheduled follow-up visits for additional drug supply. If additional visits are required during the 
Treatment Follow-up Phase, they may be occur as Unscheduled Visits. Subjects will follow the 
same instructions as previously outlined for any Unscheduled Visits during the Treatment Follow-
up Phase. The timing of blood sample collection will occur 2 hours prior to Testim treatment and 
2 hours after Fortesta treatment, as described in the respective PIs. The investigator will be 
instructed to customize and schedule the treatment follow-up visits (and study drug dispensation) 
of each subject according to the study drug characteristics in order to facilitate proper dose 
titration. Once the daily required dose is fixed, subjects will be instructed to continue the same 
dose until they complete the study (for more information on titration and dose treatment 
scheduling, see the Pharmacy Manual). Unscheduled visits may occur as necessary for the Aveed 
subjects. 
4.1.4. 
Interim Evaluation 
Not applicable. 
4.1.5. 
Ambulatory Blood Pressure Monitoring (End of Study) 
4.1.5.1. 
Testim and Fortesta Treatment Arm 
Subjects will be instructed to visit the study center on Day 113 (± 3 days) for a serum 
testosterone assessment, and again on Day 114 (± 3 days) to be fitted with the ABPM device in 
addition to completing the other EoS assessments as listed in the Testim and Fortesta SoA. 
Subjects will apply the study drug as usual at home before the Day 114 visit. A 24-hour 
ambulatory blood pressure recorder machine will be attached to the subject’s arm (using the 
same arm as for baseline), at bicep level. The machine will be set to measure BP every 
30 minutes for the next 24 hours. On Day 115 the 24-hour ambulatory blood pressure recorder 
machine must be returned to the study site by the subject. If a subject does not have a valid 
ABPM session at the end of study visit, the ABPM session may be repeated once in order to 
obtain a valid ABPM session. 
4.1.5.2. 
Aveed Treatment Arm 
Aveed subjects will be instructed to visit the study center on Day 106 (± 3 days) for a serum 
testosterone draw. Subjects will return to the study center on Day 107 (± 3 days) to be fitted with 
the ABPM device in addition to completing the other assessments as listed in the Aveed SoA. 
A 24-hour ambulatory blood pressure recorder machine will be attached to the subject's arm 
(using the same arm as the baseline), at bicep level. The machine will be set to measure BP every 
30 minutes for the next 24 hours. On Day 108 the 24-hour ambulatory blood pressure recorder 
machine must be returned to the study site by the subject. If a subject does not have a valid 
ABPM session at the end of study visit, the ABPM session may be repeated once in order to 
obtain a valid ABPM session. 


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If a subject is terminated early, an early termination visit will be scheduled and efforts will be 
taken to collect his 12-lead ECG, blood samples for clinical laboratory tests (including serum 
testosterone on the day prior to ABPM) and 24-hour ABPM data. EoS activities/assessments are 
listed in the SoA. 
4.1.6. 
Study Duration 
The duration of the study from first subject first visit to last subject last visit will be dependent 
on the ability of the sites to identify and enroll eligible subjects. The entire study is expected to 
require approximately 2 years to complete. 
4.2. 
Scientific Rationale for the Study Design 
This is an open-label exploratory study designed to investigate the effect of testosterone 
treatment on BP in hypogonadal men. 
4.3. 
Justification for Dose 
All treatments in this study are with approved, marketed drugs, using the approved doses found 
in the PI. 
4.4. 
End-of-Study Definition 
A subject is considered to have completed the study if the subject has completed the 2-day EoS 
visit. 
The EoS is defined as the completion of the final assessment for the last subject enrolled in the 
trial. 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Subject Inclusion Criteria 
In order to be eligible to participate in the study, at the Screening Visit and on Study Day 1, 
subjects must: 
1. Be male and ≥ 18 years of age at the time of consent. 
2. Have a diagnosis of primary hypogonadism (congenital or acquired) OR 
hypogonadotropic hypogonadism (congenital or acquired). 
3. Have a total serum testosterone at screening < 300 ng/dL based on 2 blood samples 
obtained at 10:00 am (± 2 hours) on 2 separate occasions at least 48 hours apart. 
4. Be naïve to androgen replacement or washout of 12 weeks following intramuscular 
androgen injections; 4 weeks following topical, buccal, nasal, or oral androgens. Washout 
should be completed by Study Day -2. 
5. Have a screening BP at rest of less than 140 mm Hg for SBP and less than 90 mm Hg for 
DBP.  


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6. Be judged to be in good general health as determined by the principal investigator based 
upon the results of a medical history, physical examination, vital signs, laboratory profile 
and a 12-lead ECG performed at screening. 
7. Subjects enrolled in the Testim or Fortesta treatment arms: Subjects agree to take 
necessary precautions (wear clothing over application sites, wash with soap and water 
etc) to avoid skin-to-skin contact and potential transfer of Testim or Fortesta to their 
female partner, children and/or others.  
8. Subjects with reproductive potential enrolled in the Testim or Fortesta treatment arms 
agrees to use effective contraception (abstinence, surgical sterilization [vasectomy], or 
condom with spermicide) with a female partner for the duration of the study and for 
28 days after any active treatment period. 
9. Be willing and able to cooperate with the requirements of the study. 
10. Be adequately informed and understand the nature and risks of the study and be able to 
provide consent as outlined in Section 10.1.3. 
5.2. 
Subject Exclusion Criteria 
A subject is ineligible for study participation if the subject: 
1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) 
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including 
but not limited to, employees (temporary, part-time, full time, etc) or a family member of 
the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
2. Has a history of significant sensitivity or allergy to the study drugs, including androgens, 
or product excipients. 
3. Has a history of or medical examination findings or concurrent diseases that might 
interfere with the conduct of the study, or endanger the subject’s well-being, or any 
significant renal, hepatic, neurologic, hematologic, endocrine, pulmonary, immunologic, 
psychiatric conditions, cardiovascular disease/dysrhythmia or any other condition(s) that 
in the investigator’s opinion might indicate the subject to be unsuitable for the study. If 
there is a history of such disease but the condition has been stable and is judged by the 
investigator not to substantially increase risk to participate in the study and, will not 
interfere with the subject’s participation in the study, the subject may be included, with 
documented approval from the Medical Monitor. 
4. Is not on a stable medication regimen for at least 3 months for the treatment of a chronic 
condition such as hypertension, hyperlipidemia or diabetes mellitus. 
5. Has had a cardiovascular and/or cerebrovascular event within 6 months prior to Study 
Day -2. 
6. Needs a BP cuff size larger than 50 cm. 
7. Works a night shift or performs heavy manual labor. 


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8. Has any known contraindication(s) to active study treatment including, but not limited to: 
a. Known or suspected carcinoma (or history of carcinoma) of the prostate clinically 
significant symptoms of benign prostatic hyperplasia, and/or clinically significant 
symptoms of lower urinary obstruction and International Prostate Symptom Score 
≥ 19. A clinically significant digital rectal examination of the prostate or clinically 
significant elevated serum prostate-specific antigen levels (> 4.0 ng/mL). 
b. Known or suspected carcinoma of the breast. Participant has cancer, or a history of 
relapse (except for basal cell carcinoma of the skin) within the previous 5 years. 
c. Liver disease defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 2 × upper limit of normal (ULN) or bilirubin > 2 × ULN. 
d. Active deep vein thrombosis or thromboembolic disorder, or a documented history of 
these conditions. 
e. Atrial fibrillation. 
f. Untreated sleep apnea. 
g. Has known immune compromised status (not related to disease/condition under 
study), including but not limited to, individuals who have undergone organ 
transplantation or who are known to be positive for the human immunodeficiency 
virus. 
9. Uses known inhibitors (eg, ketoconazole) or inducers (eg, dexamethasone, phenytoin, 
rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior to study 
drug administration and through the end of the study. 
a. Uses any of the above listed drugs within 5 half-lives of the last dose in the past 
6 months prior to study drug administration. 
b. Has received any of the above listed drugs by injection within 30 days or 10 half-lives 
(whichever is longer) prior to study drug administration. 
c. Uses neutraceuticals or homeopathic compounds which have a known effect on BP. 
10. Has a history of drug or alcohol abuse within 6 months prior to study drug administration. 
11. Has untreated moderate to severe depression. 
12. Has any skin lesions/cuts/injury at the application site that prohibits topical application 
and/or intramuscular injection of study drug. 
13. Has clinically significant changes in any medications (including dosages) or medical 
conditions in the 28 days prior to screening. 
14. Has suspected reversible hypogonadism (eg, leuprolide injection). 
15. Donated blood or blood products or experienced significant blood loss within 90 days 
prior to study drug administration. 
16. Intends to conceive at any time during the study.  
17. Donated bone marrow within 6 months prior to study drug administration. 


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18. Requires any unapproved concomitant medications as defined in the protocol that could 
not be discontinued or switched to an allowable alternative medication prior to the 
minimum allowable interval before baseline (Day 1). 
19. Has participated in a previous investigational study or received treatment with an 
investigational product within 30 days (or 5 half-lives, whichever is longer) of screening. 
20. Has a diagnosis of, is undergoing therapy for, or has received therapy for a hematologic 
malignancy in the 5 years prior to screening. 
21. Has a history of substance abuse or is taking any substance of abuse (Note: subjects on a 
stable dose of any medications that have been prescribed by a healthcare practitioner for a 
properly documented medical condition are exempt). 
22. Has evidence of abnormalities on physical examination, vital signs, ECG, or clinical 
laboratory values, unless judged to be clinically insignificant by the investigator.  
23. Has evidence of confirmed QT prolongation with QTcF ≥ 450 ms. 
24. Has any other condition that, in the investigator’s opinion, might indicate the subject to 
be unsuitable for the study. 
5.3. 
Randomization Criteria 
At screening or Day 1, subjects with office BP readings of ≥ 140/90 will be considered screen 
failures; ie subjects with SBP ≥ 140 and/or DBP ≥ 90 will be considered screen failures. At 
Day 1, only subjects with office BP readings of < 140/90 will be randomized.  
5.4. 
Lifestyle Considerations 
Subjects should not donate blood while participating in this study and for 30 days after the last 
investigational treatment. 
5.5. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in this study but are not 
subsequently randomized. 
Subjects who do not meet all of the eligibility criteria prior to randomization will be deemed 
screen failures. The following information must be recorded for all subjects who are screen 
failures: 
• Demography (age, gender, race/ethnicity). 
• Reason for screen failure. 
• Which eligibility criterion was not met. 
• Any AE experienced by the subject. 
A subject who does not meet all of the eligibility criteria and is considered a screen failure may 
be rescreened once. If a subject rescreens within 30 days of their original screening date, 
assessments from the initial screening period may be used as long as they are considered to be 


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valid and within protocol entry criteria. Any abnormal assessments must be repeated. The period 
from the start of rescreening related procedures to the study treatment must not exceed 28 days. 
6. 
STUDY TREATMENT 
Study treatment is defined as any investigational treatment, marketed products, placebo, or 
device intended to be administered to a study subject according to the study protocol. 
6.1. 
Treatment Administration 
Table 3: 
Study Treatments 
Product Name 
Testosterone undecanoate 
injection 
(Aveed)a 
Testosterone gel 
(Fortesta) 
Testosterone gel 
(Testim) 
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Solution for Injection 
Gel 
Gel 
Dose Amount and 
Frequencyb 
750 mg/3 mL  
Days 2, 30, and 100 (±3 days) 
40 mg 
once daily (in the morning) 
50 mg  
once daily (in the morning) 
Route of 
Administration 
IM Injection 
Injection site: gluteus medius 
muscle 
Topical 
Apply to upper inner thighs 
Topical 
Apply to shoulders or upper 
arms 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Packaging and 
Labeling 
Product will be provided in 
glass vials. Each vial will be 
labeled per country 
requirements. 
Product will be provided in 
metered pump. Each pump 
will be labeled per country 
requirements. 
Product will be provided in 
50 mg tubes. Each tube will 
be labeled per country 
requirements. 
a Aveed will be used in accordance with the approved REMS. 
b Detailed information on study drug administration will be available in a separate Pharmacy Manual. 
6.2. 
Study Treatment Preparation/Handling/Storage/Accountability 
The investigator or designee will confirm that appropriate temperature control conditions have 
been maintained during transit for all study treatments received and any discrepancies are 
reported and resolved prior to study treatment administration. 
The study treatment will be maintained in a monitored, environmentally controlled (in 
accordance with treatment labeling), secure, locked area with restricted access at the study site in 
compliance with standards of the Drug Enforcement Agency (DEA) for Schedule III drugs.  
Only subjects enrolled in the study will receive study treatment and only authorized study staff 
will dispense study treatment. 
In accordance with the International Council for Harmonisation (ICH) requirements, at all times 
the investigator must be able to account for all study treatment furnished to the study site. An 
accountability record must be maintained for this purpose. The investigator must maintain 
accurate records indicating dates and quantity of study treatment received, to whom it was 
administered (subject-by-subject accounting) and accounts of any study treatment accidentally or 


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deliberately destroyed. All unused study treatment not involved in immediate subject treatment 
must be maintained under locked, temperature-controlled storage at the study site. At each visit 
subjects must return all used and unused study drug tubes and canisters to the study center.  
Investigators should refer to the Pharmacy Manual for complete information regarding 
preparation, handling, storage, and accountability of study treatment. 
6.3. 
Measures to Minimize Bias 
This is an open label study; however, the specific treatment taken by each subject will be 
assigned using interactive response technology (IRT). Subjects will be randomized to receive 
study treatment in a 1:1:1 ratio. 
6.3.1. 
Interactive Response Technology 
The investigator or designee will utilize an IRT system to register subjects at screening. Each 
subject’s unique identification (ID) number will be assigned by the IRT system and will be used 
to identify the subject for the duration of the study within all systems and documentation. If the 
subject is not eligible to receive study treatment, or should discontinue from the study, the 
subject ID number will not be reassigned to another subject. Specific instructions for the use of 
the IRT system will be included in an IRT User Manual. 
The investigator must maintain a subject master log linking the subject ID to the subject’s name. 
The investigator must follow all applicable privacy laws in order to protect a subject’s privacy 
and confidentiality. Information that could identify a subject must be masked on material 
received by the sponsor. 
6.4. 
Study Treatment Compliance 
Prior to beginning the administration of study treatment, subjects and/or their caregiver will be 
trained on dosing and mode of administration and must exhibit proper technique. Subjects will 
be instructed to bring all used and unused tubes and canisters each time they return to the clinic.  
Study drug compliance during each study visit/any period will be calculated via weight and/or 
count of containers to determine treatment compliance. Subjects using too much or too little 
study drug should be re-educated on the proper use of study drug. Repeated noncompliance (less 
than 85% or greater than 100%) should be evaluated for the need to withdraw the subject.  
Accidental or intentional overdoses should be reported to the sponsor/designee promptly (see 
Section 8.3). 
6.5. 
Prior and Concomitant Medications and Procedures 
The start and stop date, dose, unit, frequency, route of administration, and indication for all prior 
(taken within the 30 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through the EoS/Early Termination Visit) medications and nondrug therapies 
(eg, blood transfusions, oxygen supplementation, physical therapy, etc) received will be 
recorded.  


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In addition, all prior treatments for the disease/condition under study administered in the 
previous 5 years will be recorded with start and stop date, dose, unit, frequency and route of 
administration. 
6.5.1. 
Prohibited Medications and Procedures 
Use of known inhibitors (eg, ketoconazole) or inducers (eg, dexamethasone, phenytoin, rifampin, 
carbamazepine) of CYP3A will be prohibited in this study. 
If any prohibited medication is taken during the study, all pertinent information will be recorded. 
The designated study Medical Monitor must be informed immediately so the sponsor may 
determine whether to continue the subject in the study. 
7. 
DISCONTINUATION FROM STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
Subjects may be discontinued from the study for the following reasons, if deemed appropriate by 
the sponsor or investigator: 
• Entered the study in violation of this protocol. 
• Safety reasons as judged by the investigator and/or sponsor. 
• Severe non-compliance to the protocol as judged by the investigator and/or sponsor. 
• Required the use of an unacceptable concomitant medication (see Section 6.5). 
• Withdrawal of informed consent; any subject who withdraws consent as a result of an 
AE, regardless of severity or investigator’s opinion, must be reported as a 
discontinuation due to an AE. 
• In the investigator’s opinion, it is not in the subject’s best interest to continue. 
• Sponsor decision. 
Subjects who discontinue or are withdrawn from study treatment for any reason, will be 
encouraged to complete the Early Termination visit and evaluations and provide any additional 
follow-up information as required by the study, unless the subject specifically indicates that they 
will not participate in any further evaluations. The date of and reason for study treatment 
discontinuation will be recorded. Subjects will be encouraged to continue in the study for safety 
and complete all assessments in the SOA for their respective treatment arm (except for study 
drug administration) and final ABPM measurements. 
If a clinically significant cardiac finding is identified (including but not limited to changes from 
baseline in QT interval corrected using Fridericia’s Formula [QTcF]) after the start of study 
treatment, the investigator or a qualified designee will determine if the subject can continue in 
the study and if any change in management is needed.  
Subjects who discontinue from study treatment at any time after the first dose of study drug will 
not be replaced. 


