Clinical trial NCT04274894
Conditions: Hypogonadism
Keywords: Hypogonadism Testosterone Replacement Therapy AndroGel
Sponsor: AbbVie
Start date: 2020-05-12; Completion date: 2022-01-07
Enrollment: 246 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Hypogonadism is an endocrine disorder characterized by absent or deficient testosterone levels along with signs and symptoms of androgen deficiency, including delayed development or regression of sexual characteristics, impaired sexual function and sense of well-being, depressed mood, decreased muscle strength associated with loss of muscle mass and reduced bone mineral density. AndroGel 1.62% has demonstrated its ability to increase total testosterone levels in the blood by absorption of testosterone through the skin when applied topically. This study evaluated the effect of AndroGel 1.62% on systolic blood pressure using ambulatory blood pressure monitoring in hypogonadal men who used testosterone replacement therapy.

AndroGel 1.62% is a drug used for the treatment of hypogonadism, which is associated with low or no testosterone. This was an open-label study which means that both the study doctor and study participants knew what drug and what dose is being used. All participants in this study were in the same group, called a treatment arm. Adult male participants with hypogonadism were enrolled and received AndroGel 1.62%. This was a multi-center study with 190 participants enrolled (initially planned) in approximately 45 sites in the United States to yield 171 subjects in the per protocol (PP) population. A blinded sample size re-estimation (BSSR) was performed when around 70% of the planned subjects in the PP population had completed the end of treatment visit. Sample size was increased at BSSR and 246 participants were actually enrolled.

Participants received daily topical gel doses of AndroGel 1.62% for approximately 16 weeks.

There may have been a higher burden for participants in this study compared to standard of care. Participants attended 8 study visits during the course of the study at a hospital or clinic and received 2 study phone calls. The effect of the treatment was checked by medical assessments, blood tests (including pharmacokinetic sampling), and 24-hour blood pressure monitors.

Detailed description:

Arms: arm 1: AndroGel 1.62% was applied topically once daily in the morning beginning at the Day 1 Visit after confirmed valid ambulatory blood pressure monitoring (ABPM) assessment and was applied at approximately the same time each day after that during the study, for approximately 16 weeks. The starting dose of AndroGel 1.62% was 40.5 mg of T (2 pump actuations, applied to the upper arms and shoulders) and was titrated up or down by 20.25 mg or remained the same as assessed by morning serum T levels at Weeks 2 and 4.
Interventions: intervention 1: AndroGel 1.62%
Intervention descriptions: intervention 1: AndroGel 1.62% was packaged in pump bottles with quantities sufficient to accommodate study design and could have been dose adjusted between a minimum of 20.25 mg of T (1 pump actuation) and a maximum of 81.0 mg of testosterone (4 pump actuations). For the first study drug administration at the Day 1 Visit, and also at Week 2, Week 4, Week 16 ambulatory blood pressure monitoring (ABPM,) and End of Treatment Visits, participants applied the study drug while on site so that the site staff could observe the proper administration of study drug. If participants forgot to apply their AndroGel 1.62% dose at their regularly scheduled dosing time, they were to take the next dose at the next dosing time.

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
6
2.1
BACKGROUND AND RATIONALE
6
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
OBJECTIVES AND ENDPOINTS
9
3.1
OBJECTIVE
9
3.2
PRIMARY ENDPOINT
9
3.3
OTHER ENDPOINTS
9
3.4
SAFETY ENDPOINTS
10
3.5
PHARMACOKINETIC ENDPOINTS
10
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
CONTRACEPTION RECOMMENDATIONS
17
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
18
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
18
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
19
5.7
STUDY DRUG
19
5.8
RANDOMIZATION/DRUG ASSIGNMENT
20
5.9
PROTOCOL DEVIATIONS
21
6
SAFETY CONSIDERATIONS
21
6.1
COMPLAINTS AND ADVERSE EVENTS
21
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
24
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7.1
STATISTICAL AND ANALYTICAL PLANS
24
7.2
DEFINITION FOR ANALYSIS POPULATIONS
24
7.3
STATISTICAL ANALYSES FOR EFFICACY
25
7.4
STATISTICAL ANALYSES FOR SAFETY
25
7.5
INTERIM ANALYSIS
26
7.6
OVERALL TYPE I ERROR CONTROL
26
7.7
SAMPLE SIZE DETERMINATION
26
8
ETHICS
27
8.1
INSTITUTIONAL REVIEW BOARD (IRB)
27
8.2
ETHICAL CONDUCT OF THE STUDY
27
8.3
SUBJECT CONFIDENTIALITY
28
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
28
10 DATA QUALITY ASSURANCE
28
11 COMPLETION OF THE STUDY
28
12 REFERENCES
28
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
33
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
35
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
36
APPENDIX D.
ACTIVITY SCHEDULE
37
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APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
39
APPENDIX F.
OPERATIONS MANUAL
40
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Testosterone (T) products have been approved in the United States (US) for over 50 years for the 
treatment of T-deficient men.  These products are currently indicated for the treatment of congenital or 
acquired primary hypogonadism and hypogonadotropic hypogonadism in men.1,2
Hypogonadism is an endocrine disorder characterized by absent or deficient T levels along with signs 
and symptoms of androgen deficiency, including delayed development or regression of secondary sexual 
characteristics, impaired sexual function, impaired sense of well-being, depressed mood, decreased 
muscle strength associated with a loss of muscle mass, and reduced bone mineral density (BMD).2-7
The efficacy of AndroGel 1.62% is demonstrated by its ability to increase serum total T levels by the 
absorption of T through the skin when applied topically.  The objective of testosterone replacement 
therapy (TRT) in hypogonadal men is to replace T within the eugonadal range for healthy men (300 to 
1000 ng/dL).  Replacement of T levels into the eugonadal range in hypogonadal men should lead to 
restoration of androgenic effects such as improvements in libido and mood, increased lean mass, 
decreased fat mass and increased BMD.2  The aforementioned endpoints have been examined in 
placebo-controlled studies with various levels of supportive evidence depending on the cohorts 
(hypogonadal, eugonadal, mixed).
Current guidelines for the use of TRT outline the appropriate assessment and monitoring of men who 
are candidates for T therapy.  Key components of the Endocrine Society Guidelines8 include criteria for 
selecting candidates with signs and symptoms consistent with hypogonadism and documented evidence 
of low T levels, for whom TRT may be indicated.  The Endocrine Society Guidelines also offer 
recommendations for confirmatory testing of serum T concentrations, additional evaluation, and TRT.8
Effects of Testosterone on Blood Pressure
Testosterone-related research evaluating effect of T on Blood pressure (BP) includes preclinical and in 
vitro experiments, as well as some clinical data.9,10
Testosterone-related effects include:

Increased nitric oxide synthase;11

Decreased endothelin-1 in humans, although opposite effects seen in animals;12

Improved endothelial function;13,14

Decreased prostacyclin;15

Increased thromboxane (TXA)16 postorchiectomy in rats appears to negatively affect nitric oxide 
and TXA release, demonstrating the complex relationship between factors influenced by 
hypogonadism itself (i.e., castration in this instance established a microenvironment where TXA 
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would be expected to cause more vasoconstriction) versus changes induced by TRT in 
hypogonadal men;17

Sodium retention:  the mechanism is unclear, may occur through activation of the renin-
angiotensin system.18,19
Blood Pressure Changes in TRT Clinical Trials
Data from trials using a variety of T formulations and routes of administration demonstrate variable BP 
responses to therapy.  The results observed range from a modest detriment to a benefit, including 
neutral effects.
In general, transdermal TRT does not appear to adversely influence overall study cohort mean BP across 
a number of studies and across a variety of patient types, including men at increased risk for 
cardiovascular disease (e.g., men with diabetes, traditional cardiovascular risk factors, and older age).  
However, BP increases have been observed with oral TRT.20
The objective of the present study is to evaluate the effect of AndroGel 1.62% on BP in hypogonadal 
men to fulfill a postmarketing requirement from the US Food and Drug Administration (FDA).
Ambulatory Blood Pressure Monitoring
Ambulatory Blood Pressure Monitoring (ABPM) has been widely used for the past decade in research 
and clinical practice around the world;21-23 however, its use has been limited in the US because of the 
expense of the equipment and the time involved in patient training and data analysis.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure,24-26 summarizes the use of ABPM as follows:

ABPM provides information about BP during daily activities and sleep.

ABPM is warranted for evaluation of "white coat" hypertension in the absence of target organ 
injury.  It is also helpful to assess patients with apparent drug resistance, hypotensive symptoms 
with antihypertensive medications, episodic hypertension, and autonomic dysfunction.

ABPM provides a measure of the percentage of BP readings that are elevated of the overall BP 
load, and of the extent of BP reduction during sleep.  In most individuals, BP decreases by 10% 
to 20% during the night; those in whom such reductions are not present are at increased risk for 
cardiovascular events, and ABPM helps to identify these individuals.
A great deal of evidence has accumulated in the past decade regarding ABPM utility.  It has been 
demonstrated that ABPM is a better indicator of a patient's true BP and correlates more closely with 
target organ damage and cardiovascular events than clinical cuff measurements.  As a result, ABPM is 
now considered to be the noninvasive gold standard.27
Rationale for an ABPM Study of Testosterone in Hypogonadal Men
The rationale for such a study includes data for a signal of hypertension risk in men treated with oral T, 
and that relatively few TRT studies have used ABPM to monitor BP in hypogonadal men treated with T.
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ABPM Validity Criteria
Data presented at the public workshop titled "Evaluating the Pressor Effects of Drugs & ABPM Studies" 
in February 2019 demonstrated that 50% of expected measurements during 24 hours within an 
individual along with other criteria may be sufficient for ABPM to be considered valid in the research 
trial settings.28
The ABPM validity criteria for present study are outlined below in Section 4.1 and in Appendix 7.1 of the 
Operations Manual.
2.2 Benefits and Risks to Subjects
Benefits/Risks of Testosterone Replacement Therapy
The efficacy of AndroGel 1.62% is demonstrated by its ability to increase serum total T levels by the 
absorption of T through the skin when applied topically.
Potential risks of treatment with AndroGel 1.62% include secondary transfer of T to others, increased 
prostate-specific antigen (PSA) levels, prostate cancer, mood swings, hematocrit (Hct) increase, and skin 
irritation at the application site.  For further details, please see findings from completed studies, 
including safety data in the current AndroGel 1.62% package insert.29
Benefits/Risks of ABPM 
Ambulatory blood pressure monitoring provides information that home BP and clinic BP cannot, 
including:

An estimate of true, or mean, BP level;

Addresses BP variability; 

Allows for evaluation of diurnal rhythm of BP;

Allows for measuring nighttime BP as nighttime hypertension correlates with a higher risk of 
cardiovascular end outcomes;

Allows for ruling out white-coat hypertension;

Allows for conducting BP medication assessment.
Ambulatory blood pressure monitoring is especially useful for recently diagnosed hypertension or the 
assessment of BP medications effectiveness.  An ABPM test can help physicians to prescribe the right 
medications to keep BP in control and reduce future cardiovascular risk.  When ABPM is incorporated 
into the hypertension diagnostic and treatment process, up to a 14% savings in the cost of healthcare 
has been calculated.30
Although subjects may not directly benefit from the ABPM procedure, their participation in the study 
may contribute to scientific advances in the area of ABPM research and its clinical practice, as well as 
provide valuable information for the medical community and hypogonadal men receiving TRT.
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The risks of ABPM are very low.  One prospective case series study demonstrated that only 4 of 
219 patients had complications during ABPM.  The most frequent complications were peripheral 
petechiae, which could be related to underlying vascular abnormalities.31
3 OBJECTIVES AND ENDPOINTS
3.1 Objective 
The objective of this study is to assess the effect of AndroGel 1.62% on BP.  The hypothesis 
corresponding to the primary objective is that AndroGel 1.62%, used as labelled, does not affect 24-hour 
average systolic blood pressure (SBP).
3.2 Primary Endpoint
The primary endpoint is the change in 24-hour average SBP from Baseline to End of Treatment (EOT).
3.3 Other Endpoints

Change from Baseline to EOT in average daytime (09:00 – 21:00 h) mean arterial pressure 
(MAP), SBP, diastolic blood pressure (DBP), pulse pressure (PP), and heart rate (HR)

