Conditions: Hypogonadism
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 168
Healthy volunteers: no

Brief summary:
This study will evaluate the effect of a once daily Androderm® dose on Blood Pressure (BP) in adult hypogonadal men as measured by 24-hour ABPM.

Detailed description:

Arms:
arm 1: Participants received Androderm® 4 mg, transdermal dose, once daily (QD) for up to 16 weeks. At Day 14, if serum concentration was less than 400 nanograms per deciliter (ng/dL), the dose was increased to 6 mg, transdermal dose, QD for up to 16 weeks and if the serum concentration was more than 930 ng/dL, the dose was decreased to 2 mg, transdermal dose, QD for up to 16 weeks. The dose was not adjusted if serum concentrations were within the normal range.

Interventions: intervention 1: Androderm®
Intervention descriptions: intervention 1: Androderm® transdermal dose.

Protocol document:
Prot_000.pdf: 


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Table of Contents
Title Page .........................................................................................................................................1
Table of Contents.............................................................................................................................2
List of Tables ...................................................................................................................................5
1. Protocol Summary .....................................................................................................................6
1.1.
Synopsis...........................................................................................................................6
1.2.
Schema ............................................................................................................................9
1.3.
Schedule of Activities (SoA).........................................................................................10
2. Introduction..............................................................................................................................13
2.1.
Study Rationale .............................................................................................................13
2.2.
Background ...................................................................................................................14
2.3.
Benefit/Risk Assessment...............................................................................................14
3. Objectives and Endpoints ........................................................................................................16
4. Study Design............................................................................................................................17
4.1.
Overall Design...............................................................................................................17
4.2.
Scientific Rationale for Study Design ...........................................................................17
4.3.
Justification for Dose.....................................................................................................17
4.4.
End of Study Definition ................................................................................................18
5. Study Population......................................................................................................................19
5.1.
Inclusion Criteria...........................................................................................................19
5.2.
Exclusion Criteria..........................................................................................................20
5.3.
Lifestyle Considerations................................................................................................22
5.4.
Screen Failures ..............................................................................................................22
6. Study Intervention....................................................................................................................23
6.1.
Study Intervention(s) Administered ..............................................................................23
6.2.
Preparation/Handling/Storage/Accountability ..............................................................23
6.3.
Measures to Minimize Bias: Randomization and Blinding...........................................24
6.4.
Study Intervention Compliance.....................................................................................24
6.5.
Concomitant Therapy....................................................................................................24
6.5.1.
Prohibited Interventions and Washout Before the 
Study...............................................................................................................24
6.5.2.
Permitted Interventions ..................................................................................25
6.5.3.
Rescue Medicine ............................................................................................25
6.5.4.
Prohibited Interventions During the Study.....................................................25
6.6.
Dose Modification.........................................................................................................25
6.7.
Intervention after the End of the Study .........................................................................25
7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................................26


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7.1.
Discontinuation of Study Intervention ..........................................................................26
7.2.
Participant Discontinuation/Withdrawal from the Study ..............................................26
7.3.
Lost to Follow-up ..........................................................................................................27
8. Study Assessments and Procedures .........................................................................................28
8.1.
Efficacy Assessments ....................................................................................................28
8.1.1.
ABPM Assessments .......................................................................................28
8.2.
Safety Assessments .......................................................................................................29
8.2.1.
Physical Examinations ...................................................................................29
8.2.2.
Vital Signs ......................................................................................................29
8.2.3.
Clinical Safety Laboratory Assessments ........................................................30
8.3.
Adverse Events and Serious Adverse Events................................................................30
8.3.1.
Time Period and Frequency for Collecting AE and 
SAE Information ............................................................................................31
8.3.2.
Method of Detecting AEs and SAEs..............................................................31
8.3.3.
Follow-up of AEs and SAEs ..........................................................................31
8.3.4.
Regulatory Reporting Requirements for SAEs ..............................................32
8.3.5.
Medication Errors...........................................................................................32
8.3.6.
Adverse Events of Special Interest.................................................................33
8.4.
Treatment of Overdose..................................................................................................33
8.5.
Pharmacokinetics...........................................................................................................34
8.6.
Pharmacodynamics........................................................................................................34
8.7.
Genetics.........................................................................................................................34
8.8.
Biomarkers and Other Assessments ..............................................................................34
8.9.
Health Economics OR Medical Resource Utilization and Health 
Economics .....................................................................................................................34
9. Statistical Considerations.........................................................................................................35
9.1.
Statistical Hypotheses....................................................................................................35
9.2.
Sample Size Determination...........................................................................................35
9.3.
Populations for Analyses...............................................................................................35
9.4.
Statistical Analyses........................................................................................................35
9.4.1.
General Considerations ..................................................................................36
9.4.1.1.
Analysis Endpoints.......................................................................36
9.4.1.2.
Primary Analyses .........................................................................37
9.4.1.3.
Secondary Analyses .....................................................................37
9.4.2.
Safety Analyses ..............................................................................................37
9.4.2.1.
Adverse Events.............................................................................37
9.4.2.2.
Clinical Laboratory Assessments .................................................38
9.4.2.3.
Vital Signs ....................................................................................38
9.4.3.
PK Analyses ...................................................................................................38
9.4.4.
Other Analyses ...............................................................................................38
9.4.4.1.
Subgroup Analyses.......................................................................39
9.5.
Interim Analyses............................................................................................................39
10. Supporting Documentation and Operational Considerations ..................................................40


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10.1. Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations...............................................................................................................41
10.1.1.
Regulatory and Ethical Considerations ..........................................................41
10.1.2.
Financial Disclosure.......................................................................................41
10.1.3.
Informed Consent Process..............................................................................42
10.1.4.
Data Protection...............................................................................................42
10.1.5.
Dissemination of Clinical Study Data ............................................................42
10.1.6.
Data Quality Assurance..................................................................................43
10.1.7.
Source Documents..........................................................................................43
10.1.8.
Study and Site Start and Closure....................................................................44
10.1.9.
Publication Policy...........................................................................................44
10.1.10. Compliance with Protocol..............................................................................45
10.2. Appendix 2: Clinical Laboratory Tests .........................................................................46
10.3. Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting........................................................47
10.3.1.
Definition of AE.............................................................................................47
10.3.2.
Definition of SAE...........................................................................................49
10.3.3.
Recording and Follow-up of AE and/or SAE ................................................50
10.3.4.
Reporting of SAEs..........................................................................................52
10.4. Appendix 4: Abbreviations ...........................................................................................53
10.5. Appendix 5: Standard Discontinuation Criteria ............................................................55
10.6. Appendix 6: Study Tabular Summary...........................................................................56
10.7. Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information ..................................................................................................57
11. References................................................................................................................................59


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List of Tables
Table 1-1
Schedule of Activities........................................................................................... 10
Table 6-1
Study Interventions ............................................................................................... 23
Table 10-1
Protocol-required Safety Laboratory Assessments............................................... 46
Table 10-2
Highly Effective and Acceptable Contraceptive Methods.................................... 57


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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase IV, Multi-center, Open-label, Single-arm, 24-hour Ambulatory Blood 
Pressure Monitoring (ABPM) Study of 16 Weeks Treatment with Androderm® in Hypogonadal 
Men
Protocol Number: 3146-402-016
Brief Title: Androderm® (testosterone transdermal system)
Study Rationale:
Prior clinical studies of Androderm collected and evaluated pre- and post-treatment systolic and 
diastolic blood pressure (BP) by cuff measurements. No significant trends in cuff BP values were 
noted in patients treated with Androderm.
The Food and Drug Administration (FDA) has issued a postapproval requirement because it is 
not fully known whether any changes in BP, when assessed using 24-hour ABPM, will occur 
with a transdermal formulation of testosterone, such as Androderm. Intensive 24-hour ABPM 
monitoring will allow for a more definitive exclusion of a clinically meaningful effect of 
Androderm on BP. Twenty-four-hour ABPM provides a much larger number of readings 
throughout the day and night, providing more reproducible mean 24-hour, daytime, and 
night-time values.
Therefore, this Phase IV, multi-center, open-label, single-arm study aims to evaluate the effect of 
once daily Androderm on BP parameters as measured by 24-hour ABPM in hypogonadal men 
after 16 weeks of treatment.


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Objectives and Endpoints:
Objectives
Endpoints
Primary

To determine whether Androderm has a 
meaningful effect on 24-hour average systolic 
blood pressure (SBP) as measured by ABPM in 
men who use testosterone replacement 
treatment 

Change from baseline in 24-hour average SBP 
obtained at Week 16
Secondary

To determine whether Androderm has a 
meaningful effect on 24-hour blood pressure 
(BP) parameters as measured by ABPM in men 
who use testosterone replacement treatment

Change from baseline in 24-hour average diastolic 
blood pressure (DBP), mean arterial pressure (MAP), 
pulse pressure and heart rate obtained at Week 16
Exploratory

To determine whether Androderm has a 
meaningful effect on BP parameters as 
measured by ABPM in men who use 
testosterone replacement treatment

Change from baseline in daytime average SBP, DBP, 
MAP, pulse pressure and heart rate obtained at 
Week 16

Change from baseline in night-time average SBP, 
DBP, MAP, pulse pressure and heart rate obtained at 
Week 16

Change from baseline over time (hourly average) by 
nominal clock time and time after dose: SBP, DBP, 
MAP, pulse pressure and heart rate

Status (yes/no) of participants with new 
anti-hypertensive medications

Status (yes/no) of participants with dose increases in 
anti-hypertensive medications

Outlier responder for participants meeting SBP 
≥160 mm Hg for 24-hour average

Outlier responder for participants meeting SBP 
change from baseline ≥20 mm Hg for 24-hour 
average 

Outlier responder for participants meeting DBP 
≥100 mm Hg for 24-hour average 

Outlier responder for participants meeting DBP 
change from baseline ≥15 mm Hg for 24-hour 
average 

Status (yes/no) of participants with normalized 
testosterone concentrations at Week 16
Safety

To demonstrate the safety of once daily 
Androderm for 16 weeks in hypogonadal men
Safety Parameters

Adverse events (AEs), clinical laboratory values, vital 
signs, and physical examination