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7.2. 
Subject Discontinuation/Withdrawal From the Study 
Subjects may withdraw from the study at any time at their own request, or may be withdrawn at 
any time at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons. The date of and reason for withdrawal will be recorded. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such withdrawal of consent. If a subject withdraws 
from the study, the subject may request destruction of any samples taken and request the samples 
not be tested. The investigator must document this in the site study records. 
A subject may be discontinued from the study for the following medical or administrative 
reasons: 
• Withdrawal by subject (reason must be specified). 
• An AE. 
• Death. 
• A protocol violation (reason must be specified, for example: lack of compliance, use 
of a prohibited concomitant medication, etc). 
• The subject was lost to follow-up.  
• Other reasons (reason must be specified, for example: the subject moved, investigator 
decision, pregnancy of partner [for subjects using Testim or Fortesta] sponsor 
decision to terminate trial, etc). 
If a subject discontinues from the study, all EoS procedures should be conducted as detailed in 
the SoA. The investigator should request that the subject agree to 24-hour ABPM measurement. 
The date a subject discontinues and the reason for discontinuation will be recorded in the source 
documentation and electronic case report form (eCRF). If, however, a subject withdraws consent, 
no additional procedures are required. This information should be recorded in the source 
documentation and the eCRF.  
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and to ascertain whether or not the subject wishes to and/or should continue 
in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls, and 
if necessary, a certified letter to the subject’s last known mailing address; or local 
equivalent methods). These attempts will be documented. 


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• Should the subject continue to be unreachable, the subject will be considered to have 
withdrawn from the study. 
Subjects who have been lost to follow-up at any time after the first dose of study drug will not be 
replaced. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Table 1 and Table 2). Adherence 
to the study design requirements, including those specified in the SoA, is essential and required 
for study conduct. Protocol waivers or exemptions are not allowed. 
Urgent safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue study treatment and/or be withdrawn from 
the study. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screen failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management and obtained before 
signing of the informed consent form (ICF) may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA. 
The maximum amount of blood collected from each subject over the duration of the study, 
including extra assessments that may be required, will not exceed 100 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1. 
Safety Assessments 
All safety assessments will be performed at the time outlined in the SoA. Additional 
(unscheduled) safety assessments may be performed as needed. 
In order to ensure subject safety and protect data integrity, Endo, in accordance with the FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency (March 2020, updated 02 July 2020), will allow virtual visits for safety assessments. 
During a potential travel restriction/lockdown due to COVID-19, subjects enrolled in the study 
may experience a delay or cancellation of important site visits that could impact serum 
testosterone levels and delay or affect the required testosterone replacement. To avoid any 
potential delay or disruption in the testosterone replacement therapy of those subjects, as our 
commitment toward every subject’s well-being, Endo may decide to temporarily delay the 
enrollment of the subjects into any of the arms of the protocol. In addition, should subjects be 
affected by the health emergency, they will be allowed to continue in the study and complete 
remaining assessments when the investigational sites re-open. 


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8.1.1. 
Serum Testosterone Assessment 
Blood samples of approximately 100 mL will be collected in this study for analysis of serum 
testosterone from all subjects participating in the study at the times outlined in the SoA (Table 1 
and Table 2). During the Screening Period, two blood samples will be obtained for serum 
testosterone, at 10 AM (± 2 hours) on 2 separate occasions spaced at least 48 hours apart (± 1 
hour). Testosterone samples collected during the Screening Period will be used for study 
inclusion. Testosterone samples collected at Day -1 will be used as a baseline for the study. The 
date and time of each sample collection will be recorded. Detailed instructions of the collection, 
processing, storage, and shipment of these samples will be provided in a separate laboratory 
manual. 
8.1.2. 
Medical and Surgical History 
Medical and surgical history will be obtained during the screening period. Medical history will 
include a review of the following systems: general, dermatological, respiratory, cardiovascular, 
gastrointestinal, genitourinary, endocrine, musculoskeletal, hematological, neuropsychological, 
immune (allergies), and head, eyes, ears, nose, and throat. Historical and current medical 
conditions will be recorded.  
History of tobacco and alcohol use (never, current, former) will also be collected at screening. 
8.1.3. 
Physical Examination 
The complete physical examination will include evaluation of the head, eyes, ears, nose, throat, 
neck (including thyroid), cardiovascular system (including assessment of heart, peripheral 
pulses, presence or absence of edema), genitourinary system, lungs, abdomen (including liver 
and spleen, bowel sounds), lymph nodes, musculoskeletal system (including spine, joints, 
muscles), neurological system (including cranial nerves, reflexes, sensation, strength), skin, 
extremities, and other conditions of note. 
All examinations will be performed by a physician or health professional listed on the Form 
FDA 1572 and licensed to perform physical examinations. The investigator will review all 
physical exam findings for clinical significance. Any physical exam finding meeting the 
investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE or serious 
adverse event (SAE) as appropriate. 
8.1.4. 
Height and Weight 
Height will be collected at screening only. Weight will be collected as outlined in the SoA. Any 
change from the Screening Visit in subject weight that is considered by the investigator to be 
clinically significant will be recorded as an AE (or SAE, if appropriate).  
8.1.5. 
Vital Signs 
Subjects receiving the Aveed injection will have vital signs taken before administration of the 
study drug. For all subjects, vital signs will be obtained after the subject has been seated for 
5 minutes (minimum), with feet flat on the floor and back supported. Site personnel will ensure 
that the same arm and cuff size will be used. Vital signs taken will include SBP and DBP, pulse 


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rate, respiratory rate, and body temperature. The results, date, and time for all vital sign 
assessments will be recorded.  
The investigator will review all vital sign values for clinical significance. Any vital sign value 
meeting the investigator’s or sponsor’s criteria for clinical significance will be recorded as an AE 
(or SAE, if appropriate). 
8.1.6. 
Electrocardiogram 
A 12-lead ECG recording will be conducted at the times indicated on the SoA. The subject 
should be in a supine position for at least 5 minutes before the recording is conducted. Lead 
position will be that of a standard 12-lead ECG; no additional or special lead placements will be 
necessary. The ECG recording should include a minimum of 5 heart cycles (beats).  
If the ECG report shows QT prolongation with QTcF ≥ 450 ms, the investigator should repeat 
the ECG within 1 hour. If the initial findings are confirmed, the investigator should exclude the 
subject from study participation.  
The investigator will review all other ECG results for clinical significance. Any ECG result 
meeting the investigator’s criteria for clinical significance will be recorded as an AE (or SAE, if 
appropriate). 
8.1.7. 
Clinical Laboratory Determinations 
Clinical laboratory tests will be conducted according to the SoA. Required clinical laboratory 
tests are outlined in Section 10.2. Clinical laboratory tests will be performed by a designated 
central laboratory. The study sites will be provided with instructions on specimen collection, 
preparation, packaging and transport. The results of the tests will be returned to the 
investigational sites.  
Samples for laboratory testing may be collected under fasted or nonfasted conditions. Fasting 
early morning samples are preferred, but a random daytime sample is acceptable. The date and 
time of the sample collection must be documented on the laboratory report. The investigator 
must review and sign laboratory reports and document the clinical significance of each 
laboratory abnormality. New clinically significant laboratory abnormalities or clinically 
significant changes in laboratory values will be reported as AEs (or SAEs, if appropriate). 
Clinical laboratory test data will be reviewed by the investigator, or designee, and additional 
clinical laboratory tests may be ordered at his/her discretion (eg, if the results of any clinical 
laboratory test falls outside the reference range or clinical symptoms necessitate additional 
testing to ensure safety). Any additional testing will be performed by the designated central 
laboratory or local laboratory if needed to ensure subject safety. 
8.2. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
All AEs, including both observed or volunteered problems, complaints, signs or symptoms must 
be recorded, regardless of whether associated with the use of study treatment. This would include 
AEs resulting from concurrent illness, reactions to concurrent medication use, or progression of 
disease states (excluding the disease under study). A condition present at baseline that worsens 


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after initiation of study treatment will be captured as an AE; the onset date will be the date the 
event worsened. The AE should be recorded in standard medical terminology when possible. 
8.2.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs and AEs will be collected by the investigator from the time the ICF is signed through 
the Day 115 EoS visit (Testim and Fortesta) and Day 108 (Aveed); or for 28 days after the last 
dose of study treatment for those who terminate early; this will include any AEs that are ongoing 
at the time of study completion/termination. All ongoing AEs must be followed until resolution 
or for 28 days after the subject’s last study treatment, whichever comes first. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Section 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
The investigator is not obligated to actively seek AEs and SAEs after conclusion of subject study 
participation. However, if the investigator learns of any SAE, including death, at any time after 
the subject has been discharged from the study, the investigator must promptly notify the sponsor 
to comply with postmarketing reporting requirements for marketed products being used for 
approved indications. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and submitting SAE reports are provided in Section 10.3. 
8.2.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences.  
At each visit, subjects will be queried regarding any AEs that have occurred since the last visit. 
Subjects will be asked to volunteer information concerning AEs with a nonleading question such 
as, “How do you feel?” Study site personnel will then record all pertinent information. The study 
drug compliance record should also be reviewed to detect potential intentional or unintentional 
overdoses. 
8.2.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs and nonserious AEs will be followed to resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up. Further 
information on follow-up procedures is provided in Section 10.3. 
8.2.4. 
Secondary Exposure to Testim and Fortesta 
The FDA has mandated that secondary exposure data be collected on anyone exposed to Testim 
and Fortesta. 
Investigators should explain to all subjects that there is the potential to transfer testosterone to 
another individual when vigorous skin-to-skin contact is made with the application site. 
Investigators should ask every subject about any possible secondary exposure of other 


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individuals due to the potential transfer. All such known secondary exposure must be reported to 
the sponsor within 24-hours on the Endo Serious Adverse Event (SAE)/Reportable Event form. 
AEs/SAEs that occur due to potential secondary exposure must be processed within the same 
SAE reporting timelines as those described in Section 10.3. 
8.2.5. 
Pregnancy 
All pregnancies that occur in the partner of a treated participant that are identified during or after 
this study, where the estimated date of conception is determined to have occurred during study 
treatment or within 28 days of the last study treatment need to be reported, followed to 
conclusion, and the outcome reported, even if the participant is discontinued from the study. The 
investigator should report (as outlined above) all pregnancies within 24 hours using the 
Pregnancy Form. Monitoring of the pregnancy should continue until conclusion of the pregnancy 
and follow-up information detailing the progress and outcome should be submitted on 1 or more 
Pregnancy Form(s) detailing progress, and a Two-Month Follow-up Pregnancy Report Form 
detailing the status of the infant should be submitted. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Likewise, elective abortions without complications are not considered AEs. Any SAEs 
associated with pregnancy (eg, congenital abnormalities/birth defects, or any other serious 
events) must additionally be reported as such using the Serious Adverse Event (SAE)/Reportable 
Event Form (see Section 10.3). Spontaneous miscarriages should also be reported and handled as 
SAEs.  
8.3. 
Treatment Overdose 
Study treatment overdose is any accidental or intentional use of treatment in an amount higher 
than the dose indicated by the protocol for that subject. Study treatment compliance should be 
reviewed to detect potential instances of overdose (intentional or accidental). 
Any treatment overdose during the study should be noted on the study drug eCRF.  
An overdose is not an AE per se, however all AEs associated with an overdose should both be 
entered on the Adverse Event eCRF and reported using the procedures detailed in Section 10.3, 
even if the events do not meet seriousness criteria. If the AE associated with an overdose does 
not meet seriousness criteria, it must still be reported using the Endo Serious Adverse Event 
(SAE)/Reportable Event Form and in an expedited manner, but should be noted as nonserious on 
the form and the Adverse Event eCRF.  
8.3.1. 
Treatment Abuse/Misuse 
Not applicable. 
8.4. 
Pharmacokinetics 
Not applicable. 
8.5. 
Pharmacodynamics 
Not applicable. 


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8.6. 
Genetics 
Not applicable. 
8.7. 
Biomarkers 
Not applicable. 
8.8. 
Medical Resource Utilization and Health Economics 
Not applicable. 
9. 
STATISTICAL CONSIDERATIONS AND METHODS 
This section provides a general summary of the statistical methods to be used in analyzing study 
data. A more detailed statistical analysis plan (SAP) will be developed and finalized prior to the 
database lock. 
9.1. 
Sample Size Determination 
The objective of this study is to determine whether the study drugs have a clinically meaningful 
effect on ambulatory BP in hypogonadal men. The primary endpoint will be the mean change 
from baseline to EoS in 24-hour average SBP. 
A sample size of 144 for each of the 3 treatment groups (Aveed, Fortesta, and Testim) achieves 
90% statistical power to exclude an upper bound of 3-mm Hg threshold SBP increase in 24-hour 
average systolic ambulatory BP at EoS from baseline using 2-sided 95% CI with paired t test. 
The SD of 11 mm Hg is assumed.  
It is assumed that 30% of enrolled subjects will be excluded from the Full Analysis Set 
(ie, subjects who discontinue early from the study, non-valid ABPM measures at baseline or 
EoS, etc), therefore a sample size of 206 for each of the 3 treatment groups is required. 
9.2. 
Analysis Populations 
Four analysis populations will be considered in the study: the Safety Population, the Intent-to-
Treat Population (ITT), the Full Analysis Set (FAS), and the ABPM Population. 
• Safety Population: will include all subjects who receive at least 1 dose/injection of 
study treatment. All safety analyses will be based on the Safety Population. 
• Intent-to-Treat Population (ITT): will include all randomized subjects who have at 
least 1 dose/injection of study medication. Sensitivity analysis for primary and 
secondary efficacy analysis will be based on this population to assess the effect due to 
study discontinuation. 
• Full Analysis Set (FAS): will include all ITT subjects with valid baseline and EoS 
ABPM assessments. All primary and secondary efficacy analysis will be based on the 
ABPM Population. 


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• ABPM Population: will include all FAS subjects with at least 85% compliance to 
treatment during the study. All primary and secondary efficacy analysis will be based 
on the ABPM Population. 
9.3. 
Statistical Analyses 
9.3.1. 
Efficacy Analysis 
9.3.1.1. 
Primary Analysis 
The primary endpoint will be the mean change from baseline to EoS in 24-hour average systolic 
ambulatory BP for each treatment group. This endpoint will be analyzed using an analysis of 
covariance (ANCOVA) model with baseline and study center, or pooled centers (if applicable), 
included as covariates. The mean estimate, and the corresponding 95% 2-sided confidence 
intervals (CIs) of the estimate, will be provided for each treatment group. If the upper limit of the 
2-sided 95% CI falls below 3.0 mm Hg, it will be concluded that the tested treatment does not 
have statistical significance in increasing of 24-hour systolic ambulatory BP.  
The mean of hourly systolic ambulatory BP at baseline and EoS will be graphically presented for 
each treatment group. The cumulative distribution function plots will also be plotted for the 
means of the daytime, nighttime, and 24-hour systolic ambulatory BP at baseline and EoS.  
Descriptive analysis for the changes from baseline at each time point and 24-hour average for all 
ABPM parameters will be presented for each treatment group.  
The ABPM Population across treatment groups will be further divided into the following 
3 groups: subjects without hypertension, with hypertension untreated, and with hypertension 
treated. In addition, subgroups such as African Americans and the elderly will be examined. A 
similar analysis described in the primary analysis will be applied to these subgroups. 
The descriptive statistics, ie, the number and percentage of subjects meeting the following BP 
thresholds will be provided: ≥ 160 mm Hg SBP, ≥ 100 mm Hg DBP, ≥ 20 mm Hg increase from 
baseline SBP and ≥ 15 mm Hg increase from baseline DBP. 
9.3.1.2. 
Secondary Analysis 
All secondary analysis will be summarized by treatment group using appropriate descriptive 
statistics. 
9.3.1.3. 
Sensitivity Analysis 
Two type of sensitivity analysis will be performed: 1) primary and secondary analysis based on 
ABPM population, 2) primary and secondary analysis based on ITT population to account for 
missing data due to study discontinuation. 
9.3.2. 
Safety Analyses 
Assessment of safety will be based on the incidence of AEs, AEs resulting in discontinuation, 
SAEs, laboratory parameters and vital signs. AE summaries will be provided showing the 
number and percentage of subjects who experienced at least 1 AE. Laboratory data and their 
change from baseline will be summarized using descriptive statistics. Shift tables to summarize 


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change from baseline to post baseline visits will also be presented (eg, normal to high, normal to 
low). Vital signs data and any changes from baseline will be summarized using descriptive 
statistics. 
9.3.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by 
preferred term within system organ class. The number of AEs and the number of subjects 
reporting AEs will be listed and summarized descriptively by body system, preferred term, 
severity, and causality for each treatment group. Only treatment-emergent adverse events 
(TEAEs) (events that are new in onset or aggravated in severity following treatment) will be 
included in all summaries. SAEs (including death) will be summarized.  
9.3.3. 
Serum Laboratory Testing 
Serum testosterone levels will be summarized by treatment group and time point using 
appropriate descriptive statistics. For more information see the SAP. 
9.4. 
Interim Analysis 
Not applicable. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This clinical study is designed to comply with the ICH Guidance on General Considerations for 
Clinical Trials (62 FR 6611, December 17, 1997), Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials for Pharmaceuticals (62 FR 62922, November 25, 1997), Good Clinical 
Practice: Consolidated Guidance (62 FR 25692, May 9, 1997) and 21 CFR parts 50, 54, 56 and 
312. 
The study will be conducted in full compliance with ICH E6, the FDA guidelines for good 
clinical practice (GCP) and in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki defined in 21 CFR, 312.120. 
Approval by the IRB/IEC prior to the start of the study will be the responsibility of the 
investigator. A copy of approval documentation will be supplied to Endo along with a roster of 
IRB/IEC members that demonstrates appropriate composition or other documentation of 
assurance of appropriate composition per local and national regulations (eg, a Department of 
Health and Human Services Assurance Number will satisfy this requirement for IRBs in the 
United States).  
The study protocol, the ICF, advertisements, materials being provided to subjects, and 
amendments (if any) will be approved to IRB/IECs at each study center in conformance with 
ICH E6, CFR Title 21 Part 56, and any other applicable local laws. The investigator is 
responsible for supplying the IRB/IEC with a copy of the current Investigator’s Brochure, 
Package Insert, or Summary of Product Characteristics, as well as any updates issued during the 
study. During the course of the study, the investigator will provide timely and accurate reports to 
the IRB/IEC on the progress of the study, at intervals not exceeding 1 year (or as appropriate), 
and will notify the IRB/IEC of SAEs or other significant safety findings, per the policy of the 
IRB/IEC. At the conclusion of the study, the investigator will submit a final report or close out 
report to the IRB/IEC and provide a copy to Endo. 
Any amendment to this protocol will be provided to the investigator in writing by Endo. No 
protocol amendment may be implemented (with the exceptions noted below) before it has been 
approved by the IRB/IEC and the signature page, signed by the investigator, has been received 
by Endo. Where the protocol is amended to eliminate or reduce the risk to the subject, the 
amendment may be implemented before IRB/IEC review and approval. However, the IRB/IEC 
must be informed in writing of such an amendment and approval obtained within reasonable time 
limits. Deviating from the protocol is permitted only if absolutely necessary for the safety or 
clinical management of the subject, and must be immediately reported to Endo.  
The investigator will be responsible for supplying updated safety and/or study information to 
study subjects as it becomes available.  