Change from Baseline to EOT in average nighttime (01:00 – 06:00 h) MAP, SBP, DBP, PP, and HR

Change from Baseline to EOT in average 24-hour MAP, DBP, PP, and HR

Change from Baseline to EOT of MAP, SBP, DBP, PP, and HR at the time of maximum observed 
T concentration (Tmax) by 24-hour recordings

Change from Baseline over time (hourly average) by nominal clock time for MAP, SBP, DBP, PP, 
and HR by 24-hour recordings at EOT

Change from Baseline over time (hourly average) by time after dose for MAP, SBP, DBP, PP, and 
HR by 24-hour recordings at EOT

Subjects with new concomitant antihypertensive medication(s) during the Treatment Period

Subjects with dose increases in antihypertensive medication(s) during the Treatment Period

Subjects and observations meeting the following BP thresholds separately by 24-hour average 
and by hourly average by 24-hour recordings:

≥ 160 mmHg SBP at EOT

≥ 100 mmHg DBP at EOT

≤ 90 mmHg SBP at EOT

≤ 60 mmHg DBP at EOT

≥ 20 mmHg increase from Baseline to EOT in SBP

≥ 15 mmHg increase from Baseline to EOT in DBP
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3.4 Safety Endpoints
Safety will be assessed by the incidence of serious adverse events (SAEs), adverse events of special 
interest (AESI), study procedure–related nonserious adverse events (AEs) and SAEs, and AEs that lead to 
study drug discontinuation.  In addition, changes from Baseline in laboratory and vital sign parameters 
to each specified timepoint will be summarized.
3.5 Pharmacokinetic Endpoints
The steady-state pharmacokinetics (PK) of T will be characterized at the EOT Visit after a valid Week 16 
ABPM 24-hour collection from serial PK blood samples (4 in total) obtained in all subjects at 0 hour 
(immediately prior to subject on-site application of study drug), and at 2 hours, 4 hours, and between 
6 to 8 hours following study drug application.  The time of on-site application of study drug and time of 
PK blood draws will be recorded by the site for each subject.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a multicenter, Phase 4, open-label, single-arm study to establish the non-inferiority with a margin 
of 3 mmHg for change in 24-hour average SBP from Baseline to EOT.  Efficacy will not be evaluated in 
this study.
The initial planned study enrollment is approximately 190 subjects based on the projected sample size 
calculation and subject discontinuation rate.  There will be approximately 45 sites in the US.
The Screening Period is up to 45 days prior to the baseline ABPM 24-hour collection and includes 
2 separate visits (Screening Visit 1 [SV1] and Screening Visit 2 [SV2]) to establish subject eligibility.  
Office BP measurements by automated oscillometric device (see Appendix 7.2 of the Operations 
Manual) will be used for evaluation of the subject for BP eligibility criteria at Screening.  Once subjects 
meet all of the eligibility criteria during Screening, they will be enrolled into the study and followed until 
approximately 30 days following EOT.
EOT is defined as a valid ABPM 24-hour collection after at least 16 weeks of treatment with AndroGel 
1.62%.  End of study (EOS) is defined as last visit/last procedure/last contact (office visit or phone call).
Ambulatory blood pressure monitoring measurements will be obtained from all subjects using a 
portable data-monitoring device.  The ABPM procedure will be performed over a 24-hour period across 
2 days and will include ABPM device application by site (1st Day) and ABPM device removal by site 
(2nd Day).
The validity of the ABPM 24-hour collection measurements will be evaluated prior to performing the 
procedures for the Day 1 Visit, and prior to performing the procedures for the EOT Visit.  Day 1 is 
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defined as start of treatment (first dose of the study drug).  Subjects will receive the first dose of the 
study drug on site only after validity of the baseline ABPM 24-hour collection is confirmed.
The investigator or designee will assess the validity of ABPM measurements based on the results that 
are immediately available on site once data is downloaded from the ABPM device, to the study 
configured laptop, utilizing ABPM specific software.  The investigator or designee can then assess if a 
repeat ABPM collection is required.
The ambulatory blood pressure (ABP) monitor will be set to automatically measure and record BP every 
30 minutes for 24 hours.  The ABPM 24-hour collection will be repeated if > 50% of collected ABPM data 
(measurements) during the 24-hour period, daytime period (09:00 – 21:00 h), or nighttime period 
(01:00 – 06:00 h) are missing or if there is an ABPM device malfunction.  Based on these criteria, a 
24-hour ABPM collection will be considered valid if all of the following are obtained:
1.
At least 24 measurements of SBP during the 24-hour period
2.
At least 12 SBP measurements between 09:00 and 21:00
3.
At least 5 SBP measurements between 01:00 and 06:00
The repeat ABPM 24-hour collection will be conducted at Unscheduled Visits within 7 days of the invalid 
APBM.  The recorded ABPM data will be transmitted to the core lab for centralized management (see 
Section 3.14 of the Operations Manual).
The study team, study statistician, study sites, and subjects will remain masked to the Week 16 ABPM 
data until the end of the Treatment Period of the last subject.
The Treatment Period will last for at least 16 weeks.  The site will record dosing times corresponding to 
the visits for ABPM collection and serial PK sampling times.  Titration evaluation of T dose will occur in 
all subjects at Week 2 and Week 4.  All subjects will start on 40.5 mg of study drug.  Subjects will return 
on Weeks 2 and 4 to have early morning pre-dose T levels evaluated for titration.  Subjects will be 
titrated up by 20.25 mg, down by 20.25 mg, or remain on the previously assigned dose if their serum T 
levels are < 350 ng/dL, > 750 ng/dL, or between 350 ng/dL and 750 ng/dL inclusive, respectively (see 
Table 2 in Section 6.4 of the Operations Manual).  The final titrated doses will be 20.25 mg, 40.5 mg, 
60.75 mg, or 81.0 mg, and subjects will remain on their final titrated dose following the Week 4 
assessment until EOT.  The Week 10 Visit will be a telephone call only.
Subjects will continue on study drug until after a valid ABPM 24-hour collection has been confirmed and 
will apply the study drug on site before the serial PK sampling at the EOT Visit.  The serial PK blood 
samples will be drawn only after validity of the ABPM 24-hour collection has been confirmed.
A Follow-up Visit phone call will occur approximately 30 days after the last dose of study drug.  During 
phone calls and in-person visits throughout the study, subjects will be asked specific questions 
pertaining to the possible occurrence of SAEs, AESI, as well as the collection of additional information 
related to ongoing AE(s).
Any change in antihypertensive medication(s), antihypertensive medication(s) dose increase and/or 
initiation of antihypertensive medication(s) will be documented throughout the study.
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Section 3.11 of the Operations Manual (Appendix E) provides details on the clinical laboratory samples 
collection during the study.
The study schematic is shown in Figure 1.  Further details regarding study procedures are outlined in the 
Operations Manual.  See Section 5 for information regarding eligibility criteria.
An analysis to estimate the standard deviation (SD) of change from Baseline in SBP average 24-hour 
recording will be conducted in a blinded fashion when approximately 70% of the planned subjects in the 
per protocol population (i.e., 120 subjects) have completed the EOT Visit.  The objective of this analysis 
is to re-estimate sample size if needed.
AbbVie or its designee will make every effort to give sites advanced notice when recruitment for the 
study is nearing completion to minimize the risk for subjects in Screening who may not be allowed to 
enroll in the study.
Rescreening
Subjects who fail to meet the eligibility criteria may be rescreened one time at the investigator's 
discretion once their clinical status changes.
Men with a SV1 T level between 300 and 333 ng/dL or men who did not have a confirmed T level 
< 300 ng/dL at SV2 can be rescreened after 3 months (90 days) following the visit (SV1 or SV2) at which 
T was measured and did not meet eligibility criteria of < 300 ng/dL.  All of the Screening procedures 
must be repeated, and the subjects must be re-consented.  Rescreened subjects will use the originally 
assigned subject number.
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Figure 1.
Study Schematic
ABPM = ambulatory blood pressure monitoring; BP = blood pressure; EOT = End of Treatment; PK = pharmacokinetics; 
QD = once a day; SV1 = Screening Visit 1; SV2 = Screening Visit 2
4.2 Discussion of Study Design
Choice of Control Group
Not applicable.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All clinical and 
laboratory procedures in this study are standard and generally accepted.
American Heart Association (AHA) recommendations for measurement of BP will be followed 
throughout the study.  Investigators or their designees responsible for obtaining BP measurements will 
complete training in AHA recommendations prior to initiating the study,32 as well as training in cuff size 
measurements and ABPM measurements prior to study initiation.
Justification of study design 
An important difference between conventional and ambulatory BP measurement is the absence of a 
placebo effect with the latter that has been demonstrated in numerous studies.33-43  Fitzgerald et al also 
postulated that ambulatory BP measurements do not regress to the mean; hence subjects with high BPs 
do not exhibit a decrease in BP and those with low BPs do not show a tendency to raise their pressure 
with repeated measurements.44
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In February 2019, results from the FDA's ABPM research database review were presented at a public 
workshop titled, "Evaluating the Pressor Effects of Drugs & ABPM Studies."  The review was aimed to 
evaluate the consistency of the BP change from Baseline to post-baseline in placebo arms across 
multiple ABPM studies.  The data from 11 placebo-controlled ABPM studies (456 subjects) showed that 
the mean estimate for 24-hour change in SBP was around zero across the number of ABPM studies, with 
no significant difference in BP change between Baseline and post-baseline placebo visits.28
The reported lack of placebo effect in ABPM placebo-controlled trials implies that ABP measurements 
taken before and repeated after the Treatment Period in a single-arm open-label trial design may be 
adequate for evaluation of the effect of the study drug on BP without using placebo arm.
Standard deviation
The only ABPM data for subjects treated with topical T are available from a Phase 3 study that compared 
oral T with topical T.  The ABPM demonstrated the mean increase of 0.2 (± 9.4) mmHg in 24-hour 
average SBP from Baseline to Visit 6 for topical T and 4.9 (± 8.7) mmHg increase for oral T.  The SD for 
24-hour SBP for both oral and topical T in this trial was slightly below 10 mmHg.  Similar results were 
observed for MAP and PP.45  The data from this study supports the choice of the open-label single-arm
trial design over other designs for this protocol, and justifies the study assumption of SD of 10 mmHg for 
24-hour SBP.
Suitability of Subject Population
Eligible subjects are hypogonadal men 18 years of age or older at the time of enrollment who have low
serum T, signs or symptoms that are associated with hypogonadism, and who may benefit from 
therapeutic intervention by raising and maintaining their T concentrations within the normal range.
Confirmation of T values below normal limits will be conducted during Screening.  Subjects either will be 
naïve to T therapy or have not been treated with T in the past 6 months.  Men for whom T therapy is 
contraindicated such as those with history of prostate or breast cancer, unprovoked pulmonary 
embolism (PE), unprovoked deep vein thrombosis (DVT), polycythemia, and those seeking fertility will 
be excluded.  See Section 5 for information regarding eligibility criteria.
Justification of the study population age group and comorbid conditions
In 2014 in preparation for the TRT Advisory Committee meeting, the TRT Sponsors assessed the age 
distribution and comorbid conditions of patients receiving T therapy by evaluating available literature 
and conducting data analysis.
The data showed that men 45 to 64 years of age received the highest number of prescriptions 
(approximately 60%), a trend that has not changed in the past few years.  Men younger than 45 years 
represented approximately 19% of prescriptions, while men older than 65 years represented 
approximately 21% of prescriptions.
The characteristics of the patient population receiving T therapy, comorbidities in particular, were 
evaluated in a study of 10,159 patients treated with TRT using the data from the Kaiser Permanente 
system.  Most frequent diagnoses were as follows:  43.7% of the patient population had hypertension, 
43.1% had hyperlipidemia, 33.5% had erectile dysfunction, 26.7% had testicular dysfunction, and 20.3% 
had diabetes.46
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In the Testim® Registry, which included men with hypogonadism at BL, 36.7% of men were determined 
to have metabolic syndrome, 19.8% had hypertension, 19.9% had dyslipidemia, 17.9% had coronary 
artery disease, and 12.5% had diabetes.46,47
Based on these data, the expected ABPM subject population for the present study will consist of men, 
with the majority in the age group of 45 to 64 years.  Up to 45% of the subject population will have 
hypertension and up to 20% will have diabetes.
Blood Pressure Variability
It has long been known that BP is characterized by an array of spontaneous variations.  Blood pressure 
values vary markedly within the 24 hours in response to physical activity, sleep, and emotional stimuli of 
various nature and duration.48-51
Blood pressure variability is different in normotensive patients with normal 24-hour BP from that in 
patients with hypertension.  Mancia et al demonstrated that the absolute short- and long-term BP 
variabilities were lowest in normotensive subjects and greatest in severe hypertensive subjects for 
systolic, diastolic, and MAPs.52
To balance BP variability in normotensive and hypertensive subjects and to assure adequate 
representation of the subject population with cardiovascular risk profile of men using marketed TRT, an 
Interactive Response Technology (IRT) system will categorize the subjects by ongoing medical history of 
hypertension (Yes/No) at Baseline.  Enrollment caps will be employed to ensure that 35% to 50% of 
subjects with an ongoing medical history of hypertension are enrolled.
Selection of Doses in the Study
All doses utilized in the study are per the product label of AndroGel 1.62%.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an institutional 
review board (IRB), prior to the initiation of any screening or study-specific procedures.
2. Able to understand and adhere to protocol requirements, restrictions and instructions (per 
investigator's judgment).
Demographic and Laboratory Assessments
3. Hypogonadal men ≥ 18 years of age at the time of enrollment.  Hypogonadism is defined as:
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
Presence of at least one of the following symptoms that may be related to low T values and 
is/are consistent with hypogonadism (confirmed prior to obtaining T levels):