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Overall Study Design:  
This is a multi-center, open-label, single-arm study in hypogonadal men to evaluate the effect of 
once daily Androderm on BP parameters as measured by 24-hour ABPM.
Number of Participants:  
Approximately 300 participants will be screened, to achieve 150 enrolled who receive 
≥1 administration of study intervention, and 120 participants with interpretable 24-hour ABPM 
data at both baseline and the end of Week 16. Participants who prematurely discontinue from the 
study will not be replaced but will be followed to obtain the last 24-hour ABPM assessment.
Intervention Groups and Study Duration:  
The study will consist of a screening period of approximately 3 weeks (21 days), followed by an 
intervention period of 16 weeks (minimum of 113 + 7 days), for a total study duration of 
approximately 19 weeks (133 days). All participants who meet the criteria for participation in the 
study will be administered Androderm at the starting dose of 4 mg/day. On Visit 2, study 
participants will have morning serum concentrations of testosterone measured. If participants 
have a serum concentration below 400 ng/dL, the dose of Androderm will be increased to 
6 mg/day (one 4 mg/day system and one 2 mg/day system). If the serum concentration is above 
930 ng/dL, the dose of Androderm will be decreased to 2 mg/day. All others will remain on 
4 mg/day.
Data Monitoring Committee: No


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1.2.
Schema








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2.
Introduction
Endogenous androgens, which include testosterone and dihydrotestosterone, are required for the 
growth and development of male sex organs, other various organs, and for the maintenance of 
secondary sex characteristics. Testosterone is a steroid hormone that exerts its physiologic effect 
throughout a man’s life. Testosterone exerts its development of secondary sex characteristics in 
men during puberty, in which men begin to observe growth and maturation of the prostate, penis, 
scrotum, etc. (Ullah 2014). 
Hypogonadism is a condition that results from insufficient physiological concentrations of serum 
testosterone produced by the testes and/or an abnormal number of spermatozoa present. 
Hypogonadism is split into primary and secondary hypogonadism. Primary hypogonadism 
occurs when there are abnormalities in the testes, whereas secondary hypogonadism is seen when 
there are defects in the hypothalamus or the pituitary. Signs and symptoms associated with 
hypogonadism include delayed sexual development, loss of body hair, reduced libido, erectile 
dysfunction, fatigue, mood depression, and osteoporosis (Bhasin 2018).
Testosterone replacement therapy has been used to maintain secondary sex characteristics and to 
halt symptoms of testosterone deficiency (Bhasin 2018). Androderm® (testosterone transdermal 
system) is an androgen indicated for replacement therapy in adult men with conditions associated 
with a deficiency or absence of endogenous testosterone. Through its self-contained transdermal 
system, Androderm provides a continuous daily dose of testosterone, delivering physiologic 
concentrations of testosterone, resulting in circulating testosterone levels that are approximately 
equal to the normal concentration range seen in healthy adult men (300 to 1030 ng/dL). 
Androderm has been available since 29 September 1995 and is recognized as a replacement 
therapy in males for the indications of primary hypogonadism (congenital or acquired) and 
hypogonadotropic hypogonadism (congenital or acquired) (Allergan 2018).
2.1.
Study Rationale
Prior clinical studies of Androderm collected and evaluated pre- and post-treatment systolic and 
diastolic BP by cuff measurements. No significant trends in cuff BP values were noted in 
patients treated with Androderm.
The FDA has issued a postapproval requirement because it is not fully known whether any 
changes in BP, when assessed using 24-hour ABPM, will occur with a transdermal formulation 
of testosterone, such as Androderm. Intensive 24-hour ABPM monitoring will allow for a more
definitive exclusion of a clinically meaningful effect of Androderm on BP. Twenty-four-hour 
ABPM provides a much larger number of readings throughout the day and night, providing more 
reproducible mean 24-hour, daytime, and night-time values. It more accurately identifies 
white-coat hypertension, where clinic BP measurements are high but ABPM readings are 
normal, and masked hypertension, where clinic BP measurements are low but ABPM readings 
are high (Parati 2014).


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Unlike cuff BP measurements, studies with ABPM evaluating hypertensive patients have shown 
a paucity, or even a lack, of a placebo effect (Dupont 1987, Mutti 1991, Mancia 1995). 
Dupont et al demonstrated that placebo significantly decreased in-clinic systolic and diastolic BP 
when measured by cuff measurements after 4 weeks (p < 0.001) but did not significantly 
decrease systolic and diastolic BP when measured by ABPM. Similarly, Mutti et al demonstrated 
that, following 4 weeks of placebo, in-clinic systolic and diastolic BP was significantly reduced 
(-9.6 ± 2.6 and -3.1 ± 1.7 mm Hg, p < 0.01, respectively), while 24-hour ABPM did not show 
any significant change. Finally, Mancia et al again demonstrated that administration of placebo 
significantly decreased systolic and diastolic BP measured in the clinic (-5.3 ± 1.1 and -4.4 
± 0.6 mm Hg, p <0.01, respectively), while no significant reductions were noted with 24-hour 
ABPM. These studies show that an open-label single-arm study design is adequate if 24-hour
ABPM is being used to assess effects on BP. 
Therefore, this Phase IV, multi-center, open-label, single-arm study aims to evaluate the effect of 
once daily Androderm on BP parameters as measured by 24-hour ABPM in hypogonadal men 
after 16 weeks of treatment.
2.2.
Background
Currently, there are several FDA-approved and commercially available options for the treatment 
of hypogonadism. Per the 2018 Endocrine Society Clinical Practice Guidelines, testosterone 
replacement therapy continues to be the mainstay of therapy for the treatment of primary 
hypogonadism and hypogonadotropic hypogonadism. Although testosterone therapy remains a 
first-line treatment option for the treatment of hypogonadism, the effect it has on BP parameters 
is not fully understood.
2.3.
Benefit/Risk Assessment
Patients with either primary hypogonadism (congenital or acquired) or hypogonadotropic 
hypogonadism (congenital or acquired), characterized by baseline morning testosterone 
< 300 ng/dL, may experience symptoms that include, but are not limited to, erectile dysfunction, 
osteoporosis, fatigue, decreased libido, hot flashes, etc.
In several clinical trials of males between 15 and 76 years old, participants with male 
hypogonadism were treated with 2 mg/day to 5 mg/day of Androderm for up to 28 days. 
Androderm produced average morning serum testosterone concentrations within the normal 
reference range in 92% to 97% of participants (Allergan 2018).
The most common adverse reactions reported in clinical trials were application site reactions in 
28% to 48% of participants. Other less common adverse reactions are prostate abnormalities, 
headache, and depression (reported in 5%, 4%, and 3% of participants in clinical studies). 
Adverse reactions reported by < 3% of participants included: chills, diarrhea, rash, fatigue, 
gastrointestinal bleeding, gastroesophageal reflux disease, hemarthrosis, hematuria, polyuria, 
prostatitis, body pain, pelvic pain, hypertension, peripheral vascular disease, increased appetite, 
accelerated growth, anxiety, confusion, decreased libido, impotence, paresthesia, thinking 


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abnormalities, vertigo, acne, dysuria, urinary incontinence, urinary tract infection, testicular 
abnormalities, and prostate carcinoma.
From postmarketing experience, AEs of myocardial infarction, stroke and venous 
thromboembolism have been reported, though because these reactions are reported voluntarily 
from a population of uncertain size, it is not always possible to reliably estimate their frequency 
or establish a causal relationship to drug exposure. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Androderm may be found in the US Package Insert.
Overall, based on the safety profile of the product, the benefit-risk of Androderm remains 
positive when used for approved indications.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To determine whether Androderm has a 
meaningful effect on 24-hour average SBP as 
measured by ABPM in men who use 
testosterone replacement treatment 

Change from baseline in 24-hour average SBP 
obtained at Week 16
Secondary

To determine whether Androderm has a 
meaningful effect on 24-hour BP parameters as 
measured by ABPM in men who use 
testosterone replacement treatment

Change from baseline in 24-hour average DBP, MAP, 
pulse pressure and heart rate obtained at Week 16
Exploratory

To determine whether Androderm has a 
meaningful effect on BP parameters as 
measured by ABPM in men who use 
testosterone replacement treatment

Change from baseline in daytime average SBP, DBP, 
MAP, pulse pressure and heart rate obtained at 
Week 16

Change from baseline in night-time average SBP, 
DBP, MAP, pulse pressure and heart rate obtained at 
Week 16

Change from baseline over time (hourly average) by 
nominal clock time and time after dose: SBP, DBP, 
MAP, pulse pressure and heart rate

Status (yes/no) of participants with new 
anti-hypertensive medications

Status (yes/no) of participants with dose increases in 
anti-hypertensive medications

Outlier responder for participants meeting SBP 
≥160 mm Hg for 24-hour average

Outlier responder for participants meeting SBP 
change from baseline ≥20 mm Hg for 24-hour 
average 

Outlier responder for participants meeting DBP 
≥100 mm Hg for 24-hour average 

Outlier responder for participants meeting DBP 
change from baseline ≥15 mm Hg for 24-hour 
average 

Status (yes/no) of participants with normalized 
testosterone concentrations at Week 16
Safety

To demonstrate the safety of once daily 
Androderm for 16 weeks in hypogonadal men
Safety Parameters

Adverse events (AEs), clinical laboratory values, vital 
signs, and physical examination


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4.
Study Design
4.1.
Overall Design
This is a multi-center, open-label, single-arm study in hypogonadal men to evaluate the effect of 
once daily Androderm on BP parameters as measured by 24-hour ABPM. It is projected that 
approximately 40 sites in the United States will enroll approximately 150 participants who will 
receive at least 1 dose for this study. 
The study will consist of a screening period of approximately 3 weeks (21 days), followed by an 
intervention period of 16 weeks (minimum of 113 + 7 days), for a total study duration of 
approximately 19 weeks (133 days). All participants who meet the criteria for participation in the 
study will be administered Androderm at the starting dose of 4 mg/day. On Visit 2, study 
participants will have morning serum concentrations of testosterone measured. If participants 
have a serum concentration below 400 ng/dL, the dose of Androderm will be increased to 
6 mg/day (one 4 mg/day system and one 2 mg/day system). If the serum concentration is above 
930 ng/dL, the dose of Androderm will be decreased to 2 mg/day. All others will remain on 
4 mg/day.
Approximately 300 participants will be screened to achieve approximately 150 enrolled 
participants who will receive at least 1 dose and 120 participants with interpretable 24-hour 
ABPM data at both baseline and the end of Week 16. Participants who prematurely discontinue 
from the study will not be replaced but will be followed to obtain the last 24-hour ABPM 
assessment.
4.2.
Scientific Rationale for Study Design
A single-arm design is utilized as there are no appropriate active comparators for this study. 
While there are many approved formulations of testosterone, including transdermal, 
intramuscular, and intravenous ones, none are considered appropriate as parallel-controls due to 
lack of available ABPM data to estimate their effect on BP in hypogonadal men. Furthermore, 
unlike cuff BP measurements, past studies that have evaluated participants with hypertension 
have shown that there is a lack of a placebo effect with ABPM (Dupont 1987, Mutti 1991, 
Mancia 1995). ABPM more accurately identifies white-coat hypertension, where clinic BP 
measurements are high but ABPM readings are normal, and masked hypertension, where clinic 
BP measurements are low but ABPM readings are high (Parati 2014).
4.3.
Justification for Dose
Androderm is approved by the FDA for replacement therapy of endogenous testosterone in 
males with primary hypogonadism (congenital or acquired) and hypogonadotropic 
hypogonadism (congenital or acquired). The recommended starting dose for Androderm is one 
4 mg/day system, applied nightly, every 24 hours. 2 mg/day and 4 mg/day Androderm 


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transdermal systems are FDA approved doses for the treatment of men with hypogonadism and 
will be used throughout this trial.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the schedule of activities for the last participant in the study.
A participant is considered to have completed the study if he has not been terminated early and 
has completed all phases of the study including Visit 6 (Day 113 [+ 7 days]).