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10.1.2. 
Financial Disclosure 
The investigator and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. The investigator is 
responsible for providing information on financial interests during the course of the study and for 
1 year after the completion of the study. 
10.1.3. 
Informed Consent Process 
The ICF must be approved by the sponsor and the IRB/IEC before any subject provides consent. 
The investigator will provide the sponsor with a copy of the IRB/IEC-approved ICF and a copy 
of the IRB/IEC’s written approval before the start of the study. 
The ICF must contain all applicable elements of informed consent and the mandatory statements 
as defined by national and local regulations, including confidentiality.  
If appropriate, the ICF will contain a separate section that addresses the use of remaining 
mandatory samples for optional exploratory research. The investigator or authorized designee 
will explain to each subject the objectives of the exploratory research. Subjects will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document a subject’s 
agreement to allow any remaining specimens to be used for exploratory research. Subjects who 
decline to participate in this optional research will not provide this separate signature. 
At the Screening Visit (and at other time as may be required by the study or when changes are 
made to the consent form), subjects will read the consent form(s) and any privacy authorization 
as required by local and national regulations (such as the Health Insurance Portability and 
Accountability Act [HIPAA] authorization form), after being given an explanation of the study. 
Before signing the consent form(s) and the privacy authorization form (if applicable), subjects 
will have an opportunity to ask questions about the study and discuss the contents of these forms 
with study site personnel. The consent/assent process shall be recorded in source documents. 
Subjects must assent understanding of and voluntarily sign these forms in compliance with ICH 
GCP and all applicable national and international regulations, before participating in any 
study-related procedures. Subjects will be made aware that they may withdraw from the study at 
any time for any reason.  
All versions of each subject’s signed ICF must be kept on file by the site for possible inspection 
by regulatory authorities and the sponsor. Signed copies of the consent form(s) and the privacy 
authorization form, if applicable, will be given to the subject.  
The subjects will be made aware of their right to see and copy their records related to the study 
for as long as the investigator has possession of this information. If the subject withdraws 
consent and/or HIPAA authorization, the investigator can no longer disclose health information, 
unless it is needed to preserve the scientific integrity of the study. 


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10.1.4. 
Data Protection 
Study subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
The subject must be informed that his personal study-related data will be used by the sponsor in 
accordance with local data protection law. The level of disclosure (in accordance with local 
and/or national law) must also be explained to the subject.  
The subject must be informed that his medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committee Structure 
No monitoring committees will be used for this study. 
10.1.6. 
Dissemination of Clinical Study Data 
Aggregate results data will be provided to the sites that actively enrolled subjects into this study 
after the clinical study report is finalized. 
Study results and de-identified individual subject data will be released as required by local and/or 
national regulation. 
10.1.7. 
Data Quality Assurance 
Steps to assure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study centers, review of protocol procedures with the investigators and 
associated personnel prior to start of the study, and periodic monitoring visits conducted by the 
sponsor or sponsor representative. Significant and/or repeated noncompliance will be 
investigated and remedial action instituted when appropriate. Failure to comply with remedial 
actions may result in investigator site termination and regulatory authority notification. 
The sponsor or its designee will utilize qualified monitors to review and evaluate activities 
conducted at investigator sites. 
The data will be entered into the clinical study database in a timely fashion and will be verified 
for accuracy, following procedures defined by the sponsor (or designee). Data will be processed 
and analyzed following procedures defined by the sponsor (or designee). 
The study will be monitored and/or audited at intervals to ensure that the clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
study protocol, ICH E6 consolidated guidelines, and other applicable regulations. The extent, 
nature, and frequency of monitoring and/or audits will be based on such considerations as the 
study objectives and/or endpoints, the purpose of the study, study design complexity, and 
enrollment rate. At the conclusion of a program, a compliance statement will be generated by the 
sponsor (or designee) listing all audit activities performed during the clinical study. 
All data recordings and source documentation (including electronic health records) must be made 
available to the sponsor (or designee), FDA and any other regulatory agencies that request access 
to study records for inspection and copying, in keeping with national and local regulations. 


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The investigator shall permit audits and inspections by the sponsor, its representatives, and 
members of regulatory agencies. The investigator should immediately notify the sponsor of an 
upcoming FDA or other regulatory agency inspection. 
10.1.8. 
Source Documents 
All subject information recorded in the eCRF will be attributable to source data from the 
investigational site unless otherwise outlined in this protocol. 
Source documents include but are not limited to original documents, data, and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, subject 
diaries, data recorded in automated instruments, microfilm or magnetic media, and pharmacy 
records, etc. At a minimum, all data required to be collected by the protocol should have 
supporting source documentation for entries in the eCRF, unless the protocol specifies that data 
can be recorded directly on/in the eCRF or other device. 
The investigator shall retain and preserve 1 copy of all data collected or databases generated in 
the course of the study, specifically including but not limited to those defined by GCP as 
essential. Essential documents should be retained until at least 3 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 3 years have elapsed since the formal discontinuation of 
clinical development of the investigational medicinal product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. Prior to 
destruction of any study essential documents, the investigator must first obtain written approval 
from the sponsor. 
10.1.9. 
Study and Site Closure 
The sponsor has the right to suspend or terminate the study at any time. The study may be 
suspended or terminated for any reason. 
10.1.10. 
Publication Policy 
All data generated in this study are the property of Endo. An integrated clinical and statistical 
report will be prepared at the completion of the study. 
Publication of the results by the investigator will be subject to mutual agreement between the 
investigator and Endo. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Red blood cell 
White blood cell (WBC) 
Platelets 
WBC Differential 
Glucose 
Sodium 
Potassium 
Calcium 
Chloride 
Carbon dioxide (CO2) 
Inorganic phosphate 
Blood urea nitrogen  
Creatinine 
Creatinine clearance (estimated)  
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Gamma-glutamyl transferase (GGT) 
Total bilirubin (TBL) (direct bilirubin reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Uric acid 
Glucose 
Protein 
Specific gravity 
pH 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Blooda 
Leukocytesa 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definitions 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc), or worsening of a preexisting 
condition associated temporally with the use of the study medication whether or not considered 
related to the study medication. AEs will be captured once a subject has signed the informed 
consent. AEs include: 
• Changes in the general condition of the subject. 
• Subjective symptoms offered by or elicited from the subject. 
• Objective signs observed by the investigator or other study personnel. 
• All concurrent diseases that occur after the start of the study, including any change in 
severity or frequency of preexisting disease. 
• All clinically relevant laboratory abnormalities or physical findings that occur during 
the study. 
A TEAE is any condition that was not present prior to treatment with study medication but 
appeared following treatment, was present at treatment initiation but worsened during treatment, 
or was present at treatment initiation but resolved and then reappeared while the individual was 
on treatment (regardless of the intensity of the AE when the treatment was initiated). 


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An SAE is defined as an AE that: 
• Results in death. 
• Is immediately life-threatening (there is an immediate risk of death from the AE as it 
occurred; this does not include an AE that had it occurred in a more serious form may 
have caused death). 
• Results in or prolongs an inpatient hospitalization (Note: a hospitalization for elective 
or preplanned surgery, procedure, or drug therapy does not constitute an SAE).  
• Results in permanent or substantial disability (permanent or substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect (in offspring of a subject using the study 
medication regardless of time to diagnosis). 
• Is considered an important medical event. 
Important medical events are defined as events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other serious outcomes. Examples of important medical 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. 
10.3.2. 
Relationship to Study Drug 
The degree of “relatedness” of the AE to the study medication must be described using the 
following scale:  
• Not related indicates that the AE is definitely not related to the study medication. 
• Unlikely related indicates that there are other, more likely causes and study 
medication is not suspected as a cause. 
• Possibly related indicates that a direct cause and effect relationship between study 
medication and the AE has not been demonstrated, but there is evidence to suggest 
there is a reasonable possibility that the event was caused by the study medication. 
• Probably related indicates that there is evidence suggesting a direct cause and effect 
relationship between the AE and the study medication. 
It is the sponsor’s policy to consider “probably related” and “possibly related” causality 
assessments as positive causality. “Not related” and “unlikely related” causality assessments are 
considered as negative causality. 
Assessments will be recorded on the eCRF and must indicate clearly the relationship being 
assessed. For example, an AE that appears during a placebo run-in phase would be assessed with 
respect to the placebo treatment received and/or study procedures conducted during this phase. If 
the AE continued into an active treatment phase, the relationship would be assessed for the active 
treatment phase only if the AE worsened. 


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10.3.3. 
Intensity Assessment 
The intensity (or severity) of AEs is characterized as mild, moderate, or severe: 
• Mild AEs are usually transient, requiring no special treatment, and do not interfere 
with the subject’s daily activities. 
• Moderate AEs introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures. 
• Severe AEs interrupt a subject’s usual daily activity and typically require systemic 
drug therapy or other treatment. 
10.3.4. 
Reporting Adverse Events and Serious Adverse Events 
10.3.4.1. Reporting Adverse Events 
Throughout the study, AEs will be documented on the source document and on the appropriate 
page of the eCRF whether or not considered treatment-related. This includes any new signs, 
symptoms, injury, or illness, including increased severity of previously existing signs, symptoms, 
injury, or illness. Conditions existing prior to screening will be recorded as part of the subject’s 
medical history. The investigator is responsible for assessing the relationship of AEs to the study 
medication; relationship will be classified as not related, unlikely related, possibly related, or 
probably related.  
All AEs will be collected by the investigator from the time of signing the ICF through the 
Day 115 EoS Visit (Testim and Fortesta) and Day 108 (Aveed); or for 28 days after the last dose 
of study treatment in those subjects who terminate early. All ongoing AEs must be followed until 
resolution or for 28 days after the last dose of study treatment, whichever comes first. 
10.3.4.2. Reporting Serious Adverse Events 
Any SAE, including death resulting from any cause, which occurs to any subject participating in 
this study must be reported via email or fax by the investigator using the Endo Serious Adverse 
Event (SAE)/Reportable Event Form within 24 hours of first becoming aware of the SAE. SAEs 
will be collected by the investigator from the time of signing the ICF through the Day 115 EoS 
visit (Testim and Fortesta) and Day 108 (Aveed); or for 28 days after the last dose of study 
medication in those subjects who terminate early. SAEs that occur within 28 days, following 
cessation of the study treatment, or within 28 days, following premature discontinuation from the 
study for any reason, must also be reported within the same timeframe. If the investigator learns 
of any SAE, including death, at any time after the subject has been discharged from the study, 
the investigator must promptly notify the sponsor to comply with postmarketing reporting 
requirements for marketed products being used for approved indications. Follow-up information 
collected for any initial report of an SAE must also be reported to the sponsor within 24 hours of 
receipt by the investigator.  
All SAEs will be followed until resolution, stabilization of condition, or until follow-up is no 
longer possible. 
All SAEs should be reported via email (safety@endo.com) or fax (610-968-7135). 


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The sponsor will determine whether the SAE must be reported within 7 or 15 days to regulatory 
authorities in compliance with local and regional law. If so, the sponsor (or the sponsor’s 
representative) will report the event to the appropriate regulatory authorities. The investigator 
will report SAEs to the IRB/IEC per their IRB/IEC policy. 
10.3.4.3. Follow-up Procedures for Serious Adverse Events 
To fully understand the nature of any SAE, obtaining follow-up information is important. 
Whenever possible, relevant medical records such as discharge summaries, medical 
consultations, and the like should be obtained. In the event of death, regardless of cause, all 
attempts should be made to obtain the death certificate and any autopsy report. These records 
should be reviewed in detail, and the investigator should comment on any event, lab abnormality, 
or any other finding, noting whether it should be considered a serious or non-serious AE, or 
whether it should be considered as part of the subject’s history. In addition, all events or other 
findings determined to be SAEs should be identified on the Endo Serious Adverse Event (SAE)/ 
Reportable Event Form and the investigator should consider whether the event is related or not 
related to study drug. All events determined to be nonserious should be reported on the eCRF. 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
See Section 5. 
10.5. 
Appendix 5: Genetics 
Not applicable. 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Not applicable. 
10.7. 
Appendix 7: Medical Device Incidents 
Not applicable. 
10.8. 
Appendix 8: Country-specific Requirements 
Not applicable. 
 


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11. 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study in accordance with the protocol, and with all applicable government 
regulations and Good Clinical Practice guidance. 
 
 
 
_____/_____/______ 
Investigator’s Signature 
Date 
 
 
 
Typed Name of Investigator 
 


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12.
REFERENCES
Clavell-Hernandez J, Wang R. Emerging Evidences in the Long Standing Controversy 
Regarding Testosterone Replacement Therapy and Cardiovascular Events. World J Mens Health. 
2018;36(2):92-102. doi:10.5534/wjmh.17050 
Elagizi A, Kohler TS, Lavie CJ. Testosterone and Cardiovascular Health. Mayo Clin Proc. 
2018;93(1):83-100. doi:10.1016/j.mayocp.2017.11.006 
Lawrence KL, Stewart F, Larson BM. Approaches to male hypogonadism in primary care. Nurse 
Pract. 2017;42(2):32-37. doi:10.1097/01.NPR.0000511774.51873.da 
Loo S, Azoulay L, Nie R, Dell’Aniello S, Yu OHY, Renoux C. Cardiovascular and 
Cerebrovascular Safety of Testosterone Replacement Therapy Among Aging Men with Low 
Testosterone Levels: A Cohort Study. Am J Med. 2019;132(9):1069-1077.e4. 
doi:10.1016/j.amjmed.2019.03.022 
Malkin C, Pugh PJ, Jones TH, Channer KS. Testosterone for secondary prevention in men with 
ischemic heart disease? Q J Med. 2003;96(7):521-9. doi:10.1093/qjmed/hcg086 
O’Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on 
ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-1768. 
doi:10.1097/HJH.0b013e328363e964 
Odell WD, Swerdloff RS. Abnormalities of gonadal function in men. Clin Endocrinol (Oxf). 
1978;8(2):149-80. 
Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 
1995;75(3):473-86. 
Rommerts F. Testosterone: an overview of biosynthesis, transport, metabolism and nongenomic 
actions. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency and Substitution. 
3rd ed. Cambridge University Press; 2004:1-31. 
Ruige JB, Ouwens DM, Kaufman JM. Beneficial and adverse effects of testosterone on the 
cardiovascular system in men. J Clin Endocrinol Metab. 2013;98(11):4300-10. 
doi:10.1210/jc.2013-1970 
Surampudi P, Swerdloff RS, Wang C. An update on male hypogonadism therapy. Expert Opin 
Pharmacother. 2014;15(9):1247-1264. doi:10.1517/14656566.2014.913022 
Thirumalai A, Berkseth KE, Amory JK. Treatment of Hypogonadism: Current and Future 
Therapies. F1000Res. 2017;6:68. doi:10.12688/f1000research.10102.1 
White WB, Bernstein JS, Rittmaster R, Dhingra O. Effects of the oral testosterone undecanoate 
Kyzatrex™ on ambulatory blood pressure in hypogonadal men. J Clin Hypertens (Greenwich). 
2021 Jul;23(7):1420-1430. doi: 10.1111/jch.14297. Epub 2021 Jun 11.  