Decreased sexual desire or libido

Decreased spontaneous erections (e.g., morning erections)

Decreased energy or fatigue/feeling tired

Low mood or depressed mood

Loss of body (axillary and pubic) hair or reduced shaving

Hot flashes 
AND

Confirmed by 2 serum T levels < 300 ng/dL by blood samples drawn at least 48 hours apart.  
These samples should be obtained between 5 am and 11 am local time.  
4. Laboratory values meeting the following criteria within the Screening Period prior to the 
first dose of study drug:  

Hematocrit (Hct) < 50%

Alanine aminotransferase and aspartate aminotransferase < 3 × upper limit of normal

PSA ≤3.0 ng/mL or PSA ≤ 1.5 ng/mL in men treated with 5-alpha reductase inhibitors (e.g., 
dutasteride, finasteride)
5. Office BP measurements > 100/60 mmHg and < 140/90 mmHg at both Screening Visits (SV1 
and SV2).
6. If on any antihypertensive therapy, such therapy must be stable for at least 4 weeks before 
SV1.
7. No history of: 

Upper arms and shoulders with current or recurrent ulcer, erosion, lichenification, 
inflammation psoriasis, eczema or use of topical corticosteroids on the upper arms and 
shoulders

Tattoo application or removal in the region of study drug application within 6 months of 
Screening

Any T replacement, clomiphene, compounded or over-the-counter (OTC) androgenic steroid 
derivatives, and dehydroepiandrosterone, including investigational products that may affect 
the reproductive hormonal system, within the past 26 weeks prior to and during Screening 
through EOT

Untreated, severe obstructive sleep apnea

Unprovoked DVT, unprovoked PE, or known thrombophilia

Polycythemia vera or secondary polycythemia, such as polycythemia due to untreated sleep 
apnea or severe chronic obstructive pulmonary disease

Prostate or breast cancer
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
Any active malignancy

Any in-subject hospitalizations (duration of hospitalization > 24 hours) or major febrile 
illness (temperature > 101°F) within 4 weeks prior to, during screening, and at the time of 
enrollment
8. No history of clinically significant (per investigator's judgment) drug or alcohol abuse 
(including illicit steroid use) within the last 12 months prior to Screening.
9. No history of clinically significant medical conditions or any other reason that the investigator 
determines would interfere with the subject's participation in this study or would make the 
subject an unsuitable candidate to receive study drug.
10. No history of known skin intolerance to alcohol or allergy to any of the ingredients of the 
study drug (see AndroGel 1.62% prescribing information).
11. No Severe (New York Heart Association Functional class III or IV) heart failure, or known 
ejection fraction ≤ 35% are present, atrial fibrillation or other serious arrhythmia that may affect 
ABP measurements.
12. Subject does not work night shifts or is not otherwise required to perform strenuous manual 
labor while wearing the ABPM monitor.
13. Subject's upper arm circumference is < 50 cm.
Contraception
14. Subject is not considering fathering a child or donating sperm during the study or for 
approximately 30 days after the last dose of study drug.
Concomitant Medications
15. Subject must not have been treated with any investigational drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to the first dose of study drug or is currently 
enrolled in another clinical study.
5.2 Contraception Recommendations
Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Baseline through at 
least 30 days after the last dose of study drug.
5.3 Prohibited Medications and Therapy
Subjects must not take oral nitrates concomitantly with drug products used to treat erectile dysfunction 
(e.g., tadalafil, sildenafil citrate, vardenafil hydrochloride).
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Subjects must not take any other form of T other than the study drug during the study as well as the 
following prohibited medications:

Compounded or OTC androgenic steroid preparations, supplements or;

Testosterone derivatives;

Topical corticosteroids on the upper arms and shoulders (e.g., hydrocortisone);

Clomiphene;

TRT from a source outside the study
5.4 Prior and Concomitant Therapy
Any prescription medications (antihypertensive medications in particular) and OTC aspirin, iron, folate, 
B12, vitamin D and calcium that the subject is receiving within 2 weeks prior to enrollment or receives 
during the study, must be recorded.  Such medications will be recorded along with the reason for use, 
date(s) of administration including start and end dates, and dosage information including dose, route 
and frequency.  Other non-prescription medications should be recorded as a result of an AESI, AE 
leading to study drug discontinuation, or SAEs.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with AndroGel 1.62% can be located in the 
AndroGel 1.62% product label.
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks prior to 
initial study drug administration.  Subjects must be consented for the study prior to discontinuing any 
prohibited medications for the purpose of meeting study eligibility.
5.5 Withdrawal of Subjects and Discontinuation of Study
Every effort will be made to ensure that subjects continue to return to the clinic for study visits and 
avoid lost to follow-up (LTFU) during the conduct of the study.  After the first missed visit, subjects that 
are potentially LTFU should receive a minimum of 3 phone calls, faxes, and or emails as well as 
one registered/certified mail letter.  All attempts should be documented in the subject's source 
documentation.
A subject may voluntarily withdraw or be withdrawn from the study drug at any time for reasons 
including, but not limited to, the following:

Confirmed serum T levels > 750 ng/dL even after down-titration to the lowest dose during the 
study;

Confirmed repeat PSA > 4.0 ng/mL for men not taking 5 alpha-reductase inhibitors and PSA 
> 2.0 ng/mL for men taking 5-ARI during the study;

Confirmed repeat Hct value > 54% during the study;
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
Confirmed prostate or breast cancer diagnosis during the study;

Any AE that in the investigator's opinion may affect the subject's safety.
Subjects who discontinue study drug with < 16 weeks of treatment may be replaced (see Section 7.7) 
and should follow the premature discontinuation procedures (Appendix D).
Discontinuation of Entire Study
AbbVie may terminate this study prematurely in its entirety or at any study site, for reasonable cause 
provided that written notice is submitted in advance of the intended termination.  The investigator may 
also terminate the study at his/her site for reasonable cause, after providing written notice to AbbVie in 
advance of the intended termination.  Advance notice is not required if the study is stopped due to 
safety concerns.  If AbbVie terminates the study for safety reasons, AbbVie, or its designee, will 
immediately notify the investigator by telephone and subsequently provide written instructions for 
study termination.
When the study ends or is terminated, all enrolled subjects continuing in the study will return for the FV 
procedures as specified in Appendix D, Study Activities.  For subjects remaining on study drug at such a 
time, the post therapy SAE collection period will continue for 30 days following the termination of study 
drug therapy.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study 
If a subject prematurely discontinues from study drug with < 16 weeks of treatment, he should not 
undergo the EOT procedures of ABPM and serial PK sampling, as he is not eligible for the per protocol 
analysis set.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation Visit should be completed as soon as possible, 
preferably within 7 days of last dose of study drug.  In addition, if a subject is willing, a 30-day follow-up 
phone call after the last dose of study drug may be completed to ensure all treatment-emergent 
AEs/SAEs have been resolved.
5.7 Study Drug
AndroGel 1.62% will be applied topically once daily in the morning beginning at the Day 1 Visit after 
confirmed valid ABPM assessment and should be applied at approximately the same time each day after 
that during the study.  The starting dose of AndroGel 1.62% is 40.5 mg of T (2 pump actuations, applied 
to the upper arms and shoulders).  It should not be administered to other parts of the body, including 
abdomen, genitals, chest, armpits (axillae), or knees.
AndroGel 1.62% can be dose adjusted between a minimum of 20.25 mg of T (1 pump actuation) and a 
maximum of 81.0 mg of T (4 pump actuations).  For the first study drug administration at the Day 1 Visit, 
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and also at Week 2, Week 4, Week 16 ABPM, and End of Treatment Visits the subjects should apply the 
study drug while on site so that the site staff can observe the proper administration of study drug.
If subjects forget to apply their AndroGel 1.62% dose at their regularly scheduled dosing time, they 
should take the next dose at the next dosing time.
Subjects will be instructed to return all used and unused pump bottles to the study site staff at each 
study visit (see Operations Manual, Appendix E).
AbbVie will supply the AndroGel 1.62% as study drug.  AbbVie provided study drug should not be 
substituted or alternately sourced unless otherwise directed by AbbVie.
AndroGel 1.62% will be packaged in pump bottles with quantities sufficient to accommodate study 
design.  Before using a new pump of study drug, the pump will need to be primed by pushing the 
actuator all the way down 3 times.  The pump only needs to be primed when using a new pump for the 
first time.
Each pump bottle will be labeled per US requirements and the label must remain affixed to the pump 
bottle.  Each pump bottle will contain a unique pump bottle kit number.  This pump bottle kit number is 
assigned to a subject via IRT and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  Study staff will fill in all pump bottle labels before dispensing to subjects.  
Study drug will only be used for the conduct of this study.
Controlled Substance Requirements
The investigator must agree to comply with all applicable Drug Enforcement Agency (DEA) laws and 
regulations regarding controlled substances as outlined in 21 CFR 1300.  Additionally, the investigator 
must agree to limit access to the study drug only to the named Sub-investigators or to other 
appropriately designated study staff or monitoring personnel.  Study drug will only be dispensed to 
subjects enrolled in the study by the investigator designee.
Study drug will only be shipped once the DEA license has been received from each site.  The study drug 
must be shipped to the address listed on the Form DEA-223.  Study drug must be securely stored at the 
same location according to DEA guidelines for CIII controlled substances.  Upon receipt of a shipment, 
the investigator or designated study staff at the site will: 
1.
Open and inspect the shipment; 
2.
Verify the study drug supplies have been received intact, in the correct amounts and at the 
correct address;
3.
Acknowledge receipt of study drug consignment via the IRT system.
5.8 Randomization/Drug Assignment
This is a single-arm open-label study; therefore, there will not be a randomization to treatment 
assignment.  All subjects will be assigned a unique identification number by the IRT at SV1.  For subjects 
who rescreen, the screening number assigned by the IRT at the SV1 should be used.
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Subjects will be categorized in IRT by ongoing medical history of hypertension (Yes/No) at Baseline to 
ensure that 35% to 50% of subjects with an ongoing medical history of hypertension are enrolled.  
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects. The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified), the investigator is responsible for notifying IRB, regulatory 
authorities (as applicable), and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of AndroGel 1.62% 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events:  Study Drug
An adverse event (AE) is defined as any untoward medical occurrence in a subject 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 unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not the event is considered causally related to the use of 
the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
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accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs.
The investigator will monitor each subject on a routine basis throughout the study for clinical and 
laboratory evidence of SAEs, AESI, AEs leading to study drug discontinuation, and study procedure-
related AEs.  Any SAEs, AESI, AEs leading to study drug discontinuation, and study procedure-related 
AEs, whether in response to a query, observed by site personnel, or reported spontaneously by the 
subject will be recorded.  All SAEs, AESI, AEs leading to study drug discontinuation, and study procedure-
related AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance as a SAE within 24 hours of the site being made aware of 
the SAE (refer to Section 4.2 of the Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken.  This does 
not include an event that would have been fatal if it had occurred in a 
more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length of 
time or prolongs the subject's hospital stay.  This does not include an 
emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in fetal 
loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with the 
activities of daily living of a study subject.  Disability is not intended to 
include experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious 
An important medical event that may not be immediately life-threatening 
or result in death or hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of subject, life 
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Outcome
threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  Additionally, 
any elective or spontaneous abortion or stillbirth is considered an 
important medical event.  
All SAEs, AESI, AEs leading to study drug discontinuation will be recorded from the time of study drug 
administration until the end of the study/study completion.  Study procedure-related non-serious AEs 
and SAEs will be collected from the time the subject signs the study-specific informed consent until 
30 days after the last dose of study drug.  All SAEs, AESI, AEs leading to study drug discontinuation, and 
study procedure–related AEs or SAEs will be followed until resolution or achievement of a new stable 
state, until the subject withdraws consent for study participation, or until the final study-related 
communication (e.g., phone call at the end of the study or final study communication in subjects truly 
considered LTFU, whichever occurs first).
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the AndroGel 1.62% product in accordance with global and local requirements.
The only AEs to be collected in the study are those that meet the definition of an AESI, resulted in study 
discontinuation, study procedure-related AEs, or meet the regulatory criteria for an SAE.  For SAEs with 
the outcome of death, the date and cause of death will be recorded on the appropriate case report form 
(CRF) page.
Adverse Events of Special Interest
The following AESI will be collected during the study: 