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be 18 to 80 years of age inclusive, at the time of signing the informed 
consent
2.
Type of Participant and Disease Characteristics
2.01
Two serum testosterone levels < 300 ng/dL in the morning, between 0700 and 1100 local 
participant’s time, on 2 separate days, at least 48 hours apart
2.02
Naïve to testosterone replacement, clomiphene, compounded or over-the-counter 
androgenic steroid derivatives, and DHEA, including investigational products that may 
affect the reproductive hormonal system or has not been treated with these compounds in 
the past 6 months
3.
Weight and Body Mass Index
3.01
BMI < 35 kg/m2
4.
Sex
4.01
Male
5.
Contraceptives
5.01
Male participants willing to minimize the risk of inducing pregnancy for the duration of 
the clinical study and follow-up period
A male participant must agree to use contraception as detailed in Appendix 7 of this 
protocol during the intervention period and for at least 30 days after the last dose of study 
intervention and refrain from donating sperm during this period.


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6.
Informed Consent
6.01
Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol
6.02
Signed informed consent from the participant has been obtained prior to any 
study-related procedures.
6.03
Signed documentation has been obtained in accordance with the relevant country and 
local privacy requirements, where applicable (eg, Written Authorization for Use and 
Release of Health and Research Study Information)
7.
Other
7.01
Able, as assessed by the investigator, and willing to follow study instructions and likely 
to complete all required study visits
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Uncontrolled systemic disease or clinically significant disease, in particular, liver, kidney 
or heart disease, including hypertension, congestive heart failure, coronary heart disease, 
chronic atrial fibrillation, sleep apnea or psychiatric illness, that in the investigator’s 
opinion, would put the participant at an unacceptable risk with exposure to Androderm
1.02
History of prostate (current or in the past) or breast cancer
1.03
Had a recent (within 2 years) history of stroke, transient ischemic attack, acute coronary 
event, venous thrombotic, or thromboembolic event
1.04
History of alcohol or other substance abuse within the previous 2 years
1.05
Known allergy or sensitivity to the study intervention or its components or other 
testosterone replacement medications


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2.
Prior/Concomitant Therapy
2.01
If receiving the following medications, doses must be stable (for at least 4 weeks) with 
no intention of changing during screening and for the duration of the study:

Medications for diabetes, hypertension, hyperlipidemia, or anticoagulation

Glucocorticoids > 7.5 mg prednisone equivalent per day (eg, hydrocortisone 
30 mg, methylprednisolone 6 mg, or dexamethasone 1.2 mg)
2.02
Use of any over-the-counter or herbal preparations containing testosterone is prohibited 
within 7 days or 5 half-lives (whichever is longer) prior to screening and for the duration 
of the study
3.
Prior/Concurrent Clinical Study Experience
3.01
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of entry into this study
4.
Diagnostic Assessments
4.01
Mean triplicate sitting BP (by cuff) > 140/90 mm Hg during all screening visits
4.02
HbA1c > 8.5%
4.03
Abnormal prostate digital rectal examination (palpable nodules) within 6 months of 
screening
4.04
PSA > 3.0 ng/mL
4.05
Hematocrit > ULN
4.06
Prolactin > ULN
4.07
Severe lower urinary tract symptoms as indicated by an I-PSS > 19 at screening
4.08
Abnormal and clinically significant results according to the investigator or designee, on 
physical examination, medical history, hematology, clinical chemistry, or urinalysis
5.
Other
5.01
Participant who works night shifts or who will need to perform strenuous manual labor 
while wearing the ABPM monitor


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5.02
Participant has a condition or is in a situation that, in the investigator’s opinion, may put 
the participant at significant risk, may confound the study results, or may interfere 
significantly with the participant’s participation in the study
5.03
Directly or indirectly involved in the conduct and administration of this study as an 
investigator, subinvestigator, study coordinator, or other study staff member; employee 
of the sponsor; first degree family member, significant other, or relative residing with one 
of the above persons involved directly or indirectly in the study; or enrolled in the study 
by another clinical site
5.3.
Lifestyle Considerations
No lifestyle considerations or restrictions are required.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes indicating screen failure as reason for 
ending the study, demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failures) may not
be rescreened.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
6.1.
Study Intervention(s) Administered
Table 6-1
Study Interventions
Study Intervention Name
Androderm® (testosterone transdermal system)
Dose Formulation
2 mg/day and 4 mg/day transdermal system
Route of Administration 
Transdermal
Dosing Instructions
All participants will receive a starting dose of Androderm 4 mg/day 
applied nightly at approximately 2200. At Visit 2, a fasting morning 
testosterone concentration will be measured. A testosterone concentration 
< 400 ng/dL will require an increase in dose to 6 mg/day (one 4 mg/day
system and one 2 mg/day system) applied nightly. A testosterone 
concentration > 930 ng/dL will require a decrease in dose to 2 mg/day 
applied nightly. Prior to ABPM sessions, the application site should not 
be on the arm used for the blood pressure cuff.
Packaging and Labeling
Study intervention will be provided in boxes. Each box will be labeled as 
required per country requirements.
Manufacturer
Allergan
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
will be provided by the sponsor.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label, single-arm study. No blinding of assigned study intervention will occur.
Each participant who provides informed consent will be assigned a participant ID number. 
Participant ID numbers will be unique 11-digit numbers that follow the participant throughout 
the study and consist of the 3-digit protocol number (402), 5-digit site number, and 3-digit 
screening number.
6.4.
Study Intervention Compliance
For home dosing, study intervention compliance will be closely monitored by counting the 
number of systems dispensed and returned. Before dispensing new study intervention at each 
visit, study center personnel will make every effort to collect all unused study intervention. 
The study staff will keep an accurate drug disposition record that specifies the amount of study 
intervention dispensed to each participant.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter, prescription medicines, vitamins, herbal 
supplements, and/or cannabis or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
At screening, during the study, and at EOS, study staff will question each participant specifically 
on the use of concomitant medications. Study staff must notify the sponsor immediately if a 
participant consumes any concomitant medications not permitted by the protocol. Participants
who admit to using prohibited concomitant medications may be discontinued from the study at 
the discretion of the investigator or the sponsor.
Concurrent chronic medications, such as medications for hypertension, hyperlipidemia, diabetes, 
and anticoagulation should be administered in dosages with no intention of changing for the 
duration of the study.
6.5.1.
Prohibited Interventions and Washout Before the Study
Over the counter or herbal preparations containing testosterone are prohibited 7 days or 
5 half-lives (whichever is longer) before screening and throughout the study.
The decision to administer a prohibited medication/intervention during the study period is done 
with the safety of the study participant as the primary consideration. When possible, the sponsor 
is to be notified before the prohibited medication/intervention is administered.


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6.5.2.
Permitted Interventions
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor.
The sponsor or designee should be contacted if there are any questions regarding concomitant or 
prior therapy.
Any medication taken during the study between the date of the first dose of study intervention
and the date of the EOS visit will be recorded in the eCRF as a concomitant medication; any 
medication started after the EOS visit will not be considered a concomitant medication and 
should not be captured in the eCRF.
6.5.3.
Rescue Medicine
Rescue medicine is not applicable.
6.5.4.
Prohibited Interventions During the Study
Participants must abstain from taking prescription or nonprescription drugs (including drugs 
containing testosterone, vitamins, and dietary or herbal supplements) within 7 days or 5 
half-lives (whichever is longer) before the start of study intervention until completion of the 
follow-up visit, unless, in the opinion of the investigator and sponsor, the medication will not 
interfere with the study.
6.6.
Dose Modification
All participants will initially receive a standard starting dose of Androderm of 4 mg/day which 
will be applied nightly at approximately 2200, starting on Visit 1. At Visit 2, a fasting morning 
testosterone concentration will be measured. Visit 3 will occur when results of the fasting 
testosterone concentration are available. Participants with a testosterone concentration 
< 400 ng/dL will require an increase in dose to 6 mg/day (one 4 mg/day system and one 
2 mg/day system) applied nightly. Participants with a testosterone concentration of > 930 ng/dL
will require a decrease in dose to 2 mg/day (one 2 mg/day system) applied nightly. All others 
will remain on 4 mg/day.
If all doses of study intervention are well-tolerated, the total duration of participation in the study 
will be approximately 19 weeks (3 weeks for screening, plus 16 weeks [Day 1 through 
Visit 6/EOS] of intervention therapy).
6.7.
Intervention after the End of the Study
No intervention will be given after the EOS.


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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and receives study 
intervention ceases participation in the study, regardless of circumstances, before the completion 
of the protocol-defined study procedures.
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented.
Reasons for discontinuation from the study treatment and/or the study may include the following
commonly used or other acceptable terms:
Commonly Used Terms
Other Acceptable Terms
Adverse event
Death
Completed
Disease relapse
Lack of efficacy
Technical problems
Lost to follow-up
Non-compliance with study drug
Other
Physician decision
Protocol deviation
Screen failure
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by subject
7.1.
Discontinuation of Study Intervention
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.
If feasible, 24-hour ABPM should be collected at the time of intervention discontinuation.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, he may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.


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7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he 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 participant fails to return for a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study.

Discontinuation of specific sites, or of the study as a whole, are handled as part of 
Appendix 1.


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA.
8.1.
Efficacy Assessments
8.1.1.
ABPM Assessments
BP parameters, including SBP, DBP, MAP, pulse pressure, and heart rate will be collected by 
24-hour ABPM according to the SoA. The ABPM device is a validated device, recommended by 
relevant, well-known international hypertension societies and is FDA approved. All ABPM 
measurements will be done using the same make and model ABPM device supplied by the 
central vendor, and for each participant, the same device used at baseline must be used for 
postbaseline measurements. BP parameters will be collected at a minimum of 2 readings per 
hour for 24-hour recordings. For ABPM assessments at baseline and Week 16, a repeat ABPM 
session must be performed if validity criteria are not met. Validity criteria are defined according 
to the European Society of Hypertension Guideline and include a minimum of 24 hours of 
readings with at least 70% of expected measurements (33 valid during the 24 hours); 20 valid 
awake (0900 to 2100); and 7 valid asleep (0100 to 0600) (O’Brien 2013). The time of the last 
dose of Androderm prior to the ABPM measurements will be recorded.