SAP_001.pdf: 
Statistical Analysis Plan (SAP) – Protocol EN3000-101 
11-Jan-2021
Endo Pharmaceuticals Inc. 
Page 1 
 
SAP MODULE 1 – DETAILED STATISTICAL METHODOLOGY 
Protocol No. EN3000-101 Amendment 2: September 15, 2020 
AN OPEN-LABEL, RANDOMIZED, PARALLEL-GROUP,  
THREE TREATMENT ARM, MULTICENTER STUDY ON 
HYPOGONADAL MALES TO EVALUATE THE EFFECT  
ON 24-HOUR AMBULATORY BLOOD PRESSURE  
AFTER 16-WEEK CONTINUOUS TREATMENT  
WITH MARKETED TESTOSTERONE PRODUCTS 
Version 2.0 
January 11, 2021 
Endo Pharmaceuticals Inc. 
1400 Atwater Drive  
Malvern, PA 19355  
USA 
NCT #: NCT04456296


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
11-Jan-2021 
Endo Pharmaceuticals Inc. 
Page 2 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES ................................................................................................9 
3. 
STUDY DESIGN AND MEASURES .........................................................................9 
3.1. 
Study Design .................................................................................................................9 
3.1.1. 
Screening Phase (Day -28 to -2) .................................................................................10 
3.1.2. 
Baseline Phase (Day -1 to 2) ......................................................................................10 
3.1.3. 
Treatment Phase ..........................................................................................................11 
3.1.3.1. 
TESTIM and FORTESTA Treatment Arm (Day 2 to 97) ..........................................11 
3.1.3.2. 
AVEED Treatment Arm (Day 2 to 100) .....................................................................11 
3.1.4. 
Ambulatory Blood Pressure Monitoring (End of Study) ............................................11 
3.1.4.1. 
TESTIM and FORTESTA Treatment Arm (Day 113 to 115) ....................................11 
3.1.4.2. 
AVEED Treatment Arm (Day 106 to 108) .................................................................12 
3.1.4.3. 
End-of-Study Definition .............................................................................................12 
3.1.5. 
Study Duration ............................................................................................................12 
3.1.6. 
Schedule of Activities .................................................................................................12 
3.2. 
Eligibility Criteria for Subject Selection ....................................................................18 
3.2.1. 
Inclusion Criteria ........................................................................................................18 
3.2.2. 
Exclusion Criteria .......................................................................................................18 
3.3. 
Randomization Criteria ...............................................................................................20 
3.4. 
Method of Assignment of Subjects to Treatment Groups ..........................................20 
3.5. 
Study Treatment ..........................................................................................................21 
3.6. 
Determination of Sample Size ....................................................................................21 
3.7. 
International Prostate Symptoms Score (IPSS) ..........................................................21 
3.8. 
Digital Rectal Examination of the Prostate.................................................................23 
3.9. 
Medical and Surgical History .....................................................................................23 
3.10. 
Substance Use .............................................................................................................23 
3.11. 
Prior and Concomitant Medications and Procedures ..................................................23 
3.12. 
Prohibited Medications ...............................................................................................23 
3.13. 
Efficacy Parameters ....................................................................................................24 
3.13.1. 
24-Hour Ambulatory Blood Pressure Monitoring (ABPM) .......................................24 
3.14. 
Safety Parameters .......................................................................................................24 


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3.14.1. 
Adverse Events ...........................................................................................................24 
3.14.1.1. 
Adverse Events (AEs) .................................................................................................24 
3.14.1.2. 
Serious Adverse Events (SAEs) .................................................................................24 
3.14.2. 
Clinical Laboratory Determinations ...........................................................................25 
3.14.3. 
Serum Testosterone Assessment .................................................................................25 
3.14.4. 
Height and Weight ......................................................................................................25 
3.14.5. 
Vital Signs ..................................................................................................................26 
3.14.6. 
Electrocardiogram .......................................................................................................26 
3.14.7. 
Physical Examination .................................................................................................26 
3.14.8. 
Study Treatment Compliance .....................................................................................27 
4. 
STUDY PARAMETERS ............................................................................................27 
4.1. 
Subject Disposition .....................................................................................................27 
4.2. 
Protocol Deviations ....................................................................................................27 
4.3. 
Demographic and Baseline Characteristics ................................................................28 
4.4. 
Prior and Concomitant Medications/Therapies ..........................................................29 
4.5. 
Efficacy Parameters ....................................................................................................29 
4.5.1. 
Valid ABPM Session ..................................................................................................29 
4.5.2. 
Primary Efficacy Parameters ......................................................................................29 
4.5.2.1. 
Mean Change from Baseline in 24-hour Average Systolic Ambulatory Blood 
Pressure .......................................................................................................................29 
4.5.3. 
Secondary Efficacy Parameters ..................................................................................30 
4.5.3.1. 
Mean Change from Baseline in 24-hour Average and Time Windows of 
Interest in ABPM Parameters .....................................................................................30 
4.5.4. 
Change from Baseline Over Time in ABPM Parameters ...........................................30 
4.5.5. 
Subjects with Antihypertensive Medication ...............................................................30 
4.5.5.1. 
Ambulatory Blood Pressure Thresholds .....................................................................30 
4.6. 
Safety Parameters .......................................................................................................31 
4.6.1. 
Extent of Exposure to Study Treatment ......................................................................31 
4.6.2. 
Adverse Events ...........................................................................................................31 
4.6.2.1. 
Treatment Emergent Adverse Events (TEAEs) ..........................................................31 
4.6.2.2. 
Intensity of Adverse Events ........................................................................................31 
4.6.2.3. 
Relationship to Study Drug ........................................................................................31 
4.6.3. 
Vital Signs and Clinical Laboratories .........................................................................32 


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4.6.3.1. 
Potentially Clinically Important Laboratory Values ...................................................32 
4.6.3.2. 
Potentially Clinically Important Vital Sign Values ....................................................32 
5. 
ANALYSIS POPULATIONS ....................................................................................33 
6. 
STATISTICAL METHODS .......................................................................................33 
6.1. 
General Methodology .................................................................................................33 
6.2. 
Adjustments for Covariates ........................................................................................34 
6.3. 
Examination of Subgroups .........................................................................................34 
6.4. 
Derived Variables .......................................................................................................34 
6.5. 
Handling of Missing Data ...........................................................................................36 
6.5.1. 
Missing data handling for Primary and Secondary Analyses .....................................36 
6.5.2. 
Missing data handling for Safety Data .......................................................................36 
6.5.3. 
Imputation of Partial Dates .........................................................................................36 
6.5.3.1. 
TEAE Status for Completely Unknown Start Date ....................................................36 
6.5.3.2. 
Concomitant Status of Medication/Non-drug Therapy for Completely 
Unknown Start Date ...................................................................................................37 
6.6. 
Pooling of Centers ......................................................................................................37 
6.7. 
Interim Analyses .........................................................................................................37 
7. 
STATISTICAL ANALYSES .....................................................................................38 
7.1. 
Subject Disposition .....................................................................................................38 
7.2. 
Protocol Deviations ....................................................................................................38 
7.3. 
Demographics and Baseline Characteristics ...............................................................38 
7.4. 
Medical and Surgical History .....................................................................................39 
7.5. 
Prior, Concomitant Medications and Procedures .......................................................39 
7.6. 
Efficacy Analyses .......................................................................................................39 
7.6.1. 
Primary Analysis ........................................................................................................39 
7.6.1.1. 
Mean Change from Baseline in 24-hour Average Systolic Ambulatory Blood 
Pressure .......................................................................................................................39 
7.6.2. 
Secondary Analysis ....................................................................................................40 
7.6.2.1. 
Mean Change from Baseline in 24-hour Average and Time Windows of 
Interest in ABPM Parameters .....................................................................................40 
7.6.2.2. 
Change from Baseline Over Time in ABPM Parameters ...........................................40 
7.6.2.3. 
Subjects with Antihypertensive Medication ...............................................................40 
7.6.3. 
Outlier Analysis ..........................................................................................................41 


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
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7.6.4. 
Sensitivity Analysis ....................................................................................................41 
7.6.4.1. 
Sensitivity Analysis on ABPM Population .................................................................41 
7.6.4.2. 
Sensitivity Analysis on ITT Population ......................................................................41 
7.6.5. 
Subgroup Analyses .....................................................................................................42 
7.7. 
Safety Analyses ..........................................................................................................42 
7.7.1. 
Study Drug Exposure ..................................................................................................43 
7.7.2. 
Adverse Events ...........................................................................................................43 
7.7.3. 
Clinical Laboratory .....................................................................................................44 
7.7.4. 
Vital Signs ..................................................................................................................44 
7.7.5. 
12-Lead ECG ..............................................................................................................45 
7.7.6. 
Physical Examination .................................................................................................45 
7.8. 
Other Analyses ............................................................................................................45 
7.8.1. 
Serum Laboratory Testing ..........................................................................................45 
8. 
CHANGE FROM PROTOCOL .................................................................................45 
9. 
REVISION HISTORY ...............................................................................................45 
10. 
REFERENCES ...........................................................................................................46 
List of Tables .................................................................................................................................48 
List of Data Listings.......................................................................................................................57 
List of Figures ................................................................................................................................59 
 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
Schedule of Activities – TESTIM and FORTESTA ..................................................13 
Table 3: 
Study Schedule of Activities – AVEED (Testosterone Undecanoate 
Injection) .....................................................................................................................16 
Table 4: 
Study Treatments ........................................................................................................21 
Table 5: 
IPSS Questionnaire .....................................................................................................22 
Table 6: 
IPSS Total Symptom Score ........................................................................................23 
Table 9: 
Potentially Clinically Important Laboratory Criteria..................................................32 
Table 10: Potentially Clinically Important Vital Sign Criteria ...................................................32 
Table 11: Analysis Populations ..................................................................................................33 
Table 12: Derived Variables and Definition ...............................................................................35 
Table 13: Changes from Protocol ...............................................................................................45 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AM 
ante meridiem 
AR (1) 
Auto-regressive (1) 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BP 
Blood pressure 
BPH 
Benign prostatic hyperplasia 
bpm 
Beats per minute 
BMI 
Body Mass Index 
brpm 
Breaths per minute 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cm 
centimeter 
CO2 
Carbon dioxide 
CYP3A 
cytochrome P450 3A 
DBP 
Diastolic blood pressure 
DMP 
Data Management Plan 
DRE 
Digital rectal examination 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EoS 
End-of-study 
ET 
Early termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GGT 
Gamma-glutamyl transferase 
HR 
Heart rate 
IEC 
Independent ethics committee 
IM 
Intramuscular 
IPSS 
International Prostate Symptom Score 
IRB 
Institutional review board 


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
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Endo Pharmaceuticals Inc. 
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Abbreviation 
Definition 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
kg 
kilogram 
MAP 
Mean arterial pressure 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
mm Hg 
millimeter of mercury 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potentially clinically important 
PI 
Prescribing information 
PP 
Pulse pressure 
PSA 
Prostate-specific antigen 
PT 
Preferred term 
REMS 
Risk evaluation and mitigation strategies 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SoA 
Schedule of activities 
SOC 
System organ class 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TOEPH 
Heterogeneous Toeplitz 
ULN 
upper limit of normal 
UN 
Unstructured 
WBC 
White blood cell 
WHO 
World Health Organization 


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the analysis that will be performed to evaluate the 
effect on 24-hour ambulatory blood pressure after 16 weeks continuous treatment with marketed 
testosterone products on hypogonadal males. 
The general information about the study is detailed in the EN3000-101 protocol, original 
protocol dated November 17, 2019, Amendment 1 dated March 19, 2020, and Amendment 2 
dated September 15, 2020 (1). 
2. 
STUDY OBJECTIVES 
The study objectives and corresponding endpoints are outlined in Table 1 below. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the change from baseline in mean 
24-hour systolic blood pressure (SBP) after 
16 weeks of continuous treatment with study 
drug as indicated by the prescribing 
information (PI). 
• 
Mean change from baseline to end-of-study 
(EoS) in 24-hour average systolic ambulatory 
blood pressure (BP). 
Secondary 
• 
To assess the safety of 16 weeks of continuous 
treatment with study drug as indicated by PI. 
• 
Mean change from baseline in 24-hour average 
and time windows of interest in mean arterial 
pressure (MAP), SBP, diastolic blood pressure 
(DBP), pulse pressure (PP), and heart rate 
(HR) obtained during treatment. 
• 
Change from baseline over time (hourly 
average) by nominal clock time and time after 
dose in MAP, SBP, DBP, PP, and HR. 
• 
Percent of subjects with new antihypertensive 
medications. 
• 
Percent of subjects with dose increases in 
antihypertensive medications. 
3. 
STUDY DESIGN AND MEASURES 
3.1. 
Study Design 
This is a Phase 4, open-label, randomized, parallel-group, 3 treatment-arm, multicenter study on 
hypogonadal males to evaluate the effect on 24-hour ambulatory blood pressure after 16 weeks 
of continuous treatment with marketed testosterone products. 


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The study will enroll a total of approximately 729 hypogonadal males with controlled 
hypertension and without hypertension across the 3 treatment arms. The study will consist of a 
Screening Phase (Day -28 to -2), followed by a 24-hour ambulatory blood pressure monitoring 
(ABPM) phase (Baseline Phase, Day -1 to 2), Treatment Phase (Day 2 to 100) and ABPM at the 
EoS visits (Day 106 to 115). Table 2 and Table 3 present the details of visit information. It can 
be seen that event days are different between AVEED® (testosterone undecanoate) injection and 
TESTIM® (testosterone gel)/FORTESTA® (testosterone) gel treatment.  
The subjects will be randomly assigned to 1 of 3 treatment arms after a valid 24-hour ABPM 
session (baseline) has been confirmed. 
Subjects who started this study prior to a COVID-19 interruption will be allowed to continue in 
the study and complete all remaining assessments, if willing to do so in accordance with the 
scheduling outlined in Protocol Section 1.2.  
A subject who does not meet all of the eligibility criteria and is considered a screen failure may 
be rescreened once rescreening related procedures to the study treatment must not exceed 28 
days.  
3.1.1. 
Screening Phase (Day -28 to -2)  
Screening will take place on multiple days between Day -28 and Day -2. Each subject’s 
eligibility will be evaluated during screening. Subjects found eligible will be instructed to return 
to the study center on Day -1 for further activities as per schedule of activities (SoA). 
A subject who does not meet all the eligibility criteria and is considered a screen failure will be 
rescreened once. If a subject rescreens within 30 days of their original screening date, 
assessments from the initial screening period will be used if they are valid and within protocol 
entry criteria. Any abnormal assessments will be repeated. The period from the start of 
rescreening related procedures to the study treatment should not exceed 28 days. 
3.1.2. 
Baseline Phase (Day -1 to 2) 
Blood samples will be collected on Day -1 for a baseline serum testosterone assessment (day 
before ABPM). All eligible subjects will come to the study center on Day 1 for ABPM. A 
24-hour ambulatory blood pressure recorder machine will be attached to the subject’s arm, at 
bicep level. The machine will be set to measure BP every 30 minutes for the next 24 hours.  
Baseline BP will be analyzed (systolic and diastolic means) for the overall 24-hour period, 
daytime (from waking up to bedtime) and night-time (from retiring to bed until waking) for each 
subject. The 24-hour ambulatory blood pressure recorder machine must be returned to the study 
site by the subject on the following day (Day 2). The subject will use the same device at both the 
Day 1 and as applicable, the EoS or Early Termination (ET) visit. 
In order to receive study drug on Day 2, the investigator (or qualified designee) must review and 
consider the baseline 24-hour ABPM as valid. If a subject does not have a valid ABPM session 
(defined as ≥ 70% of expected measurements including 20 valid awake [0900-2100 h] and 
7 valid sleep [0100-0600 h] measurements) at baseline due to device error (including 
displacement of cuff or likewise), the ABPM session will be repeated once in order to obtain a 
valid ABPM session. In case of repeat ABPM session, there will be a shift in study days to 
account for a repeat ABPM at baseline and randomization will be considered Study Day 2. 