Hypertension
Adverse Event Severity and Relationship to Study Drug
The investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's usual 
activities.
Severe
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life threatening.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
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is sufficient evidence (information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is insufficient evidence (information) to suggest a causal relationship.
Pregnancy
Pregnancy of the subject's female partner will be reported to AbbVie within 24 hours of the site 
becoming aware of the pregnancy.  Information regarding pregnancies in the partners of study subjects 
will be collected from the date of first dose through 30 days following the last dose of study drug.  
Information regarding a pregnancy occurrence in a study subject's partner and the outcome of the 
pregnancy will be collected.  In the event of pregnancy occurring in a subject's partner during the study, 
written informed consent from the partner must be obtained prior to collection of any such information.  
AbbVie will provide a separate informed consent for this purpose.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods in the protocol focus on the primary endpoint analysis.  Complete and specific 
details of the statistical analysis will be described and fully documented in the Statistical Analysis Plan 
(SAP).  
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all subjects who received at least 1 dose of study drug.  The FAS will 
be used for baseline analyses and certain sensitivity analyses.
The per protocol population includes all subjects who received at least 1 dose of study drug, are at least 
85% compliant to study drug, and have valid Baseline and EOT systolic ABP data.  The per protocol 
population will be used for all analyses on endpoints based on 24-hour recording from ABPM device, 
including the primary endpoint, except for certain sensitivity analyses of the primary endpoint.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  The Safety 
Analysis Set will be used for all other safety analyses not related to 24-hour collection from ABPM 
device.
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7.3 Statistical Analyses for Efficacy
Efficacy will not be evaluated in this study.
7.4 Statistical Analyses for Safety
Primary Safety Endpoint
For the primary analysis, the primary endpoint of change from Baseline to EOT in average 24-hour SBP 
will be evaluated using a linear regression model with average 24-hour SBP at EOT as the outcome, and 
baseline average 24-hour SBP and pooled study center as covariates in the per-protocol population.  If 
the upper confidence limit of the 1-sided 97.5% confidence interval (CI) of the estimate of the change 
from Baseline to EOT in average 24-hour SBP from the linear regression model is less than 3 mmHg, this 
will establish that the SBP at EOT is not greater than Baseline with a noninferiority margin of 3 mmHg.
Sensitivity analyses examining missingness of some SBP results during the 24-hour ABPM collections and 
impact of this missingness on the primary endpoint will be documented in the SAP.
Other Safety Endpoints
The continuous endpoints (e.g., change from Baseline to EOT in average daytime MAP, SBP, DBP, PP, 
and HR) will be summarized by mean, SD, minimum, and maximum.  The categorical endpoints 
(e.g., subjects with new concomitant antihypertensive medications) will be summarized with n and 
percentage.
The following additional analysis will be performed:

Graphical display of hourly ABPM averages that include SD bars for both SBP and DBP at the 
Baseline and EOT Visits.

Cumulative distribution curves of 24-hour average SBP and DBP at the Baseline and EOT Visits.

Forest plots of daytime, nighttime, and 24-hour average change from Baseline to EOT with 95% 
CI displays for SBP and DBP.
Subgroup Analysis of Safety Endpoints
All the analysis for the primary and other safety endpoints (except the sensitivity analyses of the primary 
endpoint) will be provided by the following subgroups based on history of hypertension:

Subjects without an ongoing medical history of hypertension and without any antihypertensive 
medication(s) at Baseline;

Subjects with an ongoing medical history of hypertension with any antihypertensive
medication(s) at Baseline;