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Term
Definition
Baseline ABPM
Any assessment recorded during the approximately 24-hour period starting on Screening 
Visit 3; after the ABPM device is applied, through Visit 1, when the ABPM device is 
removed
Week 16 (End of 
study intervention)
Any assessment recorded during the approximately 24-hour period starting on Visit 5, 
after the ABPM device is applied, through Visit 6/EOS/ET, when the ABPM device is 
removed
24-hour ABPM
Any assessment recorded at the specified analysis timepoint (baseline, Week 16) during 
the approximately 24-hour period after the ABPM device is applied through when the 
ABPM device is removed
Daytime ABPM
Any assessment recorded between 0900 and 2100 on either:

the day the ABPM device is applied

the day the ABPM device is removed
Night-time ABPM
Any assessment recorded between 0100 and 0600 on either:

the day the ABPM device is applied

the day the ABPM device is removed
Hours 0 through 23
For each Hour X, any assessment recorded between XX00 and XX59, on either:

the day the ABPM device is applied

the day the ABPM device is removed
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight 
will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

Physical examinations should be completed by a professionally trained physician or health 
professional listed on Form FDA 1572 and licensed to perform physical examinations.
8.2.2.
Vital Signs
Vital signs will be assessed as follows:

Oral temperature, and triplicate heart rate and cuff BP will be assessed.

BP and pulse measurements will be assessed sitting with a completely automated device. 
Manual techniques will be used only if an automated device is not available.

BP and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones).


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
Vital signs (to be taken before blood collection for laboratory tests) will consist of 3 pulse 
and 3 BP measurements (3 consecutive BP readings will be recorded at intervals of at least 
1 minute). All BP readings will be recorded on the eCRF.
8.2.3.
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency.

At screening, the investigator or subinvestigator will assess the clinical significance of any 
values outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study.

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the participant’s 
condition.

All laboratory tests with values considered clinically significant during participation in the 
study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
o
If laboratory values from non-protocol-specified laboratory assessments performed at 
a local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then 
the results must be recorded in the AE eCRF.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7).


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8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs/SAEs from the signing of the ICF until the follow-up visit will be collected at the 
timepoints specified in the SoA (Section 1.3), and as observed or reported spontaneously by 
study participants.
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF and will be considered 
pretreatment AEs.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be followed 
until the condition returns to pre-study status, has resolved or stabilized, or can be explained as 
being unrelated to the study drug. If a follow-up visit is deemed necessary for appropriate safety 
surveillance, it will take place within 30 days of the final protocol-defined study visit.
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor or designee with a copy of any postmortem findings 
including histopathology.


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New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to sponsor or designee within 24 hours of 
receipt of the information.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the package insert and will notify the IRB/IEC, if appropriate 
according to local requirements.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
8.3.5.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study drug/device

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration, including wrong site of administration (eg, wrong eye)

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is above the maximum recommended dose according to the 
reference safety information or protocol for the study intervention. This also takes into account 
cumulative effects due to overdose. In this study, overdose is defined as taking more than the 
assigned dose of study intervention.
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is under the minimum recommended dose according to the 
reference safety information or protocol. In this study, underdose is defined as taking less than 
the assigned dose of study intervention.


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8.3.6.
Adverse Events of Special Interest
1. Potential Hy’s Law cases:

ALT or AST ≥ 3 × ULN and 

Total Bilirubin ≥ 2 × ULN and 

Alkaline Phosphatase < 2 × ULN 
Anytime from the time the participant signs the ICF for the trial, until the final follow-up visit, 
investigators will notify the sponsor immediately when all the above criteria have been met. A 
potential Hy’s law case will be sent directly to the sponsor by emailing 
IR-clinical-SAE@allergan.com on an AE of Special Interest Form along with the SAE Report
Form as soon as possible (within 24 hours of learning of the potential Hy’s Law). The CRF for 
potential Hy’s law cases will be completed within 7 calendar days. Every effort to determine the 
cause of the liver enzyme abnormalities will be made, and close monitoring will be initiated in 
conjunction with the medical monitor and in accordance with the FDA “Guidance for Industry: 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation” July 2009. 
2. Prostate events: 

Lower urinary tract symptoms of prostatic hyperplasia
Potential lower urinary tract symptoms of prostatic hyperplasia will be sent directly to the 
sponsor by emailing IR-clinical-SAE@allergan.com on an AE of Special Interest Form along 
with the SAE Report Form as soon as possible (within 24 hours of learning of the event). The 
CRF for lower urinary tract symptoms of prostatic hyperplasia will be completed within 
7 calendar days.
8.4.
Treatment of Overdose
For this study, any dose of Androderm greater than the assigned dose within a 24-hour time 
period will be considered an overdose.
Allergan does not recommend specific intervention for an overdose
In the event of an overdose, the investigator should:
1. Contact the medical safety physician immediately.
2. Closely monitor the participant for any AE/SAE and/or laboratory abnormalities.
3. Obtain a plasma sample for PK analysis if requested by the medical safety physician
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical safety physician based on the clinical evaluation of the participant.


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8.5.
Pharmacokinetics
Fasting morning serum total testosterone concentrations will be measured prior to ABPM device 
placement during the screening period on Screening Visit 3 (Day -3 to -1) and at Visit 5 
(Day 112). The time of sample collection and ABPM device placement should be noted.
Fasting serum total testosterone concentrations will also be measured on Visit 2 (Day 14) and 
Visit 4 (Day 56), approximately 8 to 12 hours after application of the nightly dose on the 
previous night.
The serum total testosterone concentrations will be determined using a validated bioanalytical 
methodology.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers and Other Assessments
Biomarkers are not evaluated in this study.
8.9.
Health Economics OR Medical Resource Utilization and Health 
Economics
Health economics/Medical resource utilization and health economics parameters are not 
evaluated in this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The null and alternative hypotheses for change from baseline in 24-hour average SBP obtained at 
baseline and Week 16 (Week 16 minus baseline) are as follows:
H0: mE - mB ≥ 3.0 versus Ha: mE - mB < 3.0 
Where mB and mE are mean 24-hour average SBP obtained at baseline and Week 16 
respectively.
9.2.
Sample Size Determination
Based on the FDA advice letter dated 24 May 2019, and the assumption that the mean difference 
in 24-hour SBP obtained at baseline and Week 16 is 0.0, with the upper bound of 3.0 mm Hg and 
the standard deviation of 10.0 mm Hg, 120 participants with available ABPM data at Week 16 
will be required to provide 90% power to reject the null hypothesis at the 2 sided 5% 
significance level. Assuming a 25% dropout rate, 150 participants will be enrolled. 
Approximately 300 participants will be screened, to achieve 150 enrolled who receive 
≥1 administration of study intervention, for an estimated total of 120 evaluable participants.
9.3.
Populations for Analyses
The analysis populations will consist of participants as defined below:

The mITT population includes all participants with valid baseline ABPM session, who 
received ≥1 administration of study intervention, ≥1 post-treatment assessment for the 
primary ABPM endpoint, and at least 85% compliance to study intervention for the 
duration of the study.

The safety population includes all treated participants who receive ≥ 1 administration of 
study intervention. 

The PK population includes all participants who have evaluable testosterone 
concentrations.
9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints.


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9.4.1.
General Considerations
The ABPM analyses will be based on the mITT population. Baseline is defined as the last 
nonmissing assessment before the first application of study intervention. All statistical tests will 
be 2-sided hypothesis tests performed at the 5% level of significance for main effects. All CIs 
will be 2-sided 95% CIs, unless stated otherwise. No multiple comparison procedures will be 
applied.
9.4.1.1.
Analysis Endpoints
The primary and secondary efficacy endpoints are listed below and analyses will be defined in 
the following sections. All analyses for other efficacy endpoints listed below will be defined in 
the SAP.
Primary efficacy endpoint:

Change from baseline in 24-hour average SBP obtained at Week 16
Secondary efficacy endpoints:

Change from baseline in 24-hour average DBP, MAP, pulse pressure, and heart rate 
obtained at Week 16
Other efficacy endpoints:

Change from baseline in daytime average SBP, DBP, MAP, pulse pressure, and heart rate 
obtained at Week 16

Change from baseline in night-time average SBP, DBP, MAP, pulse pressure, and heart 
rate obtained at Week 16

Change from baseline over time (hourly average) by nominal clock time and time after 
dose: SBP, DBP, MAP, pulse pressure, and heart rate

The status (yes or no) of participants with new anti-hypertensive medications

The status (yes or no) of participants with dose increases in anti-hypertensive medications

Outlier responder for participants meeting SBP ≥ 160 mm Hg for 24-hour average

Outlier responder for participants meeting SBP change from baseline ≥ 20 mm Hg for 
24-hour average

Outlier responder for participants meeting DBP ≥ 100 mm Hg for 24-hour average

Outlier responder for participants meeting DBP change from baseline ≥ 15 mm Hg for 
24-hour average

Status (yes/no) of participants with normalized testosterone concentrations at Week 16


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9.4.1.2.
Primary Analyses
Continuous descriptive statistics (n, mean, SD, median, min, max, Q1 and Q3) of 24-hour 
average SBP at baseline, Week 16, and change from baseline at Week 16 will be presented. 
Change from baseline at Week 16 will be tested using paired t-test, along with a 2-sided 95% CI. 
If the upper bound of the two-sided 95% CI is less than 3.0, the alternative hypothesis of 
excluding an increase of 3 mm Hg in SBP will be inferred.
9.4.1.3.
Secondary Analyses
Continuous secondary endpoints will be summarized by descriptive statistics (n, mean, SD, 
median, min, max, Q1 and Q3).
Categorical secondary and other endpoints will be summarized by number and percentage of 
participants in specified categories.
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs, clinical laboratory, and vital signs. For each of the 
clinical laboratory and vital signs parameters, the last nonmissing safety assessment before the 
first dose of study intervention will be used as the baseline for all analyses of that safety 
parameter.
9.4.2.1.
Adverse Events
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date (and time, if known) of the first dose of study intervention. However, 
an AE that occurs more than 30 days after the last dose of study intervention will not be counted 
as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criterion.
The number and percentage of participants with TEAEs during the study will be tabulated by 
system organ class and preferred term and by system organ class, preferred term, and severity.
The number and percentage of participants with treatment-related TEAEs during the study will 
be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
Summary tables will be provided for participants with TESAEs and participants with TEAEs
leading to discontinuation if these occurred in 5 or more participants. Listings of all AEs, SAEs, 
and AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Appendix 3.