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
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Endo Pharmaceuticals Inc. 
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3.1.3. 
Treatment Phase  
After baseline ABPM is complete (Day 2) and the investigator confirmed the reading to be valid, 
each subject will be randomized to one of the 3 treatment arms: 
• Testosterone undecanoate injection (AVEED) 
• Testosterone gel (FORTESTA) 
• Testosterone gel (TESTIM) 
3.1.3.1. 
TESTIM and FORTESTA Treatment Arm (Day 2 to 97) 
FORTESTA and TESTIM subjects will be administered the study drug on Day 2. Subjects will 
continue to topically apply/administer FORTESTA or TESTIM daily as instructed according to 
the approved PI. 
Subjects will be allowed up to 4 treatment follow-up visits to the study center at Days 16, 37, 67, 
and 97 (± 3 days) for FORTESTA and TESTIM. Additional visits may occur outside this 
window as Unscheduled Visits. 
Blood samples will be collected at these treatment follow-up visits to calculate the serum 
testosterone level (not applicable to AVEED). The daily dose of the study drug will be titrated 
for each subject, according to approved dosage and administration instructions (Package Insert), 
until the circulating testosterone concentrations of the subject reaches normal concentrations 
(300-1000 ng/dL). The timing of blood sample collection will occur 2 hours prior to TESTIM 
treatment and 2 hours after FORTESTA treatment, as described in the respective PIs.  
The investigator will be instructed to customize and schedule the treatment follow-up visits (and 
study drug dispensation) of each subject according to the study drug characteristics in order to 
facilitate proper dose titration. Once the daily required dose is fixed, subjects will be instructed 
to continue the same dose until they complete the study. 
3.1.3.2. 
AVEED Treatment Arm (Day 2 to 100) 
AVEED subjects will receive an intramuscular injection on Day 2, Day 30, and Day 100 
(± 3 days). 
Unscheduled visits may occur as necessary for the AVEED subjects. 
3.1.4. 
Ambulatory Blood Pressure Monitoring (End of Study) 
3.1.4.1. 
TESTIM and FORTESTA Treatment Arm (Day 113 to 115) 
Subjects will be instructed to visit the study center on Day 113 (± 3 days) for serum testosterone 
draw, again on Day 114 to be fitted with the ABPM device to measure BP every 30 minutes for 
the next 24 hours, and on Day 115 to return the device. If a subject does not have a valid ABPM 
session at the end of study visit, the ABPM session may be repeated once in order to obtain a 
valid ABPM session. 
Subjects will apply the study drug as usual at home before the Day 114 visit and will complete 
the other EoS assessments as listed in the TESTIM and FORTESTA SoA. 


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
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3.1.4.2. 
AVEED Treatment Arm (Day 106 to 108) 
AVEED subjects will be instructed to visit the study center on Day 106 (± 3 days) for a serum 
testosterone draw. Subjects will return to the study center on Day 107 to be fitted with the 
ABPM device to measure BP every 30 minutes for the next 24 hours in addition to completing 
the other assessments as listed in the AVEED SoA, and on Day 108 to return the device. If a 
subject does not have a valid ABPM session at the end of study visit, the ABPM session may be 
repeated once in order to obtain a valid ABPM session. 
If a subject is terminated early, an ET visit will be scheduled and efforts will be taken to collect 
his 12-lead ECG, blood samples for clinical laboratory tests (including serum testosterone on the 
day prior to ABPM) and 24-hour ABPM data.  
3.1.4.3. 
End-of-Study Definition 
A subject is considered to have completed the study if the subject has completed the 2-day EoS 
visit and required assessments at this visit. 
3.1.5. 
Study Duration 
The duration of the study from first subject first visit to last subject last visit will depend on the 
ability of the sites to identify and enroll eligible subjects. The entire study is expected to require 
approximately 2 years to complete. 
3.1.6. 
Schedule of Activities 
Table 2 and Table 3 below describe the schedule of activities performed during Screening Phase, 
Baseline Phase, Treatment follow-up and EoS/ET visits. 
 


Statistical Analysis Plan (SAP) – Protocol EN3000-101 
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Table 2: 
Schedule of Activities – TESTIM and FORTESTA 
Procedures 
Screening Phase 
Day -28 to -2 
Baseline 
Treatment Follow-up Visitsa  
End-of-Study/Early Termination 
(± 3 days) 
Day -1 
Visit 1 
Day 1 
Return 
Visit 
Day 2 
Visits 2a to 2db 
Days 16, 37, 67, and 97  
Day 113 
EoS Visit 
Day 114 
Return 
Visit 
Day 115 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
Medical history including 
previous treatments 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
 
X 
 
Vital signs (temperature, HR, 
BP & RR)c 
X 
 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
X 
 
International Prostate 
Symptom Score (IPSS)d  
X 
 
 
 
 
 
 
 
Digital rectal examination of 
the prostate 
X 
 
 
 
 
 
 
 
Alcohol and tobacco screen 
X 
 
 
 
 
 
 
 
Clinical laboratorye 
 
 
 
 
X 
 
 
 
 
 
 
 


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Procedures 
Screening Phase 
Day -28 to -2 
Baseline 
Treatment Follow-up Visitsa  
End-of-Study/Early Termination 
(± 3 days) 
Day -1 
Visit 1 
Day 1 
Return 
Visit 
Day 2 
Visits 2a to 2db 
Days 16, 37, 67, and 97  
Day 113 
EoS Visit 
Day 114 
Return 
Visit 
Day 115 
Serum testosterone 
 
 
 
 
Xf 
X 
 
 
Xg 
Xg 
 
 
24-hour ABPM 
 
 
 
 
 
Xh 
 
 
 
Xh 
 
Confirm valid ABPM session 
 
 
 
 
 
 
X 
 
 
 
X 
Table 2: 
Schedule of Activities – TESTIM and FORTESTA (Continued) 
Procedures 
Screening Phase 
Day -28 to -2 
Baseline 
Treatment Follow-up Visitsa  
End-of-Study/Early Termination 
(± 3 days) 
Day -1 
Visit 1 
Day 1 
Return 
Visit 
Day 2 
Visits 2a to 2db 
Days 16, 37, 67, and 97  
Day 113 
EoS Visit 
Day 114 
Return 
Visit 
Day 115 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
TREATMENT 
Randomizationj 
 
 
 
X 
 
 
 
 
Dispense Study Drug k 
 
 
 
X 
X 
 
 
 
Collect Study Drug 
 
 
 
 
X 
 
 
X 


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Procedures 
Screening Phase 
Day -28 to -2 
Baseline 
Treatment Follow-up Visitsa  
End-of-Study/Early Termination 
(± 3 days) 
Day -1 
Visit 1 
Day 1 
Return 
Visit 
Day 2 
Visits 2a to 2db 
Days 16, 37, 67, and 97  
Day 113 
EoS Visit 
Day 114 
Return 
Visit 
Day 115 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Compliance 
Check and Discussion 
 
 
 
 
X 
 
 
X 
a Treatment follow-up visits are for checking serum testosterone levels and titrating dose accordingly. For subjects receiving FORTESTA, if further titration is 
required after Follow-up Visit on Day 37, the investigator should refer to the PI for information on subsequent follow-up visits. However, in the event 
additional visits are necessary, they may occur as Unscheduled Visits. 
b Window of ± 3 days are allowed. 
c Temperature, heart rate (HR) and respiratory rate (RR) will be captured. BP will be measured, using a sphygmomanometer, at all office visits. Subjects will be 
seated on a chair with back rest, resting the flexed dominant arm on a flat surface so that the upper arm is at heart level. Subjects with BP > 140/90 mm Hg 
should be excluded from the study. Site personnel will ensure that the same arm and cuff size will be used. Vital signs taken will include SBP and DBP, pulse 
rate, respiratory rate, and body temperature. The results, date, and time for all vital sign assessments will be recorded. 
d International Prostate Symptom Score (IPSS) ≥ 19. 
e Includes tests for hematology, biochemistry, serum prostate-specific antigen (PSA), and urine analysis. 
f Two blood samples will be obtained for serum testosterone, at 10 AM (± 2 hours) on 2 separate occasions spaced at least 48 hours apart (± 1 hour). 
g On the TESTIM treatment arm a blood sample will be collected from subjects 2 hours predose, and on the FORTESTA treatment arm a blood sample will be 
collected from subjects 2 hours postdose. 
h Onsite device activation. 
i If a subject does not have a valid ABPM session (defined as ≥ 70% of expected measurements including 20 valid awake [0900-2100 h] and 7 valid sleep 
[0100-0600 h] measurements) at baseline or at the end of study visit the ABPM session can be re-done.  
j A valid ABPM must be confirmed prior to a subject being randomized.  
k The appropriate amount of study drug will be dispensed to each subject to last until the next follow-up visit, with instructions for administration. However, if 
up titration is needed, subjects may need to return to the clinic between scheduled follow-up visits for additional drug supply. 


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Table 3: 
Study Schedule of Activities – AVEED (Testosterone Undecanoate Injection) 
Procedures 
Screening Phase 
Day -28 to -2 
Baseline 
Treatment Visits 
(± 3 days) 
End-of-Study/Early Termination 
(± 3 days) 
Day -1 
Visit 1  
Day 1 
Return 
Visit 
Day 2 
Study Visit  
Day 30 
Study Visit  
Day 100 
Day 106 
EoS Visit 
Day 107 
Return 
Visit 
Day 108 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
 
Medical history including 
previous treatments 
X 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
Vital signs (temperature, HR, 
BP & RR)a 
X 
 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
International Prostate 
Symptom Score (IPSS)b 
X 
 
 
 
 
 
 
 
 
Digital rectal examination of 
the prostate 
X 
 
 
 
 
 
 
 
 
Alcohol and tobacco screen  
X 
 
 
 
 
 
 
 
 
Clinical laboratoryc 
X 
 
 
 
 
 
 
 
 
Serum testosteroned 
X 
X 
 
 
 
 
X 
 
 
24-hour ABPM 
 
 
Xe 
 
 
 
 
Xe 
 


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Table 3: 
Study Schedule of Activities – AVEED (Testosterone Undecanoate Injection) (Continued) 
Procedures 
Screening Phase 
Day -28 to -2 
Baseline 
Treatment Visits 
(± 3 days) 
End-of-Study/Early Termination 
(± 3 days) 
Day -1 
Visit 1  
Day 1 
Return 
Visit 
Day 2 
Study Visit  
Day 30 
Study Visit  
Day 100 
Day 106 
EoS Visit 
Day 107 
Return 
Visit 
Day 108 
Confirm valid ABPM 
sessionf 
 
 
 
X 
 
 
 
 
X 
Randomizationg 
 
 
 
X 
 
 
 
 
 
Study drug administration 
 
 
 
X 
X 
X 
 
 
 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Temperature, heart rate (HR) and respiratory rate (RR) will be captured. BP will be measured, using a sphygmomanometer, at all office visits. Subjects will be 
seated on a chair with back rest, resting his flexed dominant arm on a flat surface so that his upper arm is at heart level. Subjects with BP > 140/90 mm Hg 
should be excluded from the study. Subjects receiving the AVEED injection will have vital signs taken before administration of the study drug. Site personnel 
will ensure that the same arm and cuff size will be used. Vital signs taken will include SBP and DBP, pulse rate, respiratory rate, and body temperature. The 
results, date, and time for all vital sign assessments will be recorded. 
b International Prostate Symptom Score (IPSS) ≥ 19. 
c Includes tests for hematology, biochemistry, serum prostate-specific antigen (PSA), and urine analysis. 
d Two blood samples will be obtained for serum testosterone, at 10 AM (± 2 hours) on 2 separate occasions spaced at least 48 hours apart (± 1 hour). 
e Onsite device activation. 
f If a subject does not have a valid ABPM session (defined as ≥ 70% of expected measurements including 20 valid awake [0900-2100 h] and 7 valid sleep 
[0100-0600 h] measurements) at baseline or at the end of study visit the ABPM session can be re-done.  
g A valid ABPM must be confirmed prior to a subject being randomized.  
 


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3.2. 
Eligibility Criteria for Subject Selection 
3.2.1. 
Inclusion Criteria 
In order to be eligible to participate in the study, at the Screening Visit and on Study Day 1, 
subjects must: 
1. Be male and ≥ 18 years of age at the time of consent. 
2. Have a diagnosis of primary hypogonadism (congenital or acquired) OR 
hypogonadotropic hypogonadism (congenital or acquired). 
3. Have a total serum testosterone at Screening < 300 ng/dL based on 2 blood samples 
obtained at 10:00 am (± 2 hours) on 2 separate occasions at least 48 hours apart. 
4. Be naïve to androgen replacement or washout of 12 weeks following intramuscular 
androgen injections; 4 weeks following topical or buccal or oral androgens. Washout 
should be completed by Study Day -2. 
5. Have a screening BP at rest of less than 140 mm Hg for SBP and less than 90 mm Hg for 
DBP. 
6. Be judged to be in good general health as determined by the principal investigator based 
upon the results of a medical history, physical examination, vital signs, laboratory profile 
and a 12-lead ECG performed at Screening. 
7. Subjects enrolled in the TESTIM or FORTESTA treatment arms: Subjects agree to take 
necessary precautions (wear clothing over application sites, wash with soap and water, 
etc) to avoid skin-to-skin contact and potential transfer of TESTIM or FORTESTA to 
their female partner, children and/or others. 
8. Subjects with reproductive potential enrolled in the TESTIM or FORTESTA treatment 
arms agrees to use effective contraception (abstinence, surgical sterilization [vasectomy], 
or condom with spermicide) with a female partner for the duration of the study and for 28 
days after any active treatment period. 
9. Be willing and able to cooperate with the requirements of the study. 
10. Be adequately informed and understand the nature and risks of the study and be able to 
provide consent as outlined in Protocol Section 10.1.3. 
3.2.2. 
Exclusion Criteria 
A subject is ineligible for study participation if the subject: 
1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) 
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including 
but not limited to, employees (temporary, part-time, full time, etc) or a family member of 
the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
2. Has a history of significant sensitivity or allergy to the study drugs, including androgens, 
or product excipients. 


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3. Has a history of or medical examination findings or concurrent diseases that might 
interfere with the conduct of the study, or endanger the subject’s well-being, or any 
significant renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, 
immunologic, psychiatric conditions, cardiovascular disease/dysrhythmia or any other 
condition(s) that in the investigator’s opinion might indicate the subject to be unsuitable 
for the study. If there is a history of such disease but the condition has been stable for 
more than 5 years and is judged by the investigator not to interfere with the subject’s 
participation in the study, the subject may be included, with the documented approval of 
the Medical Monitor. 
4. Is not on a stable medication regimen for at least 3 months for the treatment of a chronic 
condition such as hypertension, hyperlipidemia or diabetes mellitus. 
5. Has had a cardiovascular and/or cerebrovascular event within 6 months prior to Study 
Day -2. 
6. Needs a BP cuff size larger than 50 cm. 
7. Works a night shift or performs heavy manual labor. 
8. Has any known contraindication(s) to active study treatment including, but not limited to: 
a. Known or suspected carcinoma (or history of carcinoma) of the prostate, clinically 
significant symptoms of benign prostatic hyperplasia, and/or clinically significant 
symptoms of lower urinary obstruction and International Prostate Symptom Score 
(IPSS) ≥ 19. A clinically significant digital rectal examination of the prostate or 
clinically significant elevated serum prostate-specific antigen (PSA) levels 
(> 4.0 ng/mL). 
b. Known or suspected carcinoma (or history of carcinoma) of the breast and/or 
previous history of cancer (except basal cell carcinoma of the skin). 
c. Liver disease defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 2 × upper limit of normal (ULN) or bilirubin > 2 × ULN. 
d. Active deep vein thrombosis or thromboembolic disorder, or a documented history of 
these conditions. 
e. Atrial fibrillation. 
f. Untreated sleep apnea. 
g. Has known immune compromised status (not related to disease/condition under 
study), including but not limited to, individuals who have undergone organ 
transplantation or who are known to be positive for the human immunodeficiency 
virus. 
9. Uses known inhibitors (eg, ketoconazole) or inducers (eg, dexamethasone, phenytoin, 
rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior to study 
drug administration and through the end of the study. 
a. Uses any of the above listed drugs within 5 half-lives of the last dose in the past 
6 months prior to study drug administration. 
b. Has received any of the above listed drugs by injection within 30 days or 10 half-lives 
(whichever is longer) prior to study drug administration. 