Subjects with an ongoing medical history of hypertension without any antihypertensive 
medication(s) at Baseline.
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Adverse Events
Treatment emergent AESI, AEs leading to study drug discontinuation and SAEs will be summarized in 
descending order of overall frequency by Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term (PT), as well as in a lexicographic order by system organ class (SOC) and MedDRA PT.
Treatment emergent AESI and SAEs will also be summarized according to their relationship to study drug 
and their maximum severity.  In addition, treatment emergent AEs/SAEs that lead to study drug 
discontinuation will also be summarized.
Clinical Laboratory Data
Continuous summaries of mean changes from Baseline to each applicable visit for items such as PSA, 
lipids, Hct and hemoglobin will be summarized.
Vital Signs
Continuous summaries of the mean change from Baseline to each applicable visit in vital signs will be 
provided.  Vital sign variables include, but are not limited to, SBP and DBP by office BP measurement, 
HR, respiratory rate (RR), and oral body temperature.
7.5 Interim Analysis
An analysis to estimate the SD of the change from Baseline to EOT in average SBP from 24-hour 
recordings will be conducted in a blinded fashion when approximately 70% of the planned subjects in 
the per protocol population (i.e., 120 subjects) have completed the EOT Visit.  The objective of analysis 
is to re-estimate sample size if needed.  A study database snapshot will be performed for this analysis.  
The sample size will be re-estimated with updated assumption of SD if necessary.  The blinded sample 
size re-estimation (BSSR) analysis will be performed by an AbbVie statistician external to the study team 
who has access to unmasked ABPM data.
An interim database lock will be performed to unmask the Week 16 ABPM data after the last subject 
completes a valid EOT ABPM 24-hour collection or prematurely discontinues from the study.
7.6 Overall Type I Error Control
This study has one primary endpoint for which non-inferiority is tested, so no adjustment for multiple 
endpoints is needed.  Analytically and through simulations, it has been shown that BSSR procedures 
(Section 7.7) do not meaningfully affect Type I error rate.53  Therefore, no multiplicity adjustment is 
planned for the BSSR analysis.
7.7 Sample Size Determination
A sample size of 171 subjects will provide 90% power for a paired t-test with 0.025 one-sided
significance level to show that the EOT average 24-hour SBP is not greater than the Baseline average 
24-hour SBP with a non-inferiority margin of 3 mmHg, assuming the mean difference between EOT and 
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Baseline is an increase of 0.5 mmHg and the SD of the difference is 10 mmHg.  The paired t-test is a good 
approximation of the power for the primary analysis using linear regression with covariate adjustment.  
Assuming a 10% loss of subjects from the per protocol population due to premature discontinuation, 
invalid ABPM at the Baseline or EOT Visit, or non-adherence to study drug, approximately 190 subjects 
will be enrolled to reach a minimum of 171 subjects who are at least 85% compliant to study drug and 
have valid ABPM data from Baseline and the EOT Visits.
If the dropout, non-evaluable ABPM, or non-adherence rates are higher than expected, enrollment will 
continue until the required number of evaluable subjects in the per protocol population is reached.  If 
the SD is higher than the expected SD, an evaluation will be made to adjust the number of evaluable 
subjects if necessary.
Blinded Sample Size Re-Estimation
With a sample size of 171 subjects in the per protocol population, the study is powered at 90% if the SD 
of change from Baseline to EOT in systolic ABP is 10 mmHg.  In order to ensure the assumed SD is 
correct for the study, a review and estimate of the SD will be conducted when approximately 70% of the 
planned subjects in the per protocol population (i.e., 120 subjects) have completed the EOT Visit.  It will 
be performed by an AbbVie statistician external to the study team who has access to the unmasked 
ABPM data.  If the estimated SD is larger than 10 mmHg, the sample size may be increased according to 
prespecified procedure based on the estimated SD from the masked data.  Since the study team is 
masked to the postbaseline ABPM data until the end of the Treatment Period of the last subject and 
only SD is used in the sample size re-estimation, no multiplicity adjustment is needed for the BSSR.
A cap on the re-estimated sample size will be incorporated to ensure a feasible sample size.  The final 
recalculated sample size in the per protocol population will be greater than or equal to the initial sample 
size of 171 subjects and less than or equal to the limit of cap sample size.
The detailed BSSR plan will be documented in the SAP.
8 ETHICS 
8.1 Institutional Review Board (IRB)
The protocol, informed consent, recruitment materials, and all subject materials will be submitted to the 
IRB for review and approval.  Approval of both the protocol and the informed consent form(s) must be 
obtained before any subject is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all changes to the 
informed consent will be IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations, and guidelines governing clinical study conduct and the ethical principles that 
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have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit/last procedure/last phone call.
12
REFERENCES
1.
Mulhall JP, Trost LW, Brannigan RE, et al.  Evaluation and Management of Testosterone 
Deficiency:  AUA Guideline.  J Urol.  2018;200(2):423-32.
2.
Bhasin S, Cunningham GR, Hayes FJ, et al.  Testosterone therapy in men with androgen 
deficiency syndromes:  an Endocrine Society clinical practice guideline.  J Clin Endocrinol Metab.  
2010;95(6):2536-59.
3.
Corona G, Isidori AM, Buvat J, et al.  Testosterone supplementation and sexual function:  a 
meta-analysis study.  J Sex Med.  2014;11(6):1577-92.
4.
Amanatkar HR, Chibnall JT, Seo BW, et al.  Impact of exogenous testosterone on mood:  a 
systematic review and meta-analysis of randomized placebo-controlled trials.  Ann Clin 
Psychiatry.  2014;26(1):19-32.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.
Isidori AM, Buvat J, Corona G, et al.  A critical analysis of the role of testosterone in erectile 
function:  from pathophysiology to treatment-a systematic review.  Eur Urol.  
2014;65(1):99-112.
6.
Tracz MJ, Sideras K, Boloña ER, et al.  Testosterone use in men and its effects on bone health.  A 
systematic review and meta-analysis of randomized placebo-controlled trials.  J Clin Endocrinol 
Metab.  2006;91(6):2011-6.
7.
Isidori AM, Giannetta E, Gianfrilli D, et al.  Effects of testosterone on sexual function in men:  
results of a meta-analysis.  Clin Endocrinol (Oxf).  2005;63(4):381-94.
8.
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(5):1715-44.
9.
Lopes RA, Neves KB, Carneiro FS, et al.  Testosterone and vascular function in aging.  Front 
Physiol.  2012;3:89.
10. Traish AM, Saad F, Feeley RJ, et al.  The dark side of testosterone deficiency:  III.  Cardiovascular 
disease.  J Androl.  2009;30(5):477-94.
11. Chavoshan B, Fournier M, Lewis MI, et al.  Testosterone and resistance training effects on 
muscle nitric oxide synthase isoforms in COPD men.  Respir Med.  2012;106(2):269-75.
12. Kumanov P, Tomova A, Kirilov G.  Testosterone replacement therapy in male hypogonadism is 
not associated with increase of endothelin-1 levels.  Int J Androl.  2007;30(1):41-7.
13. Kang SM, Jang Y, Kim Ji, et al.  Effect of oral administration of testosterone on brachial arterial 
vasoreactivity in men with coronary artery disease.  Am J Cardiol.  2002;89(7):862-4.
14. Webb CM, Mcneill JG, Hayward CS, et al.  Effects of testosterone on coronary vasomotor 
regulation in men with coronary heart disease.  Circulation.  1999;100(16):1690-6.
15. Wakasugi M, Noguchi T, Kazama YI, et al.  The effects of sex hormones on the synthesis of 
prostacyclin (PGI2) by vascular tissues.  Prostaglandins.  1989;37(4):401-10.
16. Ajayi AA, Mathur R, Halushka PV.  Testosterone increases human platelet thromboxane A2 
receptor density and aggregation responses.  Circulation.  1995;91(11):2742-7.
17. Del campo M, Sagredo A, Del campo L, et al.  Time-dependent effect of orchidectomy on 
vascular nitric oxide and thromboxane A2 release.  Functional implications to control cell 
proliferation through activation of the epidermal growth factor receptor.  PLoS ONE.  
2014;9(7):e102523.
18. Hu J, Tan S, Zhong Y.  Effects of testosterone on renal function in salt-loaded rats.  Am J Med Sci.  
2011;342(1):38-43.
19. Johannsson G, Gibney J, Wolthers T, et al.  Independent and combined effects of testosterone 
and growth hormone on extracellular water in hypopituitary men.  J Clin Endocrinol Metab.  
2005;90(7):3989-94.
20. Food and Drug Administration.  FDA Briefing Document NDA 206089:  Testosterone 
Undecanoate (proposed trade name Jatenzo) for replacement therapy in adult males for 
conditions associated with a deficiency or absence of endogenous testosterone.  Bone, 
Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) Meeting; 09 January 2018 
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STUDY M19-161  |  Version 3.0  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
[cited 2019 Aug 07].  Available from:  
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Re
productiveHealthDrugsAdvisoryCommittee/UCM591416.pdf.
21. Whelton PK, Carey RM, Aronow WS, et al.  2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ 
ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of 
High Blood Pressure in Adults:  A Report of the American College of Cardiology/American Heart 
Association Task Force on Clinical Practice Guidelines.  Hypertension.  2018;71(6):e13-115.
22. Whelton PK, Carey RM, Aronow WS, et al.  2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ 
ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of 
High Blood Pressure in Adults:  Executive Summary:  A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.  J Am Coll 
Cardiol.  2018;71(19):2199-269.
23. Williams B, Mancia G, Spiering W, et al.  2018 ESC/ESH Guidelines for the management of 
arterial hypertension.  Eur Heart J.  2018;39(33):3021-104.
24. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure.  National High Blood Pressure Education Program.  Bethesda 
(MD):  National Heart, Lung, and Blood Institute (US); 2004 Aug.
25. Chobanian AV, Bakris GL, Black HR, et al.  The Seventh Report of the Joint National Committee 
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure:  the JNC 7 report.  
JAMA.  2003;289(19):2560-72.
26. Chobanian AV, Bakris GL, Black HR, et al.  Seventh report of the Joint National Committee on 
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.  Hypertension.  
2003;42(6):1206-52.
27. Hodgkinson J, Mant J, Martin U, et al.  Relative effectiveness of clinic and home blood pressure 
monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension:  
systematic review.  BMJ.  2011;342:d3621.
28. Evaluating the Pressor Effects of Drugs & Ambulatory Blood Pressure Monitoring Studies.  Public 
workshop convened by Center for Health Policy at Duke University.  Washington, DC.  
04 Feb2019 [cited 2019 Aug 15].  Available from:  
https://healthpolicy.duke.edu/events/evaluating-pressor-effects-drugs-ambulatory-blood-
pressure-monitoring-studies.
29. AndroGel 1.62% [package insert].  North Chicago, IL; AbbVie Inc, 2019.
30. Krakoff, LR.  Cost-effectiveness of ambulatory blood pressure:  a reanalysis.  Hypertension.  
2006;47(1):29-34.
31. Tapolyai M, Udvari-nagy S, Schede-don K.  The rate of complications of 24-hour ambulatory 
blood pressure monitoring (ABPM) is low.  Am J Hypertens.  2001;14 (5 Pt 1):487-8.
32. Muntner P, Shimbo D, Carey RM, et al.  Measurement of Blood Pressure in Humans:  A Scientific 
Statement From the American Heart Association.  Hypertension.  2019;73(5):e35-66.
33. Gould BA, Mann S, Davies AB, et al.  Does placebo lower blood-pressure?  Lancet.  
1981;2(8260-61):1377-81.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
34. Drayer JI, Weber MA, Deyoung JL, et al.  Long-term BP monitoring in the evaluation of 
antihypertensive therapy.  Arch Intern Med.  1983;143(5):898-901.
35. Dupont AG, Van der Niepen P, Six RO.  Placebo does not lower ambulatory blood pressure.  Br J 
Clin Pharmacol.  1987;24(1):106-9.
36. Conway J, Johnston J, Coats A, et al.  The use of ambulatory blood pressure monitoring to 
improve the accuracy and reduce the numbers of subjects in clinical trials of antihypertensive 
agents.  J Hypertens.  1988;6(2):111-6.
37. Coca A.  The placebo effect in ambulatory blood pressure monitoring.  Blood Press Monit.  
1998;3(3):195-9.
38. Mancia G, De Cesaris R, Fogari R, et al.  Evaluation of the antihypertensive effect of once-a-day 
trandolapril by 24-hour ambulatory blood pressure monitoring.  The Italian Trandolapril Study 
Group.  Am J Cardiol.  1992;70(12):60D-6D.
39. Omboni S, Ravogli A, Villani A, et al.  Permanent blood pressure control over the 24 h by 
trandolapril.  Am J Hypertens.  1995;8 (10 Pt 2):71S-4S.
40. Zanchetti A, Bianchi L, Amigoni S, et al.  Antihypertensive effects of nifedipine gastrointestinal 
therapeutic system on clinic and ambulatory blood pressure in essential hypertensives.  Italian 
GITS Study Group.  J Hypertens Suppl.  1993;11(5):S334-5.
41. Weber MA, Byyny RL, Pratt JH, et al.  Blood pressure effects of the angiotensin II receptor 
blocker, losartan.  Arch Intern Med.  1995;155(4):405-11.
42. Guthrie R, Reggi DR, Plesher MM, et al.  Efficacy and safety of fosinopril/hydrochlorothiazide 
combinations on ambulatory blood pressure profiles in hypertension. 
Fosinopril/Hydrochlorothiazide Investigators.  Am J Hypertens.  1996;9 (4 Pt 1):306-11.
43. Veteran Study Group.  Effects of verapamil SR, trandolapril, and their fixed combination on 24-h 
blood pressure:  the Veratran Study.  Am J Hypertens.  1997;10 (5 Pt 1):492-9.
44. Fitzgerald DJ, O'Malley K, O'Brien ET.  Reproducibility of ambulatory blood pressure recordings.  
In:  Weber MA, Drayer JIM, editors.  Ambulatory Blood Pressure Monitoring.  Heidelberg: 
Steinkopff; 1984.
45. Food and Drug Administration.  FDA Briefing Document NDA 206089:  Testosterone 
Undecanoate (proposed trade name Jatenzo) for replacement therapy in adult males for 
conditions associated with a deficiency or absence of endogenous testosterone.  Bone, 
Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) Meeting; 09 January 2018.  
[cited 2019 Aug 17].  Available from:  
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Re
productiveHealthDrugsAdvisoryCommittee/UCM591416.pdf.
46. US Food and Drug Administration.  Joint meeting for Bone, Reproductive and Urologic Drugs 
Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee 
(DSARM AC).  September 17, 2014.
47. Miner MM, Khera M, Bhattacharya RK, et al.  Baseline data from the TRiUS registry:  symptoms 
and comorbidities of testosterone deficiency.  Postgrad Med.  2011;123(3):17-27.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
48. Mancia G, Parati G, Di Rienzo M, et al.  Blood pressure variability.  In:  Zanchetti A, Mancia G, 
editors.  Handbook of Hypertension.  Pathophysiology of Hypertension. Amsterdam:  Elsevier 
Science BV.  1997;(17):117-69.
49. Sega R, Cesana G, Bombelli M, et al.  Seasonal variations in home and ambulatory blood 
pressure in the PAMELA population.  Pressione Arteriose Monitorate E Loro Associazioni.  
J Hypertens.  1998;16(11):1585-92.
50. Wolf-Maier K, Cooper RS, Banegas JR, et al.  Hypertension prevalence and blood pressure levels 
in 6 European countries, Canada, and the United States.  JAMA.  2003;289(18):2363-9. 
51. Rothwell PM, Howard SC, Dolan E, et al.  Prognostic significance of visit-to-visit variability, 
maximum systolic blood pressure, and episodic hypertension.  Lancet.  2010;375(9718):895-905.
52. Mancia G, Ferrari A, Gregorini L, et al.  Blood pressure and heart rate variabilities in 
normotensive and hypertensive human beings. Circ Res.  1983;53(1):96-104.
53. Kieser M, Friede T.  Simple procedures for blinded sample size adjustment that do not affect the 
type I error rate.  Stat Med.  2003;22(23):3571-81.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ABP
ambulatory blood pressure
ABPM
ambulatory blood pressure monitoring
AE
adverse event
AESI
adverse events of special interest
AHA
American Heart Association
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
BSSR
blinded sample size re-estimation
CFR
Code of Federal Regulations
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
case report form
DBP
diastolic blood pressure
DEA
Drug Enforcement Agency
DHT
dihydrotestosterone
DRE
digital rectal exam
DVT
deep vein thrombosis
E2
estradiol
IEC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOS
End of Study
EOT
End of Treatment
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Hct
hematocrit
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HR
heart rate
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
LTFU
lost to follow-up
MAP
mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities
OTC
over-the-counter
PE
pulmonary embolism
PK
pharmacokinetics
PP
pulse pressure
PSA
prostate-specific antigen
PT
preferred term
QTcF
Fridericia-corrected QT interval
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV1
Screening Visit 1
SV2
Screening Visit 2
T
testosterone
TA
Therapeutic Area
TA MD
Therapeutic Area Medical Director
Tmax
time to maximum observed concentration
TRT
testosterone replacement therapy
TXA
thromboxane
US
United States
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-161:  24-Hour Ambulatory Blood Pressure Monitoring Study in Hypogonadal Men 
Receiving Testosterone Replacement Therapy
Protocol Date:  26 August 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) GCP and local regulations and guidelines governing the study at the site location.  In signing the 
Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate IRB/Independent Ethics Committee (IEC), except when necessary to 
protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Program Development Program 
Lead
Clinical Program Development
Executive Medical Director
General Medicine Clinical Development
Medical Director, TA MD
General Medicine Clinical Development
Senior Manager
Statistics
TA Statistician
Statistics
Study Project Manager
Clinical Program Development
Associate Director
Regulatory Affairs
Director
Clinical Pharmacology and Pharmacometrics
Medical Writer
Medical Writing
TA = Therapeutic Area; TA MD = Therapeutic Area Medical Director
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
20 November 2019
Version 2.0
19 February 2020
The purpose of this version (Version 3.0) is to change the lower limit of the DBP range from 70 mmHg to 
60 mmHg in criterion number 5 (Section 5.1). Rationale: This was to optimize the DBP range.
The purpose of Version 2.0 was to correct minor clerical errors for consistency throughout the protocol 
and to clarify information in addition to the following:
Eligibility criterion number 4 (Section 5.1) was corrected to indicate that PSA values must be ≤ 3.0 ng/dL 
in men treated with 5-alpha reductase inhibitors.  Rationale:  This was to correct < 3.0 ng/dL.
A more detailed description of what constitutes an AE was added to Section 6.1.  Rationale:  
Clarification of AE definition, including worsening of pre-existing conditions.
The statistical analysis of the primary endpoint was described in greater detail, and sensitivity analyses 
were added to Section 7.4.  Rationale:  Clarification.
In the Operations Manual Section 6.2, it was specified that the study monitor is to return unused study 
drug to the depot for destruction.  Rationale:  This was to clarify that sites are not to destroy study drug 
on site.
In the Operations Manual Section 6.4 clarifies the titration notifications.  Reference to the IRT was 
removed, as the IRT is not used for dosing titration notification.  Rationale:  Clarification.
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APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical 
Contact
, MD, MS
AbbVie Inc.
1 North Waukegan Road 
North Chicago, IL 60064
EMERGENCY 24-hour Number:  
+1 (973) 784-6402
Office:
Mobile:
Fax:
Email:
Safety 
Concerns
Men's and Women's Health Safety Team
1 North Waukegan Road 
North Chicago, IL 60064
Phone:
+1 (847) 935-7577
Email:
GPRD_SafetyManagment_Hormones@abbvie.com
SAE 
Reporting 
outside of 
RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 938-0660
Protocol 
Deviations 
and Product 
complaints
Study Project Manager
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Mobile:
Email:
Certified 
Clinical Lab
Covance CLS
8211 SciCor Drive
Indianapolis, IN 46214
Phone:
+ 1 (317) 273-7872
Fax:
+1 (317) 616-4572
ABPM Lab
Bioclinica
211 Carnegie Center Drive
Princeton, NJ 08540
Phone:
+1 (877) 632-9432
Fax: 
+1 (609) 936-2602
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
13
3
STUDY PROCEDURES
14
3.1
STUDY SUBJECT INFORMATION AND INFORMED CONSENT
14
3.2
MEDICAL HISTORY
14
3.3
CONCOMITANT MEDICATIONS
14
3.4
ADVERSE EVENT ASSESSMENT
15
3.5
PHARMACOKINETIC SAMPLING
15
3.6
12-LEAD ELECTROCARDIOGRAM
15
3.7
HEIGHT AND BMI, WEIGHT
16
3.8
VITAL SIGNS
16
3.9
PHYSICAL EXAMINATION
17
3.10 DISPENSE STUDY DRUG
17
3.11 CLINICAL LABORATORY TESTS
17
3.12 SUBJECT WITHDRAWAL FROM STUDY
19
3.13 UNSCHEDULED VISITS
20
3.14 AMBULATORY BLOOD PRESSURE MEASUREMENTS
20
3.15 END OF STUDY/STUDY COMPLETION
22
4
SAFETY MANUAL
22
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
22
4.2
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
23
5
COUNTRY-SPECIFIC REQUIREMENTS
24
6
STUDY DRUG
24
6.1
TREATMENTS ADMINISTERED
24
6.2
PACKAGING AND LABELING
24
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
25
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
CONFIDENTIAL INFORMATION
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6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
25
6.5
STUDY DRUG ADHERENCE
27
7
APPENDICES
28
7.1
ABPM COLLECTION VALIDITY CRITERIA
28
7.2
CUFF SIZE AND OFFICE BLOOD PRESSURE MEASUREMENTS INSTRUCTIONS
29
LIST OF TABLES
TABLE 1.
APPROXIMATE DOSAGE AND DURATION OF USE FOR 1 BOTTLE OF STUDY DRUG
24
TABLE 2.
DOSE TITRATIONS
26
LIST OF FIGURES
FIGURE 1.
STUDY DRUG APPLICATION SITES
27
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CONFIDENTIAL INFORMATION
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3.4 Adverse Event Assessment
Please refer to Section 4.1.
3.5 Pharmacokinetic Sampling
Blood samples for analysis of testosterone (T) will be collected at time points specified in Section 2.1.
Additional information on the collection, handling/processing, disposition, and measurement methods 
can be found in the lab manual.
3.6 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the designated study visit as specified in 
Section 2.1.
The ECG should be performed prior to blood collection and after the subject has rested in a supine 
position for approximately 5 minutes.
The ECG will be interpreted by an appropriately qualified physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:

Normal ECG

Abnormal ECG – not clinically significant

Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
documents.  The automatic machine reading (i.e., machine-generated measurements and interpretation 
that are automatically printed on the ECG tracing) will not be collected.
Electrocardiogram with QT interval corrected for HR using Fridericia-corrected QT interval (QTcF) should 
be reported (or calculated) and documented in the source documents and later transcribed on to the 
appropriate electronic case report form (eCRF), if QTcF prolongation is observed (> 430 msec).  In 
addition, any clinically significant findings will be documented in the source documents and later 
transcribed on to the appropriate eCRF.  Each signed original ECG may be reviewed by the responsible 
site monitor and kept with subject's source documents on site.
If there are clinically significant findings, the investigator must contact the AbbVie TA MD before 
enrolling the subject.  The subject may have a repeat ECG at any time during the study as warranted 
based on the investigator's opinion.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.7 Height and BMI, Weight
Height and weight will be measured at SV2 only for calculation of body mass index (BMI); the subject 
will not wear shoes.  Body weight will be measured on a calibrated scale shortly after the subject 
empties his bladder.  Subject should wear light indoor clothing with pockets empty and without shoes, 
belts, jewelry or other accessories.  Weight may be recorded in kilogram (kg) to the nearest 0.1 kg or in 
pounds (lb) to the nearest 0.25 lb.  If possible, the same scale should be used for all weight 
measurements.
Body mass index is defined as the subject weight in kilograms divided by the subject height in meters 
squared (kg/m2) and should be calculated to the nearest one-tenth unit.  The BMI calculation should be 
recorded in the Screening Visit source documents and case report form.  The following formulas will be 
used to convert to metric units for calculation of BMI: 
Pound (lb) ÷ 2.2 = Kilogram (kg) 
Inch (in) × 0.0254 = Meter (m) 
Body mass index calculations will be made by the investigator or designee during SV2 using the 
following formula: 
Body mass index (kg/m2) = weight (kg) ÷ [height (m) at Screening Visit]2
3.8 Vital Signs
Vital sign determinations of HR, RR, and oral body temperature will be obtained at visits as specified in 
Section 2.1.  Measurements should be assessed consistently throughout the study.  Vital signs 
measurements determined at the Pre-ABPM assessment will serve as baseline.
Blood pressure (BP) and HR should be measured after the subject has been sitting for at least 5 minutes.
Measurements should be assessed consistently throughout the study.
Office BP Measurements
At SV1, subjects will be assessed for pre-existing hypertension based on medical history.  At SV1 and 
SV2, subjects will be assessed for BP eligibility prior to T testing.
Blood pressure will be measured in both arms with an automated oscillometric device using a 
standardized measurement protocol according to the recommendations for indirect measurement of 
arterial BP of the AHA.34
See Section 7.2 for further details.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.9 Physical Examination
A complete physical examination will be performed at SV2.  The physical examination at SV2 will serve 
as the baseline physical examination for clinical assessment.  All other physical examinations as 
indicated in Section 2.1 will be symptom-directed examinations.
Any significant physical examination findings not present at Baseline and detected on subsequent 
examinations will be documented and any significant findings will be reported.  All findings will be 
captured on the appropriate eCRF page.
When deemed necessary by the investigator, a symptom-directed physical examination can be 
performed at the Unscheduled Visit.
Digital Rectal Examination (DRE)
A digital rectal exam (DRE) will be performed at SV2 and should be performed after the PSA blood draw.  
The DRE will not be required if the subject had a previous normal DRE within 6 months of SV1 and the 
written documentation of the DRE result is provided.  An abnormal DRE necessitating further clinical 
work up will exclude the subject from the study until any prostatic abnormalities have been evaluated 
and deemed not exclusionary.  An enlarged prostate on DRE due to Benign Prostatic Hyperplasia is not 
exclusionary.
3.10 Dispense Study Drug
The first dose of study drug will be applied by subject while on site after all other Day 1 Visit procedures 
are completed and only after a valid ABPM assessment has been confirmed.  Thereafter, study drug will 
be dispensed at designated study visits during the Treatment Period.  At the designated scheduled study 
visits, subjects will return to the site to obtain new supply of study drug and return used/unused study 
drug packaging supply.  The unused study drug returned by the subject will not be re-dispensed.  The 
investigator or designee will access the IRT system at each study visit prior to dispensing study drug to 
the subject.  Study drug cannot be dispensed without using the IRT system.  Study pump bottles will be 
labeled with their unique pump bottle kit number.
3.11 Clinical Laboratory Tests
The blood samples for serum chemistry tests (and sex steroids) will be collected following a minimum 
8-hour fast (with exception of SV1, which may be non-fasting).  At the Day 1 Visit, a fasting blood sample 
should be collected prior to the first dose of study drug.  Blood samples should still be drawn if the 
subject did not fast for at least 8 hours.  Fasting or non-fasting status will be recorded in the source 
documents and on the laboratory requisition.  The laboratory test results from SV2 will serve as baseline 
for this study.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
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Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:

repeat the test to verify the out-of-range value;

follow the out-of-range value to a satisfactory clinical resolution; or

discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as a study-specific adverse event (AE) (See Section 6.1 of 
the protocol).
All Screening laboratory results must be reviewed, signed, and dated by the investigator or sub-
investigator prior to enrollment.  Subjects will not be enrolled into the study if laboratory or other 
Screening result abnormalities are deemed clinically significant by the investigator or sub-investigator.
Hematology
Clinical Chemistrya
Urinalysisb
Hematocrit
Hemoglobin
Red blood cell count
White blood cell count
Platelet count (estimate not 
acceptable)
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Blood urea nitrogen
Creatininec
Total bilirubin
Albumin
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Gamma-glutamyl transferase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
Low-density lipoprotein cholesterol
High-density lipoprotein cholesterol 
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Leukocytes
Nitrites
Other Laboratory Tests
Prostate specific antigen
Hemoglobin A1c
Sex Steroidsa
Testosteroned
Dihydrotestosterone
Estradiol
PK Assay
At EOT visit only:  Serial PK blood 
samples following ABPM 
assessment obtained at 0, 
2, 4, and 6 - 8 hours
ABPM = ambulatory blood pressure monitoring; EOT = End of Treatment; PK = pharmacokinetic; SV = Screening Visit
a.
Minimum 8-hour fast except for SV1.
b.
A dipstick urinalysis (without microscopy) will be completed by the central laboratory at SV2.
c.
Serum creatinine will be collected at SV2 only and used to calculate eGFR (central laboratory performing calculations).  An 
eGFR assessment (CKD-EPI Equation) will be performed.
d.
Testosterone alone will be measured for eligibility at SV1 and SV2, and for titration at Weeks 2 and 4.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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Clinical Chemistry
A minimum 8-hour fast will be necessary for blood samples to be drawn for chemistry.  If a subject is not 
able to fast when necessary due to unforeseen circumstances, the non-fasting status will be recorded in 
subject source documentation.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at SV2.  Specified abnormal macroscopic 
urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, or glucose 
greater than normal will be followed up with a microscopic analysis (only if needed) at the central 
laboratory.
Sex Steroids
Blood samples for serum T level, dihydrotestosterone (DHT), and estradiol (E2) will be collected at the 
visits as specified in Section 2.1.  Testosterone samples obtained at the Weeks 2 and 4 Visits will be used 
for titration of the T study drug dose.  For information on Screening serum T level, refer to the study 
inclusion criteria.  After study enrollment, pre-dose serum T level samples will be collected at 24 hours 
(± 2 hours) of the last applied dose for the purpose of titration.  For example, if the last applied dose was 
at 11:00 am the day prior to the study visit, the blood sample should be taken between 9:00 am to 
1:00 pm.  Subjects should not apply their regularly scheduled study drug dose prior to the in-person 
study visits as defined in Section 2.1.  Subjects should receive a reminder to apply the dose 24 hours 
before the study visit, even if that is not their usual study drug application time.
The following subjects should be rescheduled within 1 week for a serum T level if their serum T cannot 
be drawn 24-hours (± 2 hours) from the last applied dose:

Subjects who apply a dose less than 22 hours from the time of serum T sample collection.