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9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline (screening) and 
changes from baseline at each assessment will be presented for each clinical laboratory 
assessment.
The criteria for PCS laboratory values will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline clinical laboratory values will be tabulated at each 
assessment. The percentages will be calculated relative to the number of participants who have 
available non-PCS baseline values and at least 1 postbaseline assessment. The numerator will be 
the total number of participants with at least 1 PCS postbaseline value. A supportive listing of 
participants with PCS postbaseline values will be provided for the safety population. 
9.4.2.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic cuff BP, heart rate, weight, and 
temperature) at baseline (screening) and changes from baseline at each assessment will be 
presented.
Vital signs values will be considered to be PCS if they meet both the observed-value criteria and 
the change-from-baseline-value criteria that will be detailed in the SAP. The number and 
percentage of participants who have PCS postbaseline vital signs values will be tabulated for 
each assessment. The percentages will be calculated relative to the number of participants who 
have available non-PCS baseline values and at least 1 postbaseline assessment. The numerator 
will be the total number of participants with at least 1 PCS postbaseline value. A supportive 
listing of participants with PCS postbaseline values will be provided for the safety population.
9.4.3.
PK Analyses
Fasting morning serum total testosterone concentrations will be measured prior to ABPM device 
placement during the screening period on Screening Visit 3 (Day -3 to -1) and at Visit 5 
(Day 112). The time of sample collection and ABPM device placement should be noted.
Fasting serum total testosterone concentrations will also be measured on Visit 2 (Day 14) and 
Visit 4 (Day 56), approximately 8 to 12 hours after application of the nightly dose on the 
previous night.
Concentrations below the limit of quantitation will be treated as 0 for all PK calculations. 
Descriptive statistics for testosterone concentrations will be provided at each sampling timepoint 
for all participants in the PK population. Details of the statistical analyses of PK data will be 
described in the analysis plan finalized prior to database lock. 
9.4.4.
Other Analyses
In addition to the analysis method described in Section 9.4, all exploratory analyses will be 
described in a separate SAP. Graphical summaries may include:

Box plot of hourly average for both SBP and DBP at baseline and at endpoint


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
Cumulative distribution function curves of 24-hour average SBP and DBP at baseline and 
postbaseline

Forest plots for change from baseline SBP and DBP of daytime, night-time and 24-hour 
average
9.4.4.1.
Subgroup Analyses
Sensitivity analyses on the primary endpoint, secondary endpoints, and graphical summaries will 
be conducted on the following subgroups:

Participants without baseline medical history of hypertension

Participants with treated baseline medical history of hypertension

Participants with untreated baseline medical history of hypertension
9.5.
Interim Analyses
There is no interim analysis planned for the study.


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10.
Supporting Documentation and Operational Considerations


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10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
CIOMS International Ethical Guidelines
o
Applicable ICH/ISO GCP guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, package insert, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study by the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators 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. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, HIPAA requirements, where applicable, and the 
IRB/IEC or study center. 

The medical record must include a statement that signed informed consent was obtained 
before the participant was enrolled in the study and the date the signed consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; any identifiable 
participant information will only be transferred in accordance with the signed Informed 
Consent provisions.

The participant must be informed that his personal study-related data will be used by the 
sponsor in accordance with local privacy and data protection laws. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
personal data to be used as described in the informed consent.

The participant 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.

Management of privacy incidents relating to clinical trial participant personal data, as well as 
handling of data participant rights requests (if applicable), should be handled in accordance 
with the agreed upon CTA provisions.
10.1.5.
Dissemination of Clinical Study Data
All data generated in this study are the property of the sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.


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10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another party without written notification to the sponsor.
10.1.7.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed by the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Source data are defined as: original documents, data, and records (eg, hospital records, 
clinical and office charts, diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiche, photographic negatives, 
microfilm or magnetic media, X-rays, participant files, and records kept at the pharmacy, 
at the laboratories, and at medico-technical departments involved in the clinical study). 
These records include, but are not limited to, original signed and dated consent forms, 
relevant observations including records of AEs, and records of all exposure to study 
intervention.


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10.1.8.
Study and Site Start and Closure
For the purpose of clinical trial registries, the study start date is the date on which the clinical 
study will be open for recruitment of participants.
The first act of recruitment is the first site open and will be the study start date.
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. If a premature termination or suspension 
occurs, the sponsor shall remain responsible for providing resources to fulfill the protocol 
obligations and existing agreements for follow-up of participants enrolled in the study, and each 
investigator or authorized designee shall promptly inform enrolled participants, if applicable.
10.1.9.
Publication Policy

Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. 
As this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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10.1.10.
Compliance with Protocol
The investigator is responsible for compliance with the protocol by the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits by the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB/IEC according to the IRB/IEC’s reporting requirements.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10-1 will be performed by the central laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 10-1
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with differential 
(absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
PT
INR
Clinical Chemistry
BUN
Potassium
AST
Total, direct and 
indirect bilirubin
Creatinine
Sodium
ALT
Total protein
Glucose, fasting
Calcium
Alkaline 
phosphatase
Cholesterol, 
chloride, albumin
HbA1c
PSA
Fasting morning 
total testosterone
Prolactin
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Investigators must document their review of each laboratory safety report.














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10.4.
Appendix 4: Abbreviations
Abbreviation
Definition
ABPM
ambulatory blood pressure monitoring
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CDISC
Clinical Data Interchange Standards Consortium
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
DBP
diastolic blood pressure
DHEA
dehydroepiandrosterone
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
ET
early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID
identification
IEC
Independent Ethics Committee
INR
international normalized ratio
I-PSS
International Prostate Symptom Score
IRB
Internal Review Board
ISO
International Organization for Standardization
IUD
intrauterine device
IUS
intrauterine system
MAP
mean arterial pressure
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration


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Abbreviation
Definition
MCV
mean corpuscular volume
mITT
modified intent-to-treat
N/A
not applicable
NCI
National Cancer Institute
PCS
potentially clinically significant
PK
pharmacokinetic
PSA
prostate specific antigen
PT
prothrombin time
Q1
quartile 1
Q3
quartile 3
RBC
red blood cell
S1
Screening Visit 1
S2
Screening Visit 2
S3
Screening Visit 3
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
TC
teleconference
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal
V1
Intervention Period Visit 1
V2
Intervention Period Visit 2
V3
Intervention Period Visit 3
V4
Intervention Period Visit 4
V5
Intervention Period Visit 5
V6
Intervention Period Visit 6
WBC
white blood cell


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10.5.
Appendix 5: Standard Discontinuation Criteria
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable.  
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary)
Completed
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Lack of efficacy
The lack of expected or desired effect related to a therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Non-compliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician decision
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor 
(NCI)
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)


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10.6.
Appendix 6: Study Tabular Summary
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).
Parameter Group
Parameter
Value
Trial information
Trial Title
A Phase IV, Multi-center, Open-label, 
Single-arm 24-hour Ambulatory Blood 
Pressure Monitoring (ABPM) Study of 
16 Weeks Treatment with Androderm®
in Hypogonadal Men
Clinical Study Sponsor
Allergan
Trial Phase Classification
Phase 4 trial
Trial Indication
Hypogonadism
Trial Indication Type
Treatment
Trial Type
Safety
Trial Length
19 weeks
Planned Country of Investigational Sites
United States
Planned Number of Subjects
150
FDA-regulated Device Study
No
FDA-regulated Drug Study
Yes
Pediatric Study
No
Subject information
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18
Planned Maximum Age of Subjects
80
Sex of Participants
Males
Stable Disease Minimum Duration
N/A
Treatments
Investigational Therapy or Treatment
Androderm
Intervention Type
Drug
Dose per Administration
2 mg, 4 mg, or 6 mg
Dose Units
Dosing Frequency
once daily
Route of Administration
transdermal system
Trial design
Study Type
Interventional
Intervention Model
Single-group
Planned Number of Arms
1
Trial Is Randomized
No
Trial Blinding Schema
Open-label
Adaptive Design
No


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10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information
Contraception Guidance:
Male Participants
Nonvasectomized male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined timeframe in 
Section 5.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent

Agree to use a male condom with spermicide plus partner use of a contraceptive method 
with a failure rate of < 1% per year as described in Table 10-2 when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant
In addition, nonvasectomized male participants must refrain from donating sperm for the 
duration of the study and for 30 days after the last dose of study intervention.
Nonvasectomized male participants with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined timeframe.
Table 10-2
Highly Effective and Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb

Oral 

Intravaginal 

Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral 

Injectable 
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb

IUD

IUS

Etonogestrel implant (ie, Nexplanon®)

Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)

Intrauterine copper contraceptive (ie, ParaGard®)


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Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
Acceptable Methods
Acceptable birth control methods that result in a failure of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be used 
during the study intervention period and for at least 30 days after the last dose of study intervention.
Collection of Pregnancy Information:
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the sponsor. Generally, the 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 


CONFIDENTIAL
Protocol 3146-402-016
Androderm® (testosterone transdermal system)
59
GRD-CLN-T-01-01 v3.0
11.
References
Androderm® (testosterone transdermal system) [package insert]. Madison, New Jersey: Allergan, 
Inc; 2018.
Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men with Hypogonadism: 
An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 
2018;103:1715-1744.
Dupont AG, van der Niepen P, Six RO. Placebo Does Not Lower Ambulatory Blood Pressure. 
Br J Clin Pharmacol. 1987;24:106-109.
Mancia G, Omboni S, Parati G, et al. Lack of Placebo Effect on Ambulatory Blood Pressure. Am 
J Hypertens. 1995;8:311-315.
Mutti E, Trazzi S, Omboni S, et al. Effect of Placebo on 24-Hour Non-Invasive Ambulatory 
Blood Pressure. J Hypertens. 1991;9:361-364.
O’Brien E, Parati G, Stergiou G, et al. European Society of Hypertension Position Paper on 
Ambulatory Blood Pressure Monitoring. J Hypertens. 2013;31:1731-1768.
Parati G, Stergiou G, O’Brien E, et al. European Society of Hypertension practice guidelines for 
ambulatory blood pressure monitoring. J Hypertens. 2014;32:1359–1366.
Ullah MI, Riche DM, Koch CA. Transdermal testosterone replacement therapy in men. Drug 
Des Devel Ther. 2014;8:101-112.