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c. Uses neutraceuticals or homeopathic compounds which have a known effect on BP. 
10. Has a history of drug or alcohol abuse within 6 months prior to study drug administration. 
11. Has untreated moderate to severe depression. 
12. Has any skin lesions/cuts/injury at the application site that prohibits topical application 
and/or intramuscular injection of study drug. 
13. Has clinically significant changes in any medications (including dosages) or medical 
conditions in the 28 days prior to screening. 
14. Has suspected reversible hypogonadism (eg, leuprolide injection). 
15. Donated blood or blood products or experienced significant blood loss within 90 days 
prior to study drug administration. 
16. Intends to conceive at any time during the study. 
17. Donated bone marrow within 6 months prior to study drug administration. 
18. Requires any unapproved concomitant medications as defined in the protocol that could 
not be discontinued or switched to an allowable alternative medication prior to the 
minimum allowable interval before baseline (Day 1).  
19. Has participated in a previous investigational study or received treatment with an 
investigational product within 30 days (or 5 half-lives, whichever is longer) of screening.  
20. Has a diagnosis of, is undergoing therapy for, or has received therapy for a hematologic 
malignancy in the 5 years prior to Screening. 
21. Has a history of substance abuse or is taking any substance of abuse (Note: Subjects on a 
stable dose of any medications that have been prescribed by a healthcare practitioner for a 
properly documented medical condition are exempt).  
22. Has evidence of abnormalities on physical examination, vital signs, ECG or clinical 
laboratory values, unless judged to be clinically insignificant by the investigator. 
23. Has evidence of confirmed QT prolongation with QTc ≥ 450 ms. 
24. Has any other condition that, in the investigator’s opinion, might indicate the subject to 
be unsuitable for the study. 
3.3. 
Randomization Criteria 
At screening or Day 1, subjects with office BP readings of ≥ 140/90 will be considered screen 
failures; ie subjects with SBP ≥ 140 and/or DBP ≥ 90 will be considered screen failures. At 
Day 1, only subjects with office BP readings of < 140/90 will be eligible for randomization. A 
valid ABPM must be confirmed prior to subject being randomized. 
3.4. 
Method of Assignment of Subjects to Treatment Groups 
This is an open label study; however, eligible subjects will be randomly assigned to one of the 
following 3 treatment arms in a 1:1:1 ratio: 
• Testosterone undecanoate injection (AVEED) 


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• Testosterone gel (FORTESTA) 
• Testosterone gel (TESTIM) 
Treatment assignment will be managed through an Interactive Response Technology (IRT) 
system.  
3.5. 
Study Treatment  
Subjects will be administered assigned study drug on Day 2 and will be instructed to continue 
applying/administering the study drug (not applicable for AVEED injection). The study 
treatment detail is explained in Table 4 below. 
Table 4: 
Study Treatments 
Product Name 
Testosterone undecanoate 
injection 
(AVEED)a 
Testosterone gel 
(FORTESTA) 
Testosterone gel 
(TESTIM) 
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Solution for Injection 
Gel 
Gel 
Dose Amount and 
Frequencyb 
750 mg/3 mL  
Days 2, 30, and 100 (± 3 days) 
40 mg  
once daily (in the morning) 
50 mg 
once daily (in the morning) 
Route of Administration 
Intramuscular (IM) Injection 
Injection site: gluteus medius 
muscle 
Topical  
Apply to upper inner thighs 
Topical  
Apply to shoulders or upper 
arms 
a AVEED will be used in accordance with the approved REMS.  
b Detailed information on study drug administration will be available in a separate Pharmacy Manual.  
3.6. 
Determination of Sample Size 
The sample size is based on the primary efficacy endpoint of analyzing mean change from 
baseline to EoS in 24-hour average SBP to determine whether the study drugs have a clinically 
meaningful effect on ambulatory BP in hypogonadal men. 
A sample size of 170 for each of the 3 treatment groups (AVEED, FORTESTA, and TESTIM) 
achieves 90% statistical power to exclude an upper bound of 3 mm Hg threshold SBP increase in 
24-hour average systolic ambulatory blood pressure at EoS from baseline using 2-sided 95% 
confidence interval (CI) with paired t test. The standard deviation (SD) of 12 mm Hg is assumed. 
It is assumed that 30% of enrolled subjects will be excluded from the Full Analysis Set (FAS) 
(ie, subjects who discontinue early from the study, non-valid ABPM measures at baseline or 
EoS, etc), therefore a sample size of 243 for each of the 3 treatment groups for a total of 729 is 
required. 
3.7. 
International Prostate Symptoms Score (IPSS) 
The International Prostate Symptom Score (IPSS) is a written screening tool used to screen for, 
rapidly diagnose, track the symptoms of, and suggest management of the symptoms of benign 
prostatic hyperplasia (BPH).(2) 


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IPSS is based on the answers to 7 questions concerning urinary symptoms and 1 question 
concerning quality of life. This assessment will be used for screening purposes only; this study 
will not use question 8 referring to perceived quality of life. 
Table 5: 
IPSS Questionnaire 
 
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  
Your Score 
Incomplete Emptying 
Over the past month, how often have you had the 
feeling of not completely emptying your bladder after 
you finished urinating? 
0 
1 
2 
3 
4 
5 
X 
Frequency  
Over the past month, how often have you had to 
urinate again less than two hours after you finished 
urinating?  
0 
1 
2 
3 
4 
5 
X 
Intermittency  
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 
X 
Urgency  
Over the last month, how difficult have you found it to 
postpone urination?  
0 
1 
2 
3 
4 
5 
X 
Weak stream  
Over the past month, how often have you had a weak 
urinary stream?  
0 
1 
2 
3 
4 
5 
X 
Straining  
Over the past month, how often have you had to push 
or strain to begin urination?  
0 
1 
2 
3 
4 
5 
X 
 
None  
1 time  
2 times  
3 times  
4 times  
5 times or 
more  
Your score  
Nocturia  
Over the past month, many times did you most 
typically get up to urinate from the time you went to 
bed until the time you got up in the morning?  
0 
1 
2 
3 
4 
5 
X 
IPSS Total Symptom Score (sum of all the individual scores) 
XX 
The total symptom score shows the severity of the symptoms. The first 7 questions of the IPSS 
are identical to the question appearing on the American Urological Association Symptom Index, 
which currently categorizes symptom as follows: 
 
 


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Table 6: 
IPSS Total Symptom Score  
Rating 
Level of Severity 
Description 
1 
Mild 
Total symptom score ≤ 7 
2 
Moderate 
Total symptom score range 8-19 
3 
Severe 
Total symptom score range 20-35 
3.8. 
Digital Rectal Examination of the Prostate 
A digital rectal examination (DRE) is an important element of a clinical examination of the 
rectum and nearby organs, including the anal canal, prostate and bladder. It can detect conditions 
like an enlarged prostate (benign prostatic hyperplasia) and prostate cancer. This assessment will 
be recorded as normal and abnormal for screening purposes only. 
3.9. 
Medical and Surgical History 
A medical and surgical history of the subject will be taken during screening. Medical history will 
include relevant diagnoses and/or procedures/therapies with onset/resolutions dates. 
Medical history will include a review of the following systems: general, dermatological, 
respiratory, cardiovascular, gastrointestinal, genitourinary, endocrine, musculoskeletal, 
hematological, neuropsychological, immune (allergies), and head, eyes, ears, nose, and throat. 
Historical and current medical conditions with onset/resolutions dates will be recorded. 
3.10. 
Substance Use 
History of tobacco and alcohol use will be taken during screening and the following information 
will be recorded: 
• Type of substance (Alcohol/Tobacco) 
• History of usage (Never/Currently/Former) 
• Number of years the product was used (for current or former users) 
• Stop date of using the product (for former users) 
3.11. 
Prior and Concomitant Medications and Procedures 
Any medications and non-drug therapies (eg, blood transfusions, oxygen supplementation, 
physical therapy, etc) taken during the study or within 30 days prior to Screening visit will be 
recorded.  
In addition, all prior treatments for the disease/condition under study administered in the 
previous 5 years will be recorded. 
3.12. 
Prohibited Medications 
Use of known inhibitors (eg, ketoconazole) or inducers (eg, dexamethasone, phenytoin, rifampin, 
and carbamazepine) of CYP3A are prohibited in this study. If any prohibited medication is taken 
during the study, all pertinent information will be recorded. 


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3.13. 
Efficacy Parameters 
3.13.1. 
24-Hour Ambulatory Blood Pressure Monitoring (ABPM) 
ABPM will be performed using a 24-hour ambulatory blood pressure recorder machine. The 
device will be attached to the subject’s arm at bicep level on Day 1. The machine will be set to 
measure BP every 30 minutes for the next 24 hours. The device will be returned to the study site 
by the subject on the following day (Day 2). 
TESTIM and FORTESTA subjects will be instructed to visit the study center again on Day 114 
to be fitted with the ABPM device to measure BP every 30 minutes for the next 24 hours, and on 
Day 115 to return the device.  
AVEED subjects will be instructed to visit the study center again on Day 107 to be fitted with 
the ABPM device to measure BP every 30 minutes for the next 24 hours, and on Day 108 to 
return the device.  
Baseline BP will be analyzed (systolic and diastolic means) for the overall 24-hour period, 
daytime (from waking up to bedtime) and nighttime (from retiring to bed until waking) for each 
subject.  
3.14. 
Safety Parameters 
3.14.1. 
Adverse Events 
All adverse events (AE) will be recorded from the time informed consent is signed through the 
EoS visit or for 28 days after the last dose of the study treatment for those who terminate early. 
Conditions existing prior to screening will be recorded as part of subject’s medical history.  
3.14.1.1. Adverse Events (AEs) 
An AE is any unfavorable or unintended change in body structure (signs), body function 
(symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc), or worsening of a pre-existing 
condition associated temporally with the use of the study medication whether or not considered 
related to the study medication. This would include AEs resulting from concurrent illness, 
reactions to concurrent medication use, or progression of disease states (excluding the disease 
under study). A condition present at baseline that worsens after initiation of study treatment will 
be captured as an AE; the onset date will be the date the event worsened.  
3.14.1.2. Serious Adverse Events (SAEs) 
Serious adverse event are those AEs that meet any of the following criteria: 
• Results in death  
• Life-threatening event  
• Results in or prolongs an inpatient hospitalization  
• Results in permanent or substantial disability 
• Is a congenital anomaly or birth defect  


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• Any important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
3.14.2. 
Clinical Laboratory Determinations 
Blood and urine samples will be collected at the Screening visit for testing the clinical laboratory 
parameters shown in Table 7 below. Testing includes serum PSA. 
Table 7: 
Clinical Safety Laboratory Parameters 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Red blood cell 
White blood cell (WBC) 
Platelets 
WBC Differential 
Glucose 
Sodium 
Potassium 
Calcium 
Chloride 
Carbon dioxide (CO2) 
Inorganic phosphate 
Blood urea nitrogen  
Creatinine 
Creatinine clearance (estimated) 
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Gamma-glutamyl transferase (GGT) 
Total bilirubin (TBL) (direct bilirubin reflex if elevated) 
Albumin 
Alkaline phosphatase (ALP) 
Uric acid 
Glucose 
Protein 
Specific gravity 
pH 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Blooda 
Leukocytesa 
a Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 
Any clinically significant laboratory abnormality observed will be considered as an AE or SAE 
as appropriate. 
3.14.3. 
Serum Testosterone Assessment 
Blood samples of approximately 100 mL will be collected for analysis of serum testosterone 
from all subjects participating in the study during Screening (2 separate times), Baseline 
(Day -1), Treatment Follow-up visits, and EoS visit as mentioned in SoA table (see Table 2 and 
Table 3). 
3.14.4. 
Height and Weight 
Height will be collected at screening only. Weight will be obtained at the Screening visit only for 
AVEED, and at Screening, Baseline (Day 1), Treatment Follow-up visits, and EoS visit for 
TESTIM and FORTESTA treatment arms.  
Any clinically significant abnormality in weight compared to the screening value will be 
considered as an AE or SAE as appropriate. 


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3.14.5. 
Vital Signs 
Vital signs measurements (SBP, DBP, HR, RR, and body temperature) will be taken at 
Screening, Baseline (Day 1 and 2), Treatment Follow-up visits, and EoS (Day 114 and 115 for 
TESTIM and FORTESTA, Day 107 and 108 for AVEED) visit. 
For subjects receiving the AVEED injection, vital signs will be taken before administration of 
the study drug. 
For all subjects, vital signs will be obtained after the subject has been seated for 5 minutes 
(minimum), with feet flat on the floor and back supported. 
Subjects with BP ≥ 140/90 mm Hg (SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg) at screening 
will be excluded from study participation. 
Any clinically significant abnormality in vital signs observed will be considered as an AE or 
SAE as appropriate. 
3.14.6. 
Electrocardiogram 
A 12-lead ECG will be performed during the Screening and EoS (Day 114 for TESTIM and 
FORTESTA, Day 107 for AVEED) visits while the subject is in a supine position for at least 
5 minutes before the recording is conducted.  
If the ECG report shows QT prolongation with QTc ≥ 450 ms, the investigator will repeat the 
ECG within 1 hour. If the initial findings are confirmed, the investigator will exclude the subject 
from study participation. 
ECGs will be assessed by the investigator and graded as:  
• Normal  
• Abnormal, not clinically significant  
• Abnormal, clinically significant  
Any clinically significant abnormality in ECG observed will be considered as an AE or SAE as 
appropriate. 
3.14.7. 
Physical Examination 
The complete physical examination (by body system) on each subject will be performed at the 
Screening and EoS (Day 114 for TESTIM and FORTESTA, Day 107 for AVEED) visits. 
Physical examination will include: evaluation of the head, eyes, ears, nose, throat, neck 
(including thyroid), cardiovascular system (including assessment of heart, peripheral pulses, 
presence or absence of edema), genitourinary system, lungs, abdomen (including liver and 
spleen, bowel sounds), lymph nodes, musculoskeletal system (including spine, joints, muscles), 
neurological system (including cranial nerves, reflexes, sensation, strength), skin, extremities, 
and other conditions of note. 
The investigator will assess the physical examination findings as normal or abnormal. If physical 
examination findings meet the investigator’s criteria for clinical significance, they will be 
reported as an AE or SAE as appropriate. 


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3.14.8. 
Study Treatment Compliance 
Prior to beginning the administration of study treatment, subjects and/or their caregiver will be 
trained on dosing and mode of administration and must exhibit proper technique.  
Study drug compliance during each study visit/any period for the FORTESTA and TESTIM 
treatment arms will be calculated via weight and/or count of containers to determine treatment 
compliance. Subjects using too much, or too little study drug should be re-educated on the proper 
use of study drug. Repeated noncompliance (less than 85% or greater than 100%) should be 
evaluated for the need to withdraw the subject.  
4. 
STUDY PARAMETERS 
4.1. 
Subject Disposition 
A subject will be considered to have completed the study if the subject has completed the 2-day 
EoS visit.  
Subjects who discontinue or are withdrawn from study treatment will be encouraged to complete 
the remaining study visits and evaluations and provide any additional follow-up information as 
required by the study, unless the subject specifically indicates that they will not participate in any 
further evaluations. The reason and date for study treatment discontinuation will be recorded in 
the electronic case report form (eCRF). 
If a subject withdraws from the study, all EoS/ET procedures will attempt to be conducted as 
detailed in the SoA. The reason and date for early withdrawal will be recorded in the eCRF for 
subjects who do not complete the study. If, however, a subject withdraws consent, no additional 
procedures are required except the collection of AE information. This information will be 
recorded in the source documentation and the eCRF.  
Subjects who discontinue from the study treatment or who have been lost to follow-up at any 
time after the first dose of the study drug will not be replaced. 
The reason for screen failure will also be recorded in eCRF for subjects:  
• who consent to participate in this study but are not subsequently randomized 
• who do not meet all of the eligibility criteria prior to randomization 
Subjects who do not meet all the eligibility criteria and are considered screen failures may be 
rescreened once. 
4.2. 
Protocol Deviations 
Potential deviations will be identified prior to database lock. Protocol deviations will be derived 
from the eCRF data, electronic vendor data, and will be obtained from the clinical monitoring 
reports. All deviations from these sources will be reconciled and duplicate deviations will be 
removed. 
Possible protocol deviations include, but are not restricted to the following deviation types:  
• Ineligible subject/study entry criteria not satisfied  


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• Informed consent not completed correctly  
• Non-compliance of study treatment 
• Prohibited medications/procedure  
• Visit/procedure missing or out of window 
The study team will approve all final protocol deviation assignments and classify them as either 
major or minor during ongoing protocol deviation review meetings held throughout the study 
and a final meeting prior to the database lock. 
All study assessments conducted outside of the allowed windows outlined in the Schedule of 
Activities due to a COVID-19 interruption will be documented as a protocol deviation. COVID-
19 will be recorded as the reason for these out-of-window assessments.   
4.3. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics include the following parameters: 
• Age 
• Age group (< 45 years, 45-64 years and ≥ 65 years) 
• Height (at Screening) 
• Weight (at Screening) 
• Body Mass Index (BMI) in kg/m2 (at Screening) 
• Gender (Male) 
• Race 
• Race group (African Americans and Others) 
• Ethnicity 
• Report of tobacco and alcohol use 
− Alcohol use (Never, Current, and Former) 
− Tobacco use (Never, Current, and Former) 
• IPSS (at Screening) 
• Digital rectal examination of the prostate (at Screening) 
• Serum prostate-specific antigen (at Screening) 
• Hypertension Classification (subjects without hypertension, with hypertension 
untreated, and with hypertension treated) 
• Diabetes status (Yes and No) 


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4.4. 
Prior and Concomitant Medications/Therapies 
All medications will be coded using World Health Organization (WHO) Drug Dictionary, by 
active ingredient and WHO anatomical therapeutic chemical (ATC) classification of ingredients. 
The dictionary version to be used will be defined in the Data Management Plan (DMP). 
A prior medication is defined as any medication taken within the 30 days prior to and stopped 
before the Screening visit.  
A concomitant medication (or non-drug therapy) is any medication (or therapy) taken on or after 
the Screening visit through the EoS visit or taken prior to the Screening visit and continuing 
during the study. 
A new antihypertensive medication is any antihypertensive medication taken on or after the 
Screening visit through the EoS visit and not taken prior to the Screening visit. 
4.5. 
Efficacy Parameters 
4.5.1. 
Valid ABPM Session 
An ABPM session is defined as valid if there is ≥ 70% of expected measurements including at 
least 20 valid awake [0900-2100 h] and at least 7 valid sleep [0100-0600 h] measurements.  
4.5.2. 
Primary Efficacy Parameters 
4.5.2.1. 
Mean Change from Baseline in 24-hour Average Systolic Ambulatory Blood 
Pressure 
24-hour average systolic ambulatory blood pressure is computed by averaging hourly systolic 
ambulatory blood pressures. The hourly systolic ambulatory blood pressure is the average of 
observed systolic ambulatory blood pressure measurement within an hour.  
24 −Hour Average SBP = 1
24 ∑𝑆𝐵𝑃𝑖
24
𝑖=1
; 
where SBPi is systolic ambulatory blood pressure at ith hour. 
Baseline: 24-hour average systolic ambulatory blood pressure at baseline visit will be baseline 
for the primary endpoint, observed systolic ambulatory blood pressure and hourly average 
systolic ambulatory blood pressure. 
To measure the change in daytime, the hourly average systolic ambulatory blood pressure 
observed/measured during 0900 to 2100 hours will be baseline. To measure the change in 
nighttime, the hourly average systolic ambulatory blood pressure observed/measured during 
0100 to 0600 hours will be baseline. 
24-hour average systolic ambulatory blood pressure will be assessed at Baseline and EoS visits. 
The mean change from Baseline in 24-hour average systolic ambulatory blood pressure at the 
EoS visit will be analyzed. 