Subjects who apply a dose greater than 26 hours from the time of serum T sample collection.
Subjects should bring their current study drug to each on-site study visit.  Subjects who forget to bring 
the study drug to their study visit should arrange to return study drug to study site as soon as possible.  
The dose applied during the study visit will come from the newly dispensed study drug.
Prostate-specific antigen
A blood draw to measure PSA should occur prior to the DRE as prostate manipulation can falsely elevate 
PSA.  Only men who have a T < 300 ng/dL at SV1 will have a PSA evaluated from that same sample.  At 
Screening, the PSA must be ≤ 3.0 ng/mL (≤ 1.5 ng/mL in men receiving 5-alpha reductase inhibitors).
3.12 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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investigator's best clinical judgment, irrespective of whether the subject decides to continue 
participation in the study.
3.13 Unscheduled Visits
An Unscheduled Visit may occur for a variety of reasons.  During Unscheduled Visits, concomitant 
medication, AE assessments, vital signs (including office BP), and a symptom-directed physical 
examination (only if needed) should be performed.  Blood and urine samples may be obtained for the 
laboratory tests listed in Section 3, or for other tests, at the investigator's discretion.
If a blood sample is collected for PSA or hematocrit at the Unscheduled Visit and there is an increase in 
absolute values as specified in Section 5.5 of the protocol, the increase should be confirmed by 
repeating the test.  If the increase is confirmed after 2 blood draws, the subject should be discontinued 
from receiving study drug.
If an ABPM assessment requires a repeat due to device malfunction or confirmation of the invalid ABPM 
collection, the repeat ABPM 24-hour collection should be performed at the Unscheduled Visit.  Study 
activities for the Unscheduled Visit are outlined in Section 2.1.
3.14 Ambulatory Blood Pressure Measurements
ABP measurements will be collected at the visits as specified in Section 2.1.  Every effort should be made 
to use the same ABPM device for the Baseline and Week 16 ABPM for each individual subject.  The start 
of each ABPM 24-hour collection is to be performed around the same time of day for each visit, 
between 06:00 – 11:00.
Study sites will be provided with a SpaceLabs ABP monitor from the cardiac safety core lab.  The ABPM 
recordings will be transmitted to the core lab for centralized management of the data.
The ABP monitor will be set to automatically measure and record BP every 30 minutes for 24 hours.  The 
inflation sequence for this protocol will be outlined in the ABPM training manual.  The ABPM 24-hour 
collection will be conducted over a 2-day period.  On the first day, the ABP monitoring device is fitted on 
the subject by the site; the subject leaves and then returns the following day for ABP monitor removal.
At the completion of each ABPM 24-hour collection, the ABPM data will be downloaded from the device 
to a laptop provided by the core lab.  The ABPM data will be evaluated against a set of quality control 
criteria designed specifically for this study to define a valid monitoring.  The quality control results will 
be immediately available for the clinical staff.  If the quality criteria are not met, the investigator will ask 
the subject to return to the clinical site to repeat the ABPM 24-hour collection within 7 days.  In this 
case, Day 1 Visit would follow completion of the repeat Baseline ABPM and the End of Treatment (EOT) 
Visit would follow completion of the repeat Week 16 ABPM.  Repeat ABPM will be performed at an 
Unscheduled Visit.
A complete listing and definitions of the quality control criteria are outlined in the ABPM training 
manual.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
CONFIDENTIAL INFORMATION
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Study sites will remain masked to the Week 16 ABPM data until the End of Treatment Period of the last 
subject; however, the site will be unmasked to the ABPM validity report.  The investigator or designee 
will assess the validity of ABPM data based on the results that are immediately available on site once 
data is downloaded from the monitoring device, to the study configured laptop, utilizing ABPM specific 
software.  PI or designee can then determine if a repeat ABPM 24-hour collection is required.
Sites will receive training on the use of the ABPM technology and software platform provided by the 
core lab.  Additional information related to the ABPM procedures for the study will be provided in the 
ABPM Site Manual and ABPM Quick Reference Guide provided by the ABPM core lab.
The following ABPM procedures will be performed over a 2-day period:
First Day:  Application
The BP cuff of the ABP monitor will be fitted, preferably on the subject's non-dominant arm, by 
designated study staff completing the clinic BP readings.  The designated study site staff will use the 
24-hour ABPM Application Worksheet provided by the core lab during the ABPM application process.  
Verification readings will be obtained prior to the beginning of test reading.  The subject will be 
instructed regarding ABPM procedures and the ABPM Subject Instruction/Error Codes Handout provided 
by the core lab will be reviewed with the subject.
Second Day:  Removal
The subject will return to the study site and the ABP monitor will be removed only after it has been 
worn for a minimum of 24 hours from the "Beginning of Test" reading.  The ABPM data will be 
downloaded and quality control evaluated on site, using the study specific ABPM software.  The quality 
control criteria for the specific monitoring will be immediately displayed on the ABPM laptop.  If an 
ABPM 24-hour collection does not meet the study specific criteria ("fails"), the designated site staff 
should contact the ABPM core lab project team to review and determine if a repeat ABPM 24-hour 
collection is required for that specific ABPM Visit.
SpaceLabs System
The SpaceLabs 90217 ABP monitor is a small, light-weight unit with batteries, pouch, and strap and is 
designed to take up to 240 BP measurements (range:  systolic 60 to 260 mmHg; diastolic 30 to 200; 
mean 40 to 230 mmHg) and HR measurements (range:  40 to 180 beats) for a 24- or 48-hour period.  
The monitor is carried in a pouch that may be worn on a waist-belt or on a shoulder strap.  Blood 
pressure and HR measurements are taken oscillometrically, using a cuff, which is inflated twice hourly 
over a 24-hour period.  Programming will allow the ABP monitor to specify the duration of the 
monitoring period, subject information to be incorporated in the analysis, the time format, the 
measurement interval, the presence or absence of the audible monitor tone during specified periods of 
the recording period (e.g., sleep), event code display and whether or not to display data on the digital 
display for reading by the subject.
Selection of Cuff Size for ABPM
Correct measurement of BP for ABPM requires the use of a cuff that is appropriate to the size of the 
non-dominant upper arm.  The non-dominant arm will be preferred for consistency.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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ABPM Procedures for Subject
The ABPM vendor (Bioclinica) will provide the site staff with access to electronic training modules and a 
Study Site Training Manual inclusive of subject instructions for use.
3.15 End of Study/Study Completion
The last visit/procedure/contact (e.g., office visit or phone call) with the subject will serve as the End of 
Study (EOS) for each subject.  For subjects completing at least 16 weeks of treatment on study drug, 
there will be a follow up phone call in approximately 30 days.  For subjects prematurely discontinuing 
study drug prior to Week 16/EOT, the follow up phone call at approximately 30 days after the last visit 
will serve as the EOS.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All SAEs, AESI, and AEs leading to study drug discontinuation, will be recorded from the time of study 
drug administration until the end of the study/study completion.  Study procedure-related non-serious 
AEs and SAEs will be collected from the time the subject signs the study-specific informed consent until 
30 days after the last dose of study drug.  All SAEs, AESI, AEs leading to study drug discontinuation, and 
study procedure-related non-serious AEs or SAEs will be followed until resolution or achievement of a 
new stable state, until the subject withdraws consent for study participation, or until the final study-
related communication (e.g., phone call at the end of the study or final study communication in subjects 
truly considered LTFU, whichever occurs first).
AE = adverse event; AESI = adverse event of special interest; d/c = discontinuation; SAE = serious adverse event
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting 
for the Investigational Medicinal Product in accordance with Directive 2001/20/EC.
5 COUNTRY-SPECIFIC REQUIREMENTS
This section is not applicable, as this study does not have sites outside of the US.
6 STUDY DRUG
6.1 Treatments Administered
The study drug (AndroGel 1.62%) will be dispensed in the form of a topical gel at the visits listed in 
Section 2.1.  Subjects will be instructed to take study drug at the same time every day.  The first dose of 
study drug will be applied by subject while on site after all other Day 1 Visit procedures are completed 
and only after a valid ABPM 24-hour collection has been confirmed.  Subject will be instructed to bring 
study drug in at Week 2, Week 4, Week 16 ABPM, and EOT Visits, and apply the study drug while on site.
Study drug must not be dispensed without contacting the IRT system.  Study drug may only be 
dispensed to subjects enrolled in the study through the IRT system.  At the end of the Treatment Period 
or at the Premature Discontinuation Visit, the site will contact the IRT system to provide visit date 
information and study drug return information for each kit.
6.2 Packaging and Labeling
The study drug will be supplied in a metered-dose pump, containing AndroGel 1.62%.  Each actuation 
delivers 20.25 mg T.
Each pump bottle will be labeled per US requirement.  Labels must remain affixed to the pump bottles.  
Site staff should fill in all pump bottle labels prior to dispensing to subject.  The approximate dosage and 
duration for one bottle are depicted in Table 1.
Table 1.
Approximate Dosage and Duration of Use for 1 Bottle of Study Drug
Dosage 
Duration of Use for 1 Bottle
20.25 mg (1 actuation)
60 days
40.5 mg (2 actuations)
30 days
60.75 mg (3 actuations)
20 days
81.0 mg (4 actuations)
15 days
Storage and Disposition of Study Drug
Upon receipt, study drug should be stored as specified on the label and kept in a secure location:

Store AndroGel 1.62% at 59°F to 86°F (15°C to 25°C);
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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
Keep AndroGel 1.62% away from fire;