SAP_001.pdf: 
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Statistical Analysis Plan 
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Page 1 of 31
Title Page
Protocol Title: A Phase IV, Multi-center, Open-label, Single-arm 24-hour Ambulatory 
Blood Pressure Monitoring (ABPM) Study of 16 Weeks Treatment with Androderm® in 
Hypogonadal Men
Protocol Number: 3146-402-016
Compound Number: AGN-195263
Brief Protocol Title: Androderm® ABPM Study in Hypogonadal Men
Study Phase: IV
Sponsor Name: Allergan Sales, LLC
Legal Registered Address:
Allergan Sales LLC 
5 Giralda Farms 
Madison, NJ 07940
USA 
Regulatory Agency Identifying Number(s): NDA 020489, IND 034028
Approval Date: 28 May 2020
NCT04320745


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Page 2 of 31
Table of Contents
Title Page .........................................................................................................................................1
Table of Contents.............................................................................................................................2
List of Tables ...................................................................................................................................3
SAP Version History........................................................................................................................4
1.
Introduction.......................................................................................................................5
1.1.
Objectives and Endpoints .................................................................................................6
1.2.
Study Design.....................................................................................................................8
2.
Statistical Hypotheses.....................................................................................................11
3.
Sample Size Determination ............................................................................................12
4.
Populations for Analysis.................................................................................................13
5.
Statistical Analyses.........................................................................................................14
5.1.
General Considerations...................................................................................................14
5.2.
Participant Disposition....................................................................................................14
5.3.
Primary Endpoint Analysis.............................................................................................14
Definition of Endpoint....................................................................................................14
Primary Efficacy Analysis..............................................................................................14
Sensitivity Analysis ........................................................................................................14
5.4.
Secondary and Other Endpoints Analyses......................................................................14
5.5.
Other Safety Analyses ....................................................................................................16
Extent of Exposure..........................................................................................................16
Treatment Compliance....................................................................................................16
Adverse Events ...............................................................................................................16
5.5.3.1.
Adverse Events of Special Interest.....................................................................17
Additional Safety Assessments.......................................................................................17
5.5.4.1.
Clinical Laboratory Parameters..........................................................................17
5.5.4.2.
Vital Signs..........................................................................................................18
5.6.
Other Analyses................................................................................................................18
Other variables and/or parameters. .................................................................................18
Subgroup analyses ..........................................................................................................18
5.7.
Interim Analyses.............................................................................................................19
6.
Supporting Documentation.............................................................................................20
6.1.
Appendix 1 List of Abbreviations ..................................................................................20
6.2.
Appendix 2: Changes to Protocol-Planned Analyses .....................................................22
6.3.
Appendix 3: Supporting Study Information ...................................................................22
Demographics .................................................................................................................22
Baseline and Disease Characteristics..............................................................................22
Protocol Deviations.........................................................................................................22
Medical and Surgical History .........................................................................................22
Prior/Concomitant/Follow-up medications (including dictionary).................................22


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Adverse Events of Special Interest .................................................................................23
Potentially Clinically Significant Criteria for Safety Endpoints.....................................23
6.3.7.1.
Potential Clinically Significant for Clinical Laboratory 
Parameters ..........................................................................................................23
6.3.7.2.
Potentially Clinically Significant Criteria for Vital Signs..................................25
6.4.
Data handling convention...............................................................................................25
Analysis Window............................................................................................................25
Derived Efficacy and Health Outcome Data ..................................................................26
6.4.2.1.
Derivation of Efficacy Endpoints.......................................................................26
Repeated or Unscheduled Assessments of Safety Parameters........................................26
Missing Date of the Last Dose of Study treatment.........................................................27
Missing Severity Assessment for Adverse Events..........................................................27
Missing Causal Relationship to Study treatment for Adverse 
Events..............................................................................................................................27
Missing Date Imputation.................................................................................................27
Missing Date Information for Prior or Concomitant Medications..................................28
6.4.8.1.
Incomplete Start Date.........................................................................................28
6.4.8.2.
Incomplete Stop Date.........................................................................................29
Character Values of Clinical Laboratory Parameters .....................................................30
7.
References.......................................................................................................................31
List of Tables
Table 1-1 ......................................................................................................................................... 6
Table 1-2
Schedule of Visits and Procedures...................................................................... 9
Table 6-1
Visit Time Windows for Safety Analysis ......................................................... 25
List of Figures
Figure 1-1
Study Design ....................................................................................................... 8


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SAP Version History
SAP Version History Summary
SAP 
Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version


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1.
Introduction
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of the efficacy and/or safety data as outlined and specified in the final 
protocol of 3146-402-016 dated 08 Nov 2019. Specifications of tables, figures and data listings 
are contained in a separate document.


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1.1.
Objectives and Endpoints
Table 1-1
Objective
Clinical 
Category
Statistical Category
Estimand1
Primary Objective:  To determine whether Androderm has a meaningful effect on 24-hour average systolic blood pressure (SBP) as measured by ABPM in 
men who use testosterone replacement treatment.
Efficacy 
category 1
Primary

Variable: change from baseline in 24-hour average SBP obtained at Week 16

Population: modified intent-to-treat (mITT)

IES: Hypothetical Strategy
o
Data after treatment discontinuation are treated as missing

PLS:  the difference in the variable means between at baseline and at Week 16
o
Descriptive analysis including two-sided 95% confidence interval
Sensitivity (Missing in 24-
hour average SBP at Week 
16 under missing at 
random assumption)
o
Multiple imputation (MI) for missing data 
Secondary Objective:  To determine whether Androderm has a meaningful effect on 24-hour blood pressure (BP) parameters as measured by ABPM in men 
who use testosterone replacement treatment
Efficacy 
category 2
Secondary

Variable: Change from baseline in 24-hour average diastolic blood pressure (DBP), mean arterial 
pressure (MAP), pulse pressure and heart rate obtained at Week 16.

Population: mITT
Exploratory:  To determine whether Androderm has a meaningful effect on BP parameters as measured by ABPM in men who use testosterone replacement 
treatment
Efficacy 
category 3
        Other 

Change from baseline in daytime average SBP, DBP, MAP, pulse pressure and heart rate obtained 
at Week 16


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                                                                                                                                Statistical Analysis Plan 
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Objective
Clinical 
Category
Statistical Category
Estimand1

Change from baseline in night-time average SBP, DBP, MAP, pulse pressure and heart rate 
obtained at Week 16

Change from baseline over time (hourly average) by nominal clock time and time after dose: SBP, 
DBP, MAP, pulse pressure and heart rate

Status (yes/no) of participants with new anti-hypertensive medications

Status (yes/no) of participants with dose increases in anti-hypertensive medications

Outlier responder for participants meeting SBP ≥160 mm Hg for 24-hour average

Outlier responder for participants meeting SBP change from baseline ≥20 mm Hg for 24-hour 
average 

Outlier responder for participants meeting DBP ≥100 mm Hg for 24-hour average

Outlier responder for participants meeting DBP change from baseline ≥15 mm Hg for 24-hour 
average

Status (yes/no) of participants with normalized testosterone concentrations at Week 16
Safety Objective:  To demonstrate the safety of once daily Androderm for 16 weeks in hypogonadal men.
Safety

Variable: Presence of TEAEs

Population: Safety

Analysis: descriptive

Variable: change from baseline in clinical laboratory tests and vital sign

Population: Safety

Analysis: descriptive

Variable: potentially clinically significant in clinical laboratory tests and vital sign

Population: Safety

Analysis: descriptive
IES = Intercurrent event(s) strategy; PLS = Population-level summary.
1 All estimand attributes explicitly identified for primary/secondary and select key estimands only.


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1.2.
Study Design
This is a multi-center, open-label, single-arm study in hypogonadal men to evaluate the effect of 
once daily Androderm on BP parameters as measured by 24-hour ABPM. It is projected that 
approximately 40 sites in the United States will enroll approximately 150 participants who will 
receive at least 1 dose for this study. 
The study will consist of a screening period of approximately 3 weeks (21 days), followed by an 
intervention period of 16 weeks (minimum of 113 + 7 days), for a total study duration of 
approximately 19 weeks (133 days). All participants who meet the criteria for participation in the 
study will be administered Androderm at the starting dose of 4 mg/day. On Visit 2, study 
participants will have morning serum concentrations of testosterone measured. If participants 
have a serum concentration below 400 ng/dL, the dose of Androderm will be increased to 
6 mg/day (one 4 mg/day system and one 2 mg/day system). If the serum concentration is above 
930 ng/dL, the dose of Androderm will be decreased to 2 mg/day. All others will remain on 
4 mg/day.
Approximately 300 participants will be screened to achieve approximately 150 enrolled 
participants who will receive at least 1 dose and 120 participants with interpretable 24-hour 
ABPM data at both baseline and the end of Week 16. Participants who prematurely discontinue 
from the study will not be replaced but will be followed to obtain the last 24-hour ABPM 
assessment.
Figure 1-1
Study Design






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2.
Statistical Hypotheses
The null and alternative hypotheses for change from baseline in 24-hour average SBP obtained at 
baseline and Week 16 (Week 16 minus baseline) are as follows:
H0: mE - mB ≥ 3.0 versus Ha: mE - mB < 3.0 
Where mB and mE are mean 24-hour average SBP obtained at baseline and Week 16 
respectively.


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3.
Sample Size Determination
Based on the FDA advice letter dated 24 May 2019, and the assumption that the mean difference 
in 24-hour SBP obtained at baseline and Week 16 is 0.0, with the upper bound of 3.0 mm Hg and 
the standard deviation of 10.0 mm Hg, 120 participants with available ABPM data at Week 16 
will be required to provide 90% power to reject the null hypothesis at the 2 sided 5% 
significance level. Assuming a 25% dropout rate, 150 participants will be enrolled. 
Approximately 300 participants will be screened, to achieve 150 enrolled who receive 
≥1 administration of study intervention, for an estimated total of 120 evaluable participants.


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4.
Populations for Analysis
The analysis populations will consist of participants as defined below:

The mITT population includes all participants with valid baseline ABPM session, who 
received ≥1 administration of study intervention, ≥1 post-treatment assessments of SBP,
and at least 85% compliance to study intervention for the duration of the study.

The safety population includes all treated participants who receive ≥ 1 administration of 
study intervention.


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5.
Statistical Analyses
5.1.
General Considerations
The ABPM analyses will be based on the mITT population. Baseline is defined as the last 
nonmissing assessment before the first application of study intervention. All statistical tests will 
be 2-sided hypothesis tests performed at the 5% level of significance for main effects. All CIs 
will be 2-sided 95% CIs, unless stated otherwise. No multiple comparison procedures will be 
applied.
5.2.
Participant Disposition
Number of participants screened for the study will be provided.
The summary of study disposition in the Safety population will be provided as treated for the 
following:

Number and percentage of participants treated

Number and percentage of participants completed

Number and percentage of participants discontinued

Reasons for discontinuation from study

In addition, a listing will be provided for participant disposition.
5.3.
Primary Endpoint Analysis
Definition of Endpoint
The primary efficacy endpoint is change from baseline in 24-hour average SBP obtained at Week 
16. 
Primary Efficacy Analysis
Continuous descriptive statistics (n, mean, SD, median, min, max, Q1 and Q3) of 24-hour 
average SBP at baseline, Week 16, and change from baseline at Week 16 will be presented. 
Change from baseline at Week 16 will be tested using paired t-test, along with a 2-sided 95% CI. 
If the upper bound of the two-sided 95% CI is less than 3.0, the alternative hypothesis of 
excluding an increase of 3 mm Hg in SBP will be inferred.
Sensitivity Analysis
Missing value in 24-hour average 24 hours SBP obtained at Week 16 will be imputed using 
multiple imputation (MI).  In the MI analysis, the missing data will be assumed to follow a 
missing at random (MAR) pattern.
5.4.
Secondary and Other Endpoints Analyses
Secondary and other efficacy endpoints are defined as follows.