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4.5.3. 
Secondary Efficacy Parameters 
4.5.3.1. 
Mean Change from Baseline in 24-hour Average and Time Windows of Interest 
in ABPM Parameters 
The mean change from Baseline in 24-hour average, and at each time windows of interest or 
time point (ie, time windows, daytime [0900-2100 hours], and nighttime [0100-0600 hours]) will 
be analyzed for the following parameters: 
• MAP 
• SBP 
• DBP 
• PP 
• HR 
The maximum change from baseline during the 24-hour duration will also be analyzed for the 
above-mentioned ABPM parameters. 
Computational formula for MAP and PP is defined in Table 12. 
4.5.4. 
Change from Baseline Over Time in ABPM Parameters 
There will be 2 readings (1 reading every 30 minutes) per hour for 24-hour recordings except for 
the first hour. For the first hour, there will be 3 readings (at 0, 30, and 60 minutes). The mean 
change from baseline over time (hourly average) will be analyzed by nominal clock time for the 
following parameters: 
• MAP 
• SBP 
• DBP 
• PP 
• HR 
4.5.5. 
Subjects with Antihypertensive Medication 
Antihypertensive medications are the class of drugs that are used to treat hypertension (high 
blood pressure). The antihypertensive class of medications will be identified from the 
concomitant medication page of the eCRF and will be reviewed by the medical monitor; the dose 
of antihypertensive medication will be captured on the eCRF. The percent of subjects with new 
antihypertensive medications and percent of subjects with dose increases in antihypertensive 
medications will be evaluated. 
4.5.5.1. 
Ambulatory Blood Pressure Thresholds 
Blood pressure threshold values are presented in Table 8 below. 


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Table 8: 
Blood Pressure Thresholds 
Parameter 
Thresholds 
SBP 
≥ 160 mm Hg and/or ≥ 20 mm Hg increase from baseline 
DBP 
≥ 100 mm Hg and/or ≥ 15 mm Hg increase from baseline 
4.6. 
Safety Parameters 
4.6.1. 
Extent of Exposure to Study Treatment  
The duration of study drug exposure will be summarized. In case of early withdrawal, the early 
withdrawal date will be used to calculate the exposure duration. Refer to Table 12 for duration of 
exposure formula. 
4.6.2. 
Adverse Events 
Adverse event verbatim terms as reported by the investigator will be mapped to system organ 
class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. The dictionary version to be used will be defined in the DMP. 
4.6.2.1. 
Treatment Emergent Adverse Events (TEAEs) 
TEAEs are defined as any AEs that occur or worsen (increase in severity) on the same day or 
after the treatment initiation. 
The following rules will apply in cases where the start date of an AE is known:  
• If the AE onset date is prior to first application/administration of the study drug, then 
the AE will not be considered a TEAE.  
• If the AE onset date or date of AE worsening is equal to or later than first 
application/administration of the study drug, then the AE will be considered a TEAE. 
Refer to Section 6.5.1.1 to identify TEAE status when start date of an AE is unknown. 
4.6.2.2. 
Intensity of Adverse Events 
Intensity (or severity) of AEs will be graded as “Mild”, “Moderate” or “Severe”. For AEs with 
missing severity, the most severe assessment will be imputed for analyses, following worst case 
principle. 
4.6.2.3. 
Relationship to Study Drug 
Causal relationship of AEs to study drug will be classified by the investigator and will be 
reported as follows: 
• Not related 
• Unlikely related 
• Possibly related 
• Probably related 


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Related adverse events are AEs with the relationship described by the investigator as “Probably 
related” or “Possibly related”. “Not related” or “Unlikely related” causality assessments are 
considered as negative causality. 
Any missing relationship of an AE to study drug will be considered as related to study drug for 
the analyses, following worst case principle.  
4.6.3. 
Vital Signs and Clinical Laboratories 
4.6.3.1. 
Potentially Clinically Important Laboratory Values 
Potentially Clinically Important (PCI) laboratory values are presented in Table 9 below. 
Table 9: 
Potentially Clinically Important Laboratory Criteria 
Parameter 
PCI Low: Less than or equal to 
PCI High: Greater than or equal to 
Hemoglobin (g/L) 
100 
190 
Hematocrit (%) 
30 
60 
Platelets (109/L) 
100 
650 
ALT (U/L) 
 
3×ULN 
AST (U/L) 
 
3×ULN 
Creatinine (μmol/L) 
 
300 
BUN (mmol/L) 
 
12 
BUN=Blood urea nitrogen 
4.6.3.2. 
Potentially Clinically Important Vital Sign Values  
Vital sign values are PCI if they meet both the observed value criteria and the change from 
baseline criteria. The PCI vital sign values are presented in Table 10 below. 
Table 10: 
Potentially Clinically Important Vital Sign Criteria 
Parameter 
PCI Low 
PCI High 
Systolic Blood 
Pressure 
≤ 90 mm Hg and decrease ≥ 20 mm Hg 
from baseline 
≥ 180 mm Hg and increase ≥ 20 mm Hg 
from baseline 
Diastolic Blood 
Pressure 
≤ 50 mm Hg and decrease ≥ 15 mm Hg 
from baseline 
≥ 105 mm Hg and increase ≥ 15 mm Hg 
from baseline 
Heart Rate 
≤ 50 bpm and decrease ≥ 15 bpm from 
baseline 
≥ 120 bpm and increase ≥ 15 bpm from 
baseline 
Respiratory Rate 
≤ 8 brpm and decrease ≥ 7 brpm from 
baseline 
≥ 25 brpm and increase ≥ 7 brpm from 
baseline 
Temperature 
 
≥38.3°C and increase ≥1.1°C from baseline 
bpm=Beats per minute, brpm=Breaths per minute 


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5. 
ANALYSIS POPULATIONS 
The study will use the following analysis populations for data summaries.  
Table 11: 
Analysis Populations 
Population 
Definition 
Displays 
Safety 
Population 
The Safety Population will include all subjects 
who have at least 1 dose/injection of study 
medication.  
All demographic, baseline characteristics and 
safety parameters will be summarized based 
on this population. 
Intent-to-Treat 
(ITT) Population 
The ITT Population will include all 
randomized subjects who have at least 1 
dose/injection of study medication.  
Sensitivity analyses on primary and secondary 
endpoints to assess the impact of missing 
ABPM data at EoS will be based on this 
population. 
FAS 
The FAS will include all ITT subjects with 
valid baseline and EoS ABPM assessments. 
All primary and secondary efficacy analysis 
will be based on this population. 
ABPM 
Population 
The ABPM Population will include all 
subjects in FAS with at least 85% compliance 
to treatment during the study. 
All primary and secondary efficacy 
parameters as a part of sensitivity analysis will 
be analyzed based on this population. 
6. 
STATISTICAL METHODS 
6.1. 
General Methodology 
All statistical tests, summary tables and data listings will be prepared using SAS version 9.4. 
All statistical tests of efficacy parameters will be 2-sided with a significance level of =0.05, 
unless specified otherwise. Statistical tests will be supported by presenting estimates and 95% CI 
for each treatment group. These estimates and CIs will be based on the linear regression model.  
Continuous data will be summarized using descriptive statistics (number of subjects [N], mean, 
SD, median, minimum, and maximum). Discrete data will be summarized using frequency counts 
and percentages. The denominator will be based on the number of subjects in the appropriate 
population.  
For the purpose of display, the summary results will be rounded as follows:  
• Minimum and maximum: same number of decimal places as the raw data.  
• Mean and median: 1 more decimal place than the raw data.  
• SD: 2 more decimal places than the raw data.  
• Percentages will be displayed with 1 decimal place precision. A zero count will be 
left blank. 
• The standard form of a percentage change variable is 1 decimal place. 
For categorical variables with missing values, a category documenting the frequency of missing 
values will be displayed in the summary tables.  
Summary tables, subject listings, graphs and any supportive SAS output will include footnotes 
that will indicate: 


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• date of data extraction 
• date and time of output generation 
• SAS program name, including the path, that generated the output 
When calculating percentages, the denominator will be based on the number of subjects with 
non-missing values. If the denominator is expected to change over time, then the denominator 
used to calculate the percentage will be based on the number of subjects with non-missing values 
at each visit. Any subject removed from an analysis will be noted at the bottom of the table along 
with the reason the subject was removed.  
Empty summary tables will be presented with a note stating that “No Subjects Met Criteria.” 
Subject listings of all data from the eCRFs as well as any derived variables will be presented. 
6.2. 
Adjustments for Covariates 
The baseline value of the efficacy parameter and study center (or pooled centers, if applicable) 
will be used as a covariate in the statistical model.  
6.3. 
Examination of Subgroups 
Exploratory subgroup analyses will be performed on the primary, secondary, and outlier 
analyses. The subgroups are:  
• Hypertension classification (subjects without hypertension, with hypertension 
untreated, with hypertension treated) 
• Race (African Americans and Other) 
• Age group (< 45 years, 45-64 years and ≥ 65 years) 
• Diabetes status (Yes and No) 
• Tobacco use status (Never, Current and Former) 
6.4. 
Derived Variables 
Table 12 defines the derived variables for study parameters. 


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Table 12: 
Derived Variables and Definition 
Variable 
Definition 
Age Group  
< 45 Years 
45-64 Years 
≥ 65 Years  
Height (cm) 
If height is recorded in inches, then height is equal to the recorded value 
multiplied by 2.54 and then rounded to 1 decimal place. 
Weight (kg) 
If weight is recorded in pounds, then weight is equal to the recorded value 
multiplied by 0.454 and then rounded to 1 decimal place. 
Body Mass Index (BMI) 
BMI will be computed using height and body weight measured at Screening 
as BMI (kg/m2) = Weight (kg) / Height (m)2 
Race Group 
African Americans  
Other 
Hypertension Classification 
Subjects without Hypertension  
Subjects with Hypertension Untreated 
Subjects with Hypertension Treated 
Baseline Diabetes Status 
Yes 
No 
Tobacco Use Status 
Never 
Current 
Former 
Relative Day 1 
The designated Day 1 when eligible subject comes to study centres for 
ABPM will be considered as relative Day 1 
Study Day (for assessment on or 
after Day 1) 
Study Day will be computed as, Date of Assessment – Date of Day 1 + 1 
Study Day (for assessment before 
Day 1) 
Study Day will be computed as, Date of Assessment – Date of Day 1 
Baseline 
Baseline is defined as the last non-missing measurement/assessment prior to 
the first dose of study drug.  
Baseline for ambulatory parameters (SBP, DBP, PP, MAP and HR) is 
derived in Section 4.5.2.1. 
Change from Baseline 
Change from baseline will be derived as, post-baseline visit/time point value 
– the baseline value. 
Last Date in Study 
The date of Day 115 if the TESTIM and FORTESTA subjects complete the 
study 
The date of Day 108 if the AVEED subjects complete the study. The date of 
ET visit if the subject is terminated early from study at a non-scheduled visit. 
The date of the latest scheduled visit if the subject is terminated early from 
study at a scheduled visit or lost to follow-up. 
PP 
PP is computed as (SBP-DBP) 
MAP 
MAP is computed as [SBP + 2 (DBP)]/3  
Duration of Exposure 
Date of last dose of study medication – Date of first dose of study 
medication + 1 
Duration of AE 
AE end date – AE start date + 1 
AE Onset Day (for AE onset date 
on or after date of first applying/ 
administering the study drug) 
AE start date - Date of first applying/administering the study drug + 1 
AE Onset Day (for AE onset date 
before date of first applying/ 
administering the study drug) 
AE start date - Date of first applying/administering the study drug 


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6.5. 
Handling of Missing Data 
The subjects having missing value at baseline for age, race, hypertension status, and diabetes 
status will be excluded from corresponding subgroup analyses (see Section 7.6.5 for subgroup 
analyses). Missing value for these variables will not be imputed. 
6.5.1. 
Missing data handling for Primary and Secondary Analyses 
24-hour average ABPM parameters at EoS: ABPM post baseline is performed at EoS; the 
readings are taken every 30 minutes for 24 hours. Hourly average and 24-hour average ABPM at 
EoS are derived from these 49 readings.  
The subjects can have missing data for 24-hour average ABPM at EoS in following two cases: 
(i) 
Subject discontinued the study without any ABPM assessment done. 
(ii) 
Subject does not have valid ABPM session to compute 24-hour average value 
Primary and secondary efficacy analyses will be on FAS. Only subjects with valid ABPM 
measurements at baseline and EoS will be analyzed.  
Sensitivity analyses mentioned below will be done to assess impact of missing 24-hour ABPM 
measurement at EoS. No sensitivity analyses described in Section 7.6.4.2 will be performed if 
only less than 10% subjects in each treatment group has missing 24-hour average ABPM 
measurement at EoS. 
Multiple Imputation: Missing change from baseline 24-hour average ABPM measurement at 
EoS will be imputed using Multiple Imputation (MI).  
Mixed Model Repeated Measure: Mixed Model Repeated Measures (MMRM) analysis will be 
conducted using hourly average based on observed ABPM measurements. 
Refer Section 7.6.4 for details regarding sensitivity analyses. 
6.5.2. 
Missing data handling for Safety Data 
There will be no imputation of missing values for safety data, however missing relationship 
between AE and study drug will be considered as related to study drug following worst case 
principle. Missing severity of an AE will be summarized as a severe AE. 
6.5.3. 
Imputation of Partial Dates 
6.5.3.1. 
TEAE Status for Completely Unknown Start Date 
The following rules will apply in cases where start date of an AE is completely unknown:  
• If the AE onset date is unknown and the end date is after first application/ 
administration of the study drug on Day 1 or ongoing, then the AE will be considered 
a TEAE.  
• If the AE onset date is unknown and the end date is before first application/ 
administration of the study drug on Day 1, then the AE will not be considered a 
TEAE.  


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• If both the start and end dates are unknown (or end date is ongoing), then the AE will 
be considered a TEAE, following the worst-case principle.  
If the AE onset date is partly present and month/year is prior to the first application/ 
administration of the study drug date, then the AE will not be considered a TEAE. 
6.5.3.2. 
Concomitant Status of Medication/Non-drug Therapy for Completely Unknown 
Start Date 
The following rules will apply in cases where start date of medication/therapy is completely 
unknown:  
• If the onset date is unknown or partially present and the end date is after the date of 
screening but before the EoS visit or medication/therapy is ongoing, then the 
medication/therapy will be considered as concomitant.  
• If the onset date is unknown or partially present and the end date is before the date of 
screening, then the medication/therapy will not be considered as concomitant.  
• If both the start and end dates are unknown, then the medication/therapy will be 
considered as concomitant. This approach is considered to be the most conservative 
following the worst-case principle.  
If the end date is partly present and month/year is prior to the date of screening, then the 
medication/therapy will not be considered as concomitant. If the onset date or end date is partly 
present and month/year for either of them is after to the date of screening or medication/therapy 
is ongoing, then the medication/therapy will be considered as concomitant. 
6.6. 
Pooling of Centers 
In the event that a site has fewer than 5 subjects, site will be considered to have an insufficient 
number of subjects and will be considered eligible for pooling. 
Any sites with fewer than 5 subjects will be ordered numerically in ascending order, based on the 
investigator number. The median number of subjects in the sites where the number of subjects 
≥ 5 subjects will be estimated. Sites with 4 or fewer subjects will be sequentially pooled in 
ascending order of site number until the resulting pseudo-site has at least as many subjects as the 
median size of the other sites. A new pseudo-site to account for additional low-enrolling sites 
will be started upon achieving the median number of subjects. The process will be repeated until 
there are no sites with subjects less than 5. 
The list of pooled study centers will be finalized prior to database lock. 
6.7. 
Interim Analyses 
No interim analysis is planned in this study.  


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7. 
STATISTICAL ANALYSES 
7.1. 
Subject Disposition 
The number of subjects included in each study population will be summarized by treatment 
group. Subjects excluded from the analysis populations will be listed. 
The frequency counts and percentages of subjects screened, completed, and discontinued from 
the study treatment and/or withdrawn from the study, as well as the reason for withdrawal from 
study and reason for discontinuation of study drug will be summarized by treatment group.  
A listing of disposition data will be provided. Screen failure reasons will also be listed. In 
addition, listing for inclusion/exclusion criteria will also be presented. 
7.2. 
Protocol Deviations 
Protocol deviations will be divided into categories and severity (major/minor) and summarized 
by category, severity (major/minor), and treatment group. A listing of all protocol deviations will 
be presented. 
7.3. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for the Safety 
Population.  
Age, height (at baseline), body weight (at baseline) and BMI in kg/m2 will be summarized as 
continuous variables using descriptive statistics.  
Gender, race, ethnicity, age group, race group, hypertension classification, and diabetes status 
will be summarized as categorical variables using frequency counts and percentages.  
Refer to Table 12 for descriptions of age categories, race group, hypertension classification and 
diabetes status. 
The following baseline characteristics will be summarized as categorical variables using 
frequency counts and percentages: 
• International Prostate Symptom Score (IPSS) (at Screening) 
• Digital rectal examination of the prostate (at Screening) 
• Report of tobacco and alcohol use  
− Alcohol use (Never, Current, and Former) 
− Tobacco use (Never, Current, and Former) 
Serum PSA will be summarized as continuous variables using descriptive statistics.  
The demographic and baseline characteristics will also be summarized using ITT, FAS, and 
ABPM Population only if these populations are not identical to Safety Population. 
All demographic and baseline characteristics will be presented in a subject listing. In addition, all 
subgroup classifications (refer to Section 6.3) will be presented in a subject listing. 


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7.4. 
Medical and Surgical History 
Medical history will be coded using the MedDRA dictionary. The version to be used will be 
defined in the DMP. Medical and surgical history data will not be summarized; however, a 
subject listing will be provided. 
7.5. 
Prior, Concomitant Medications and Procedures 
Prior and concomitant medication use will be summarized by treatment group using frequency 
counts and percentages for subjects in the Safety Population, by active ingredient within each 
ATC, with ATC and active ingredients ordered alphabetically. Multiple use of the same 
medication by a subject will be counted only once.  
Listings of prior and concomitant medications and therapies/procedures will be provided for all 
subjects. Similarly, a separate listing of prior treatments for the condition will be provided.  
A subject listing of prior treatments for the disease/condition under study administered in the 
previous 5 years will be provided.  
7.6. 
Efficacy Analyses 
Efficacy parameters will be summarized and analyzed by treatment group using the FAS. 
7.6.1. 
Primary Analysis  
7.6.1.1. 
Mean Change from Baseline in 24-hour Average Systolic Ambulatory Blood 
Pressure 
The primary endpoint, the mean change from baseline to EoS in 24-hour average systolic 
ambulatory blood pressure, for each treatment group will be analyzed using an analysis of 
covariance (ANCOVA) model with treatment and study center (or pooled centers, if applicable) 
as fixed effect, and baseline 24-hour average systolic ambulatory blood pressure as covariate.  
The least square mean and the corresponding 2-sided 95% CI for change from baseline in SBP 
will be provided for each treatment group. If the upper limit of the 2-sided 95% CI of mean 
change in SBP falls below 3.0 mm Hg, it will be concluded that the tested treatment does not 
have statistical significance in increasing of 24-hour average systolic ambulatory blood pressure. 
The mean change from baseline to EoS in daytime average (0900–2100 hours) and nighttime 
average (0100–0600 hours) SBP for each treatment group will be analyzed similar to the primary 
efficacy endpoint. 
A forest plot will be generated for least square mean and corresponding 2-sided 95% CI for 
change from baseline in SBP at EoS for 24-hour average, daytime average (0900–2100 hours), 
and nighttime average (0100–0600 hours) for systolic ambulatory blood pressure for each 
treatment group. 
The descriptive statistics for observed and change from baseline for each time point, 24-hour 
average, daytime average (0900–2100 hours), and nighttime average (0100–0600 hours) systolic 
ambulatory blood pressure for each treatment group will be provided. The maximum change 
from baseline during 24-hour duration will also be summarized. 


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The mean of hourly average systolic ambulatory blood pressure at baseline and EoS along with 
corresponding SD will be graphically presented for each treatment group. The cumulative 
distribution function plots will also be plotted for the means of the daytime (0900–2100 hours), 
nighttime (0100–0600 hours), and 24-hour systolic ambulatory blood pressure for each treatment 
group at baseline and EoS. 
7.6.2. 
Secondary Analysis  
7.6.2.1. 
Mean Change from Baseline in 24-hour Average and Time Windows of Interest 
in ABPM Parameters 
The mean change from baseline to EoS in 24-hour average ABPM parameters, ie, MAP, DBP, 
PP, and HR for each treatment group will be analyzed similar to the primary efficacy endpoint. 
The mean change from baseline to EoS in daytime average (0900–2100 hours) and nighttime 
average (0100–0600 hours) DBP and MAP for each treatment group will be analyzed similar to 
the primary efficacy endpoint. 
The descriptive statistics for observed and change from baseline for each time point, 24-hour 
average, daytime average (0900–2100 hours), and nighttime average (0100–0600 hours) for 
MAP, DBP, PP, and HR for each treatment group will be provided. The maximum change from 
baseline during 24-hour duration will also be summarized. 
Forest plots will be generated for least square mean estimate of change from baseline and 
corresponding 95% CI at EoS for 24-hour average, daytime average (0900–2100 hours), 
nighttime average (0100–0600 hours) for DBP and MAP for each treatment group. 
The mean of hourly average diastolic ambulatory blood pressure at baseline and EoS along with 
corresponding SD will be graphically presented for each treatment group. Cumulative 
distribution function plots will also be plotted for the means at baseline and EoS and mean 
changes at EoS of the daytime (0900–2100 hours), nighttime (0100–0600 hours), and 24-hour 
DBP for each treatment group. 
7.6.2.2. 
Change from Baseline Over Time in ABPM Parameters 
The observed and mean change from baseline over time (hourly average) for MAP, SBP, DBP, 
PP, and HR will be summarized by nominal clock time and timing after dosing using descriptive 
statistics for each treatment group. 
The mean of hourly average for MAP, PP, and HR at baseline and EoS along with corresponding 
SD will be graphically presented for each treatment group.  
7.6.2.3. 
Subjects with Antihypertensive Medication 
The frequency counts and percentage of subjects with new antihypertensive medications and 
with dose increases in antihypertensive medications will be summarized for each treatment 
groups. 
A subject listing for antihypertensive medications will be provided. 


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7.6.3. 
Outlier Analysis 
In addition to the above analyses, an outlier analysis will be performed. This analysis will depict the 
frequency counts and percentages of number of subjects along with number of outlier observations in 
each treatment group who meet the following BP threshold criteria:  
• ≥ 160 mm Hg SBP at EoS 
• ≥ 100 mm Hg DBP at EoS 
• ≥ 20 mm Hg increase from baseline SBP at EoS 
• ≥ 15 mm Hg increase from baseline DBP at EoS 
A subject listing for above listed outliers will be provided. 
7.6.4. 
Sensitivity Analysis 
7.6.4.1. 
Sensitivity Analysis on ABPM Population 
In order to access the impact of treatment compliance primary and secondary analyses will be 
performed on ABPM Population using the same method as described in the Section 7.6.1.1. 
7.6.4.2. 
Sensitivity Analysis on ITT Population  
The following analyses will be performed on ITT Population to determine the robustness of the 
results and to assess the impact of the missing data.  
7.6.4.2.1. Sensitivity Analysis for Association 
Sensitivity analysis to assess the association between data missingness at EoS and baseline 
ABPM measurements, and data missingness at EoS and baseline characteristics will be 
performed for each treatment. 
The subjects are classified into two groups based on 24-hour average ABPM measurement at 
EoS i.e. “observed” or “missing”. The proportion of subjects by age group (< 45 years, 45-64 
years and ≥ 65 years), by race group (African Americans, and other), by hypertension category 
(no hypertension, hypertensive but on treatment, and hypertensive but not treated), and by 
diabetes status (Yes/No) will be summarized for observed and missing groups and Chi-square 
test will be used to determine statistical significance of the difference in proportions. The 
difference in mean age and baseline 24-hour average ABPM measurement for observed and 
missing groups will be analyzed using two sample t-test. 
7.6.4.2.2. Sensitivity Analysis to Assess Impact of Missingness 
Multiple Imputation Method 
Missing change from baseline 24-hour average ABPM measurement at EoS will be imputed 
using model-based MI. The model-based MI process requires the data to have a monotone 
missing pattern. The imputation model for change from baseline for 24-hour average ABPM 
measurement at EoS will include treatment group and site/pooled sites, and covariate of baseline 
ABPM.  


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The model-based MI process will involve 4 principal tasks:  
• Calculate the number of missing EoS values to be imputed (nmiss).  
• Missing values will be filled in ‘10 x nmiss’ times to generate ‘10 x nmiss’ complete data 
sets. 
• Perform the primary (refer Section 7.6.1) and secondary (refer Section 7.6.2 analyses on 
imputed data. 
• Results from these analyses will be combined into a single inference using SAS PROC 
MIANALYZE. 
The least square mean and associated 95% CI and standard error will be presented for each 
treatment group. 
MMRM Method 
The MMRM model will use all available hourly data at baseline and EoS.  
The hourly average ABPM measurements will be analyzed using a MMRM model. The model 
will include treatment group and site/pooled sites as fixed effects, and treatment-by-visit-by-
timepoint as interaction effect. The model will use timepoint as repeated component in the 
model.  
An unstructured (UN) covariance structure will be applied for the MMRM. In the event the UN 
covariance matrix results in non-convergence of the model, then the auto-regressive [i.e. AR (1)] 
covariance structures will be used. Estimate statement in PROC MIXED (SAS) will be 
constructed to estimate change from baseline at EoS for each treatment. 
The least square mean for change from baseline and associated 95% CI, and standard error will be 
presented for each treatment group. 
7.6.5. 
Subgroup Analyses 
The primary, secondary, and outlier analyses will be repeated for the following subgroups:  
• Baseline hypertension status (subjects without hypertension, with hypertension 
untreated, and with hypertension treated) 
• Race Group (African Americans and Other) 
• Age group (< 45 years, 45-64 years and ≥ 65 years) 
• Diabetes status (Yes and No) 
• Tobacco use status (Never, Current and Former) 
The analysis will be based on the same methods described for the primary efficacy endpoint in 
Section 7.6.1.1. 
7.7. 
Safety Analyses 
Safety data will be summarized by treatment group using the Safety Population. 


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7.7.1. 
Study Drug Exposure 
The duration of study drug exposure will be summarized descriptively for each treatment group. 
A subject listing of overall exposure will be provided. 
7.7.2. 
Adverse Events 
All AE summary tables will include only TEAEs, unless otherwise specified.  
AEs will be summarized by SOC and PT. A subject will only be counted once per SOC and PT. 
For AEs by severity grade (mild, moderate, severe), if a subject has multiple events occurring in 
the same SOC or same PT, then the event with the maximum intensity (ie, severe) will be 
counted.  
For AEs by relationship to study drug, if a subject has multiple events occurring in the same 
SOC or same PT, the event with the highest association (ie, related) to study drug will be 
summarized.  
AEs will be presented in decreasing order of the incidences at SOC level and within each SOC, 
in decreasing order of the incidences at the PT level. 
An overall summary of AEs and AEs related to study drug will be presented and will include:  
• Total number of TEAEs reported 
• Total number of TEAEs reported by severity 
• Subjects with any TEAE  
• Subjects with any serious TEAE  
• Subjects with any severe TEAE  
• Subjects with no severe TEAEs, but at least 1 moderate TEAE 
• Subjects with no severe TEAEs, but at least 1 mild TEAE 
• Subjects with any TEAEs leading to drug interruption/withdrawn  
• Subjects with any TEAEs leading to study discontinuation  
• Subjects with any TEAEs resulting in death  
The following summary tables will be presented by SOC and PT:  
• All TEAEs  
• TEAEs by severity 
• TEAEs by relationship to study drug 
• All study drug related TEAEs 
• Study drug related TEAEs by severity 
• Serious TEAEs 
• Serious study drug related TEAEs 


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• TEAEs leading to drug interruption/withdrawn 
• Study drug related TEAEs leading to drug interruption/withdrawn 
• TEAEs leading to study discontinuation 
• Study drug related TEAE leading to study discontinuation 
• TEAEs resulting in death 
• Study drug related TEAEs resulting in death 
Serious and most common non-serious TEAEs by order of frequency (most frequent, 2nd most 
frequent, and 3rd most frequent) will be summarized by PT. Serious and most common non-
serious study drug related TEAEs by order of frequency (most frequent, 2nd most frequent, and 
3rd most frequent) will be summarized by PT. Most common non-serious AEs are those that at 
least 5% of the subjects reported at least once (using PT). 
The following listings will be presented by subject:  
• All AEs 
• Serious AEs  
• AEs resulting in drug interruption/withdrawn 
• AEs resulting in study discontinuation 
• AEs resulting in death  
Refer to Table 12 for computation of duration of AEs. 
7.7.3. 
Clinical Laboratory 
Actual value and change from baseline will be summarized by hematology and biochemistry 
laboratory parameters and study visit. In addition, a shift table will be provided for them between 
baseline and ET/EoS visit. 
The PCI laboratory values will be summarized by frequency counts and percentages. Refer to 
Table 10 for PCI criteria. 
A subject listing will be presented for all laboratory parameters (hematology, biochemistry and 
urinalysis).  
7.7.4. 
Vital Signs 
Vital signs (SBP, DBP, HR, RR, body temperature, and body weight) will be summarized for 
each treatment group using descriptive statistics for observed and change from baseline values 
for all assessment visits. A shift table will be provided for them between baseline and ET/EoS 
visit. 
The PCI vital signs values will be summarized by frequency counts and percentages. Refer to 
Table 10 for PCI criteria. 
A subject listing will be presented for vital signs results. 


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7.7.5. 
12-Lead ECG 
The investigator interpretation of ECG results (normal, abnormal not clinically significant or 
abnormal clinically significant) will be summarized using frequency counts and percentages at 
baseline and EoS visits by treatment group.  
A subject listing will be presented for ECG results.  
7.7.6. 
Physical Examination 
A subject listing will be presented for the physical examination (by body system) Screening and 
EoS results. 
7.8. 
Other Analyses 
7.8.1. 
Serum Laboratory Testing 
Serum testosterone and metabolites levels will be summarized using descriptive statistics for all 
assessment visits for each treatment group using the Safety Population.  
In addition, for TESTIM and FORTESTA subjects, frequency counts and percentages will be 
presented for subjects with the same dose throughout the trial, doses titrated up and doses titrated 
down for all assessment visits using the Safety Population. 
A subject listing will be presented for serum testosterone and metabolites levels/laboratory 
results. 
8. 
CHANGE FROM PROTOCOL 
This SAP is prepared based on the study protocol, Original version dated November 17, 2019 
Amendment 1 dated March 19, 2020, and Amendment 2 dated September 15, 2020.(1)  
Table 13 lists any significant changes in the SAP from what is proposed in the protocol. 
Table 13: 
Changes from Protocol 
Text in Protocol 
Text in SAP 
Justification 
Section 9.2: All primary 
and secondary efficacy 
analysis will be based on the 
ABPM Population. 
Section 5: All primary and 
secondary efficacy analyses 
will be based on FAS. The 
primary and secondary efficacy 
parameters as a part of 
sensitivity analysis will be 
based on ABPM Population. 
Additionally, sensitivity 
analyses to assess the impact of 
missing ABPM data at EoS will 
be based on ITT population. 
Add FAS and ITT populations, in addition to 
ABPM population. FAS will be the primary 
population for primary and secondary analyses. 
ITT and ABPM populations will be used for 
sensitivity analyses.  
9. 
REVISION HISTORY 
SAP Module 2 is added. 


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10. 
REFERENCES 
1. An open-label, randomized, parallel-group, three treatment arm, multicenter study on 
hypogonadal males to evaluate the effect on 24-hour ambulatory blood pressure after 
16-week continuous treatment with marketed testosterone products [Clinical Study 
Protocol EN3000-101, Amendment 2]. Endo Pharmaceuticals Inc.; September 15, 2020. 
2. International Prostate Symptom Score (IPSS) - The Management of Lower Urinary Tract 
Symptoms in Men, 1992, International – Prostate Symptom Score© (I-PSS©) Michael J. 
Barry.