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Page 15 of 31
Secondary efficacy endpoints:

Change from baseline in 24-hour average DBP, MAP, pulse pressure, and heart rate 
obtained at Week 16
Other efficacy endpoints:

Change from baseline in daytime average SBP, DBP, MAP, pulse pressure, and heart rate 
obtained at Week 16

Change from baseline in night-time average SBP, DBP, MAP, pulse pressure, and heart 
rate obtained at Week 16

Change from baseline over time (hourly average) by nominal clock time and time after 
dose: SBP, DBP, MAP, pulse pressure, and heart rate

The status (yes or no) of participants with new anti-hypertensive medications

The status (yes or no) of participants with dose increases in anti-hypertensive medications

Outlier responder for participants meeting SBP ≥ 160 mm Hg for 24-hour average and for 
hourly average

Outlier responder for participants meeting SBP change from baseline ≥20 mm Hg for 
24-hour average and for hourly average

Outlier responder for participants meeting DBP ≥ 100 mm Hg for 24-hour average and for 
hourly average

Outlier responder for participants meeting DBP change from baseline ≥15 mm Hg for 
24-hour average and for hourly average 

Status (yes/no) of participants with normalized testosterone concentrations (within range 
of 300 to 1030 ng/dL inclusive) at Week 16
Continuous secondary endpoints will be summarized by descriptive statistics (n, mean, SD, 
median, min, max, Q1 and Q3).
Categorical secondary and other endpoints will be summarized by number and percentage of 
participants in specified categories.
Plots of hourly average in SBP and DBP included deviation bars for baseline and Week 16.
Cumulative distribution curves of change from baseline in 24-hour average SBP and DBP at 
Week 16.
Forest plots of daytime, nighttime, and 24-hour change from baseline with 95% confidence 
interval displays for SBP and DBP.


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5.5.
Other Safety Analyses
Extent of Exposure
The exposure to study intervention, calculated as (last study intervention date - first study 
intervention date + 1), will be summarized using descriptive statistics for the Safety population. 
Patient-years, defined as exposure to the study intervention in years, will be summarized for the 
Safety Population
Treatment Compliance
Dosing compliance for a specified period is defined as the number of transdermal systems 
applied by a patient during that period divided by the number of transdermal systems prescribed 
for the same period multiplied by 100. This information will be obtained from Study Intervention
Record of the patient’s electronic case report form.
Descriptive statistics for study intervention compliance will be presented for each period 
between 2 consecutive visits for the Safety Population. 
Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 or higher.
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date (and time, if known) of the first dose of study intervention. However, 
an AE that occurs more than 30 days after the last dose of study intervention will not be counted 
as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criterion.
The number and percentage of participants with TEAEs during the study will be tabulated by 
system organ class and preferred term and by system organ class, preferred term, and severity.
The number and percentage of participants with treatment-related TEAEs during the study will 
be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
The incidence of common (≥ 2% of participants in any treatment group) TEAEs will be 
summarized by preferred term.
Summary tables will be provided for participants with TESAEs and participants with TEAEs
leading to discontinuation if these occurred in 5 or more participants. Listings of all AEs, SAEs, 
and AEs leading to discontinuation by participant will be presented.


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5.5.3.1.
Adverse Events of Special Interest
Potential Hy’s Law criteria within a 24-hour window is defined by a post baseline elevation of 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 x ULN, along with total 
bilirubin (TBL) ≥ 2 x ULN and a non-elevated alkaline phosphatase (ALP) < 2 x ULN, all based 
on blood draws collected within a 24-hour period. Potential Hy’s Law criteria without time 
window is defined by maximum of post baseline elevation of ALT or AST ≥ 3 x ULN, along 
with maximum of post baseline elevation of TBL ≥ 2 x ULN. Patients who meet the potential 
Hy’s Law criteria from the first dose of study drug to the end of study will be summarized. 
Supportive tabular displays will also be provided.
Prostate events will be summarized and provided in a listing.
Additional Safety Assessments 
For clinical laboratory, vital sign, and ECG, the last nonmissing safety assessment before the 
first dose of study intervention will be used as the baseline for all analyses of that safety 
parameter.
5.5.4.1.
Clinical Laboratory Parameters
Descriptive statistics for values and changes from the baseline in standard units at each 
assessment time point will be presented for the following laboratory parameters:
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with differential 
(absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
PT
INR
Clinical Chemistry
BUN
Potassium
AST
Total, direct and 
indirect bilirubin
Creatinine
Sodium
ALT
Total protein
Glucose, fasting
Calcium
Alkaline 
phosphatase
Cholesterol, 
chloride, albumin
HbA1c
PSA
Fasting morning 
testosterone
Prolactin
Routine Urinalysisa

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
a
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.


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Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Section 6.3.7.1. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by study intervention group. The percentages will be calculated relative to the number of 
participants with available non-PCS baseline values and at least 1 postbaseline assessment for 
the double-blind treatment period. The numerator will be the total number of participants with 
available non-PCS baseline values and at least 1 PCS postbaseline value during the study. A 
supportive tabular display of PCS values will be provided, including the PID number, baseline 
and all postbaseline values. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
5.5.4.2.
Vital Signs
Descriptive statistics for vital signs and their changes from baseline at each assessment timepoint 
will be presented by study intervention group. 
Vital sign values will be considered PCS if they meet both the observed value criterion and the 
change from baseline value criterion, if both criteria are available, or meet either the observed 
value criterion or the change from baseline value criterion that will be detailed in
Section 6.3.7.2. The number and percentage of participants who have PCS postbaseline vital sign 
values will be tabulated by study treatment. The percentages will be calculated relative to the 
number of participants who have available baseline or non-PCS baseline (for parameters with 
only the observed value criterion) values and at least 1 postbaseline assessment. The numerator 
will be the total number of participants with at least 1 PCS postbaseline value during the study. A 
supportive listing of PCS values will be provided. In addition, a tabular display showing all AEs 
that occurred in participants who had PCS postbaseline vital sign values will be provided.
5.6.
Other Analyses
Other variables and/or parameters.
Subgroup analyses
Participants without baseline medical history of hypertension, with baseline medical history of 
hypertension untreated and with baseline medical history of hypertension treated will be 
performed for following endpoints and graphs.   

Change from baseline in 24-hour average SBP and DSP obtained at Week 16

Change from baseline hourly average by nominal clock time and time after dose: SBP and 
DBP

Outlier responder for participants meeting SBP ≥ 160 mm Hg for 24-hour average and for 
hourly average


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
Outlier responder for participants meeting SBP change from baseline ≥20 mm Hg for 
24-hour average and for hourly average

Outlier responder for participants meeting DBP ≥ 100 mm Hg for 24-hour average and for 
hourly average

Outlier responder for participants meeting DBP change from baseline ≥15 mm Hg for 
24-hour average and for hourly average

Plots of hourly average in SBP and DBP included deviation bars for baseline and Week 16

Cumulative distribution curves of change from baseline in 24-hour average SBP and DBP 
at Week 16

Forest plots of daytime, nighttime, and 24-hour change from baseline with 95% 
confidence interval displays for SBP and DBP.
5.7.
Interim Analyses 
No interim analysis is planned.


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6.
Supporting Documentation
6.1.
Appendix 1 List of Abbreviations
Abbreviation
Definition
ABPM
ambulatory blood pressure monitoring
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CDISC
Clinical Data Interchange Standards Consortium
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
DBP
diastolic blood pressure
DHEA
dehydroepiandrosterone
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
ET
early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID
identification
IEC
Independent Ethics Committee
INR
international normalized ratio
I-PSS
International Prostate Symptom Score
IRB
Internal Review Board
ISO
International Organization for Standardization
IUD
intrauterine device
IUS
intrauterine system


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Abbreviation
Definition
MAR
missing at random
MAP
mean arterial pressure
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MI
multiple imputation
mITT
modified intent-to-treat
N/A
not applicable
NCI
National Cancer Institute
PCS
potentially clinically significant
PK
pharmacokinetic
PSA
prostate specific antigen
PT
prothrombin time
Q1
quartile 1
Q3
quartile 3
RBC
red blood cell
S1
Screening Visit 1
S2
Screening Visit 2
S3
Screening Visit 3
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
TC
teleconference
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal
V1
Intervention Period Visit 1
V2
Intervention Period Visit 2
V3
Intervention Period Visit 3
V4
Intervention Period Visit 4
V5
Intervention Period Visit 5
V6
Intervention Period Visit 6
WBC
white blood cell


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6.2.
Appendix 2: Changes to Protocol-Planned Analyses
There are no changes from the protocol-planned analyses.
6.3.
Appendix 3: Supporting Study Information
Demographics
Demographic parameters (eg, age, race, ethnicity, sex) will be summarized descriptively for the 
Safety Population.
Baseline and Disease Characteristics
Baseline characteristics (weight; height; and body mass index, calculated as weight [kg]/(height 
[m])2 and baseline medical history of without hypertension, with hypertension untreated and 
treated will be summarized descriptively for the Safety Population.
Protocol Deviations
Protocol deviations will be defined in Protocol Deviation Requirement Specification, including 
importance classification. The number and percentage of participants with important protocol 
deviations will be summarized for Safety Population.
Medical and Surgical History
Abnormalities in participants’ medical and surgical history will be coded using the Medical 
Dictionary for Regulatory Activities, version 22.1 or higher.  The number and percentage of 
participants with abnormalities in medical and surgical histories in each system organ class and 
preferred term will be summarized for the Safety Population. 
Prior/Concomitant/Follow-up medications (including dictionary)
The medication data will be coded using the World Health Organization (WHO) Drug Global B3 
version March 2019 or higher. 
Prior medication is defined as any medication taken before the first dose of study intervention. 
Concomitant medication is defined as any medication taken on or after the date of the first dose 
of study intervention. 
The number and percentage of participants reporting prior or concomitant medications will be 
summarized for ATC class and code, and preferred drug name. If more than one medication is 
coded to the same preferred drug name for the same participant, the participant will be counted 
only once for that preferred drug name. Prior and concomitant medications will be summarized 
separately.


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Adverse Events of Special Interest
1. Potential Hy’s Law cases:

ALT or AST ≥ 3 × ULN and 

Total Bilirubin ≥ 2 × ULN and 

Alkaline Phosphatase < 2 × ULN 
Anytime from the time the participant signs the ICF for the trial, until the final follow-up visit, 
investigators will notify the sponsor immediately when all the above criteria have been met. A 
potential Hy’s law case will be sent directly to the sponsor by emailing
IR-clinical-SAE@allergan.com on an AE of Special Interest Form along with the SAE Report 
Form as soon as possible (within 24 hours of learning of the potential Hy’s Law). The CRF for 
potential Hy’s law cases will be completed within 7 calendar days. Every effort to determine the 
cause of the liver enzyme abnormalities will be made, and close monitoring will be initiated in 
conjunction with the medical monitor and in accordance with the FDA “Guidance for Industry: 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation” July 2009. 
2. Prostate events: 

Lower urinary tract symptoms of prostatic hyperplasia
Potential lower urinary tract symptoms of prostatic hyperplasia will be sent directly to the 
sponsor by emailing IR-clinical-SAE@allergan.com on an AE of Special Interest Form along 
with the SAE Report Form as soon as possible (within 24 hours of learning of the event). The 
CRF for lower urinary tract symptoms of prostatic hyperplasia will be completed within 
7 calendar days.
Potentially Clinically Significant Criteria for Safety Endpoints
The potentially clinically significant criteria for clinical laboratory parameters and vital signs are 
provided in the following sections. 
6.3.7.1.
Potential Clinically Significant for Clinical Laboratory Parameters  
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Albumin
g/L
< 0.9 × LLN
> 1.1 × ULN
Alanine 
aminotransferase 
(ALT)
U/L
—
≥ 3 × ULN
Alkaline phosphatase
U/L
—
≥ 3 × ULN


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Parameter
SI Unit
Lower Limit
Higher Limit
Aspartate 
aminotransferase 
(AST)
U/L
—
≥ 3 × ULN
Bilirubin, total
μmol/L
—
> 1.5 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, Total
mmol/L
—
> 1.3× ULN
Creatinine
μmol/L
—
> 1.3 × ULN
Glucose, fasting, 
serum
mmol/L
< 0.8 × LLN
> 1.2× ULN
Glucose, random, 
serum
mmol/L
< 0.8 × LLN
> 1.4 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Urea Nitrogen (BUN)
mmol/L
—
> 1.2 × ULN
HEMATOLOGY
Basophils, absolute 
cell count
109/L
—
> 3 × ULN
Neutrophils, absolute 
cell count
109/L
< 0.8 × LLN
> 1.5 × ULN
Hematocrit
Ratio 
< 0.9 × LLN
> 1.1 × ULN
Hemoglobin
g/L
< 0.9 × LLN
> 1.1 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.7 × LLN
> 1.5 × ULN
URINALYSIS
pH
—
< 0.9 × LLN
> 1.1 × ULN
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités
(International System of Units); ULN = upper limit of normal value provided by the laboratory.


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Statistical Analysis Plan  
Androderm® (testosterone transdermal system)
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6.3.7.2.
Potentially Clinically Significant Criteria for Vital Signs
Parameter
Flag
Criteria
Observed Value
Change from Baseline
Systolic blood pressure, mm Hg
High
≥ 140
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Diastolic blood pressure, mm Hg
High
≥ 90
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Pulse rate, bpm
High
≥ 100
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 5%
Low
—
Decrease of ≥5%
SBP = Systolic blood pressure, DBP = Diastolic blood pressure, bpm = beats per minute.
6.4.
Data handling convention
Analysis Window
Table 6-1 presents the visits assigned for analyses and the corresponding range of treatment days 
(window) during which an actual visit may occur.
Table 6-1
Visit Time Windows for Safety Analysis
Derived Visit
Scheduled Test / Visit Daya
Window
Day 1
Day 1
Days ≤ 1
Week 2
Day 14
Days [2, 17]
Week 3
Day 21
Days [18, 38]
Week 8
Day 56
Days [39, 79]
Week 16
Day 112
Days > 79
End of Treatment Period
Final or termination visit during the Treatment Period


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Test/Visit Day will be calculated as follows: test/visit date – date of the first dose of study drug + 
1.
If a participant has 2 or more visits within the same window, the last visit with a nonmissing 
value will be used for analysis
Derived Efficacy and Health Outcome Data
6.4.2.1.
Derivation of Efficacy Endpoints 
BP parameters, including SBP, DBP, MAP, pulse pressure, and heart rate will be collected by 
24-hour ABPM at Baseline and Week 16.
Term
Definition
Baseline ABPM
Any assessment recorded during the approximately 24-hour period starting on Screening 
Visit 3; after the ABPM device is applied, through Visit 1, when the ABPM device is 
removed
Week 16 (End of 
study intervention)
Any assessment recorded during the approximately 24-hour period starting on Visit 5, 
after the ABPM device is applied, through Visit 6/EOS/ET, when the ABPM device is 
removed
24-hour ABPM
Any assessment recorded at the specified analysis timepoint (baseline, Week 16) during 
the approximately 24-hour period after the ABPM device is applied through when the 
ABPM device is removed
Daytime ABPM
Any assessment recorded between 0900 and 2100 on either:

the day the ABPM device is applied

the day the ABPM device is removed
Night-time ABPM
Any assessment recorded between 0100 and 0600 on either:

the day the ABPM device is applied

the day the ABPM device is removed
Hours 0 through 23
For each Hour X, any assessment recorded between XX00 and XX59, on either:

the day the ABPM device is applied

the day the ABPM device is removed
Continuous BP endpoints are 24-hour, daytime or night-time average on nonmissing values in 
BP for baseline, Week 16 or change from baseline at Week 16.
Repeated or Unscheduled Assessments of Safety Parameters
Baseline is defined as the last assessment made before the first dose of study intervention. If end-
of-study assessments are repeated or if unscheduled visits occur, the last nonmissing postbaseline 
assessment will be used as the end-of-study assessment for generating summary statistics. 
However, all postbaseline assessments will be used for PCS value determinations, and all 
assessments will be presented in the data listings.


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Missing Date of the Last Dose of Study treatment 
When the date of the last dose of study intervention is missing, all efforts should be made to 
obtain the date from the Investigator. If it is still missing after all efforts have been made, the last 
available study medication date will be used in the calculation of treatment duration. 
Missing Severity Assessment for Adverse Events
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned. If severity is missing for an AE that started on or after the 
date of the first dose of study intervention, an intensity of severe will be assigned. The imputed 
values for severity assessment will be used for the incidence summary; the values will be shown 
as missing in the data listings.
Missing Causal Relationship to Study treatment for Adverse Events
If the causal relationship to the study intervention is missing for an AE that started on or after the 
date of the first dose of study intervention, a causality of yes will be assigned. The imputed 
values for causal relationship to double-blind treatment will be used for the incidence summary; 
the values will be shown as missing in the data listings.
Missing Date Imputation
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(ie, partly missing).
Missing month and day
If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to the 
missing fields
If the year of the incomplete start date is before the year of the first dose of study intervention, 
December 31 will be assigned to the missing fields
If the year of the incomplete start date is after the year of the first dose of study intervention, 
January 1 will be assigned to the missing fields
Missing month only
If only the month is missing, the day will be treated as missing and both the month and the day 
will be replaced according to the above procedure
Missing day only
If the month and year of the incomplete start date are the same as the month and year of the first 
dose of study intervention, the day of the first dose of study intervention will be assigned to 
the missing day


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If either the year of the incomplete start date is before the year of the date of the first dose of 
study intervention or if both years are the same but the month of the incomplete start date is 
before the month of the date of the first dose of study intervention, the last day of the month 
will be assigned to the missing day
If either the year of the incomplete start date is after the year of the date of the first dose of study 
intervention or if both years are the same but the month of the incomplete start date is after 
the month of the date of the first dose of study intervention, the first day of the month will be 
assigned to the missing day
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date:

If the stop date is after the date of the first dose of study intervention, the date of the first 
dose of study intervention will be assigned to the missing start date
If the stop date is before the date of the first dose of study intervention, the stop date will be 
assigned to the missing start date
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, including rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
6.4.8.1.
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day
If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to the 
missing fields
If the year of the incomplete start date is before the year of the first dose of study intervention, 
December 31 will be assigned to the missing fields
If the year of the incomplete start date is after the year of the first dose of study intervention, 
January 1 will be assigned to the missing fields
Missing month only
If only the month is missing, the day will be treated as missing and both the month and the day 
will be replaced according to the above procedure


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Missing day only
If the month and year of the incomplete start date are the same as the month and year of the first 
dose of study intervention, the day of the first dose of study intervention will be assigned to 
the missing day
If either the year of the incomplete start date is before the year of the date of the first dose of 
study intervention or if both years are the same but the month of the incomplete start date is 
before the month of the date of the first dose of study intervention, the last day of the month 
will be assigned to the missing day.
If either the year of the incomplete start date is after the year of the date of the first dose of study 
intervention or if both years are the same but the month of the incomplete start date is after 
the month of the date of the first dose of study intervention, the first day of the month will be 
assigned to the missing day
6.4.8.2.
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study treatment is missing, 
replace it with the last visit date in the imputations described below. If the imputed stop date is 
before the start date (imputed or nonimputed start date), the imputed stop date will be equal to 
the start date.
Missing month and day
If the year of the incomplete stop date is the same as the year of the last dose of study treatment, 
the month and day of the last dose of study treatment will be assigned to the missing fields
If the year of the incomplete stop date is before the year of the last dose of study treatment, 
December 31 will be assigned to the missing fields
If the year of the incomplete stop date is after the year of the last dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only
If only the month is missing, the day will be treated as missing and both the month and the day 
will be replaced according to the above procedure
Missing day only
If the month and year of the incomplete stop date are the same as the month and year of the last 
dose of study treatment, the day of the last dose of study treatment will be assigned to the 
missing day
If either the year of the incomplete stop date is before the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is 
before the month of the date of the last dose of study treatment, the last day of the month will 
be assigned to the missing day


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If either the year of the incomplete stop date is after the year of the date of the last dose of study 
treatment or if both years are the same but the month of the incomplete stop date is after the 
month of the date of the last dose of study treatment, the first day of the month will be 
assigned to the missing day
Character Values of Clinical Laboratory Parameters
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, a 
coded value must be appropriately determined for use in the statistical analyses. The actual 
values, however, as reported in the database will be presented in the data listings.


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7.
References
None.