Keep AndroGel 1.62% and all medicines out of the reach of children.
The investigational products are for investigational use only and are to be used only within the context 
of this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or returned by the 
study monitor to the depot for destruction.
6.3 Method of Assigning Subjects to Treatment Groups
This is an open-label, single arm study.  All eligible subjects will receive AndroGel 1.62%.
At SV1, all subjects will be assigned a unique identification number through the use of the IRT.  For 
subjects who do not meet the study eligibility criteria, the site staff must contact the IRT system and 
identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at SV1 throughout the study.  Upon 
receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
The starting dose of AndroGel 1.62% is 40.5 mg of T (2 pump actuations, applied topically once daily in 
the morning).  Based on serum T levels obtained at the Weeks 2 and 4 visits, subjects will be titrated up 
or down by 20.25 mg if their serum T levels are < 350 ng/dL or > 750 ng/dL, respectively.  The final 
titrated doses will be 20.25 mg, 40.5 mg, 60.75 mg, or 81.0 mg, and subjects will remain on their final 
titrated dose following the Week 4 assessment until EOT.
Before using a new pump of study drug, the pump will need to be primed by pushing the actuator all the 
way down 3 times.  Study drug dispensed while priming the pump should not be used.  Subject should 
be instructed to dispose of it by washing it down the sink to avoid accidental exposure to others.  The 
pump only needs to be primed when using a new pump for the first time.
Titration Instructions
Titration will be based on the predose morning total serum T concentrations.  Subjects will return for 
predose serum T assessment 24 hours (± 2 hours) after the last applied dose according to the schedule 
in Section 2.1.  Subjects will be asked when they last applied study drug.  Subjects should be rescheduled 
within 1 week for a serum T level if their serum T cannot be drawn 24 hours (± 2 hours) from the last 
applied dose.  Within approximately 7 days of these titration study visits, the subject's dose may be 
titrated up or down in 20.25 mg increments or remain on the previously assigned dose, based on 
prespecified criteria (Table 2).  No dose can be titrated below 20.25 mg or above 81.0 mg during the 
course of the study.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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Table 2.
Dose Titrations
Pre-Dose (Preferably Morning) Sample Collection for 
Serum Testosterone Concentrations to Occur Within 
24 Hours (± 2 hours) Following the Last Applied Dose
Dose Titration
Greater than 750 ng/dL 
Decrease daily dose by 20.25 mg (one pump 
actuation)
Between 350 ng/dL and 750 ng/dL, inclusive
No change:  continue on current dose
Less than 350 ng/dL 
Increase daily dose by 20.25 mg (one pump actuation)
If the serum total T is > 750 ng/dL, the dose should be decreased by 1 actuation.  If the serum total T is 
< 350 ng/dL, the dose should be increased by 1 actuation.  If the serum total T is between 350 ng/dL and 
750 ng/dL, inclusive, the dose should remain the same.  The site staff will contact the subject (by phone, 
via email, etc.) and instruct the subject to reduce the dose by 1 study drug actuation, to increase by 
1 study drug actuation, or to remain on the same dose of the study drug.
If the serum T is > 750 ng/dL even after down-titration to the lowest dose, the results should be 
confirmed by a repeat blood sample by the central laboratory.  If the repeat total T is > 750 ng/dL, 
subject may need to be discontinued from study drug.
If subjects are instructed by site staff to titrate following Week 2 and Week 4 titration visits, they will be 
required to cross out the previous instructions on pump bottle label specifying their previous number(s) 
of pumps/actuations per day or dose and fill in their updated number of pumps/actuations per day or 
dose.
Should a subject's dose require titration, site personnel will communicate this to the subjects within
approximately 3 days from the receipt of the lab results.
Study Drug Application Sites
For the first study drug administration at Day 1 Visit, the subject should administer the study drug while 
on site so that the site staff can observe the proper administration of study drug.
On subsequent study visit days, subjects should not apply their daily dose until after a sample is 
collected to measure serum T (See Section 2.1 for titration study visits).  Following sample collection, 
subjects will apply study drug while on site.  Subjects should be rescheduled within 1 week for a serum T 
level if their serum T cannot be drawn 24 hours (± 2 hours) from last applied dose (see Section 3.11).
The subject will self-administer study drug once daily in the morning to the shoulder(s) and upper 
arm(s).  The study drug should not be administered to other parts of the body, including abdomen, 
genitals, chest, armpits (axillae), or knees.  See Figure 1 for acceptable application sites.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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Figure 1.
Study Drug Application Sites
Following study drug administration, the subjects should wash their hands with soap and water.  After 
the study drug has completely dried, the subject should cover up the application site with a t-shirt.
6.5 Study Drug Adherence 
Subjects will be instructed to return all used or unused bottles at each visit to determine adherence via 
bottle weight.  At each of the visits as specified in Section 2.1, the study coordinator will question the 
subject regarding adherence to the assigned regimens.  A weight measurement of the study drug pump 
bottle will be conducted.  Study drug lot number, the date that the study drug bottle(s) were 
dispensed/returned, and the weight of the returned study drug bottles will be recorded.  The bottle 
weight of the returned study drug bottles will be compared to an average bottle weight to determine 
adherence.  The number of doses that should have occurred between visits will be calculated.  Subjects 
with adherence values below 85% or above 120% adherence will be re-instructed on proper use and 
informed of the importance of adherence to continue in the study.  An overall accountability of study 
drug will be performed and verified by AbbVie/designee.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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7 Appendices
7.1 ABPM Collection Validity Criteria
The ABP monitor will be set to automatically measure and record BP every 30 minutes for 24 hours.  A 
24-hour ABPM collection will be considered valid if all of the following are obtained:
1.
At least 24 measurements of SBP during the 24-hour period
2.
At least 12 SBP measurements between 09:00 and 21:00
3.
At least 5 SBP measurements between 01:00 and 06:00
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-161 Version 3.0
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7.2 Cuff Size and Office Blood Pressure Measurements Instructions
1.
Measure subject's arm by wrapping a tape measure around the subject's bicep at mid-arm to 
determine the arm circumference (measured inches or cm).
2.
Select a proper cuff size based on arm circumference. 
The ideal cuff bladder length is ≥ 80 percent of the subject's arm circumference.  The ideal cuff bladder 
width is ≥ 40 percent of the subject's arm circumference.
Key Steps for Proper BP 
Measurements
Specific Instructions
Step 1:  Properly prepare the subject
1.
Have the subject relax, sitting in a chair (feet flat on the floor and 
legs uncrossed, back straight and supported) for > 5 min.
2.
The subject should avoid caffeine, caffeinated beverages, exercise, 
and smoking for at least 30 minutes before measurement.
3.
Ensure subject has emptied his bladder.
4.
Neither the subject nor the observer should talk during the rest 
period or during the measurement.
5.
Remove all clothing covering the location of cuff placement.
6.
Do not measure BP while the subject is sitting or lying on an 
examining table.
Step 2:  Use proper technique for BP 
measurements
1.
Use an automated oscillometric device.
2.
Support the subject's arm (e.g., resting on a flat surface such as a 
desk or table, with the upper arm at heart level).
3.
Position the middle of the cuff on the subject's upper arm at the 
level of the right atrium (the midpoint of the sternum).
4.
Use the correct cuff size, such that the bladder encircles 80% of the 
arm, and note if a larger- or smaller-than–normal cuff size is used.
Step 3:  Take the proper BP 
measurements
1.
At the first visit, record BP in both arms.  Use the arm that gives the 
higher reading for subsequent readings.
2.
Separate repeated measurements by approximately 2 minutes. 
Step 4:  Properly document accurate 
BP readings
1.
Record SBP and DBP. 
2.
Document the time of most recent BP medication taken before 
measurements.
Step 5:  Average the readings
Two or 3 readings will be averaged.  If the first 2 readings differ by more 
than 5 mmHg, additional readings will be obtained and averaged.  The 
average BP reading should be recorded.
BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure
Adapted from Whelton PK, Carey RM, Aronow WS, et al.  2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA 
Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults:  A Report of the 
American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.  Hypertension.  
2018;71(6):e13-115.
Page 69 of 71
 

SAP_001.pdf: 
Androgel 1.62%
M19-161 – Statistical Analysis Plan
Version 2.0 – 14 August 2020
1
Statistical Analysis Plan for Study M19-161
24-Hour Ambulatory Blood Pressure Monitoring 
Study in Hypogonadal Men Receiving Testosterone 
Replacement Therapy
Date:  14 August 2020
Version 2.0
 
NCT04274894


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Table of Contents
1.0
Introduction .............................................................................4
2.0
Study Design and Objectives..................................................4
2.1
Objectives and Hypotheses ........................................................................4
2.2
Study Design Overview .............................................................................4
2.3
Treatment Assignment and Blinding .........................................................8
2.4
Sample Size Determination........................................................................9
3.0
Endpoints..................................................................................9
3.1
Primary Endpoint.......................................................................................9
3.2
Other Endpoints .........................................................................................9
3.3
Safety Endpoint(s) ...................................................................................10
3.4
Additional Endpoint(s).............................................................................10
4.0
Analysis Populations .............................................................10
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration and Compliance................................11
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................15
7.1
Demographics and Baseline Characteristics............................................15
7.2
Medical History .......................................................................................16
7.3
Prior and Concomitant Medications ........................................................16
8.0
Efficacy Analyses...................................................................17
9.0
Safety Analyses ......................................................................17
9.1.1
Primary Safety Endpoint..........................................................................17
9.1.2
Handling of Missing Data for the Primary Safety Endpoint....................17
9.1.3
Primary Safety Analysis ..........................................................................18
9.1.3.1
Sensitivity Analyses of the Primary Safety Endpoint..............................21
9.1.3.2
Supportive Analyses of the Primary Safety Endpoint .............................23
9.2
Other Safety Endpoints and Analyses......................................................24
9.2.1
Handling of Missing Data for Other Safety Endpoints............................24
9.2.2
Other Safety Endpoints............................................................................24
9.3
Safety Subgroup Analyses .......................................................................25
10.0
Additional Safety Analyses...................................................26
 


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10.1
General Considerations............................................................................26
10.2
Adverse Events ........................................................................................26
10.2.1
Treatment-emergent Adverse Event (TEAE) ..........................................26
10.2.2
Adverse Event Overview .........................................................................27
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................27
10.2.4
Adverse Events of Special Interest ..........................................................28
10.3
Analysis of Laboratory Data....................................................................28
10.4
Analysis of Vital Signs ............................................................................30
11.0
Interim Analyses....................................................................30
12.0
Overall Type-I Error Control ..............................................32
13.0
Version History......................................................................33
14.0
References...............................................................................34
List of Tables
Table 1.
Regions of the United States....................................................................21
Table 2.
Clinical Laboratory Tests.........................................................................29
Table 3.
SAP Version History Summary...............................................................33
Table 4.
Adverse Event of Special Interest............................................................36
List of Figures
Figure 1.
Study Schematic.........................................................................................8
List of Appendices
Appendix A.
Protocol Deviations..................................................................................35
Appendix B.
Definition of Adverse Events of Special Interest ....................................36
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Androgel 1.62% 
Study M19-161 24-Hour Ambulatory Blood Pressure Monitoring Study in Hypogonadal 
Men Receiving Testosterone Replacement Therapy.
Study M19-161 assesses the effect of Androgel 1.62% on blood pressure (BP) in 
hypogonadal men.
The analyses of pharmacokinetic endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The objective of this study is to assess the effect of AndroGel 1.62% on BP.  The 
hypothesis corresponding to the primary objective is that AndroGel 1.62%, used as 
labelled, does not affect 24-hour average systolic blood pressure (SBP).
2.2
Study Design Overview
This is a multicenter, Phase 4, open-label, single-arm study to establish that the average 
24-Hour SBP at End of Treatment (EOT) is not greater than Baseline SBP with a non-
inferiority margin of 3 mmHg.  Efficacy will not be evaluated in this study.
The initial planned study enrollment is approximately 190 subjects based on the projected 
sample size calculation and subject discontinuation rate.  There will be approximately 
45 sites in the US.  
 


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The Screening Period is up to 45 days prior to the baseline ABPM 24-hour collection and 
includes 2 separate visits (Screening Visit 1 [SV1] and Screening Visit 2 [SV2]) to 
establish subject eligibility.  Office BP measurements by automated oscillometric device 
will be used for evaluation of the subject for BP eligibility criteria at Screening.  
Once subjects meet all of the eligibility criteria during Screening, they will be enrolled 
into the study and followed until approximately 30 days following EOT.
EOT is defined as a valid ABPM 24-hour collection after at least 16 weeks of treatment 
with AndroGel 1.62%.  End of study (EOS) is defined as last visit/last procedure/last 
contact (office visit or phone call).  
Ambulatory blood pressure monitoring (ABPM) measurements will be obtained from all 
subjects using a portable data-monitoring device.  The ABPM procedure will be 
performed over a 24-hour period across 2 days and will include ABPM device application 
by site (1st Day) and ABPM device removal by site (2nd Day).  
The validity of the ABPM 24-hour collection measurements will be evaluated prior to 
performing the procedures for the Day 1 Visit, and prior to performing the procedures for 
the EOT Visit.  Day 1 is defined as start of treatment (first dose of the study drug).  
Subjects will receive the first dose of the study drug on site only after validity of the 
baseline ABPM 24-hour collection is confirmed. 
The investigator or designee will assess the validity of ABPM measurements based on the 
results that are immediately available on site once data is downloaded from the ABPM 
device, to the study configured laptop, utilizing ABPM specific software.  The 
investigator or designee can then assess if a repeat ABPM collection is required.
The ambulatory blood pressure (ABP) monitor will be set to automatically measure and 
record BP every 30 minutes for 24 hours.  The ABPM 24-hour collection will be repeated 
if > 50% of collected ABPM data (measurements) during the 24-hour period, daytime 
period (09:00 – 21:00 h), or nighttime period (01:00 – 06:00 h) are missing or if there is 
 


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an ABPM device malfunction.  Based on these criteria, a 24-hour ABPM collection will 
be considered valid if all of the following are obtained:
1.
At least 24 measurements of SBP during the 24-hour period.
2.
At least 12 SBP measurements between 09:00 and 21:00.
3.
At least 5 SBP measurements between 01:00 and 06:00.
The repeat ABPM 24-hour collection will be conducted at Unscheduled Visits within 
7 days of the invalid APBM.  The recorded ABPM data will be transmitted to the core lab 
for centralized management. 
The study team, study statistician, study sites, and subjects will remain masked to the 
Week 16 ABPM data until the end of the Treatment Period of the last subject. 
The Treatment Period will last for at least 16 weeks.  The site will record dosing times 
corresponding to the visits for ABPM collection and serial PK sampling times.  Titration 
evaluation of T dose will occur in all subjects at Week 2 and Week 4.  All subjects will 
start on 40.5 mg of study drug.  Subjects will return on Weeks 2 and 4 to have early 
morning pre-dose T levels evaluated for titration.  Subjects will be titrated up by 
20.25 mg, down by 20.25 mg, or remain on the previously assigned dose if their serum 
T levels are < 350 ng/dL, > 750 ng/dL, or between 350 ng/dL and 750 ng/dL inclusive, 
respectively.  The final titrated doses will be 20.25 mg, 40.5 mg, 60.75 mg, or 81.0 mg, 
and subjects will remain on their final titrated dose following the Week 4 assessment until 
EOT.  The Week 10 Visit will be a telephone call only.  
Subjects will continue on study drug until after a valid ABPM 24-hour collection has been 
confirmed and will apply the study drug on site before the serial PK sampling at the EOT 
Visit.  The serial PK blood samples will be drawn only after validity of the ABPM 
24-hour collection has been confirmed.   
 


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A Follow-up Visit phone call will occur approximately 30 days after the last dose of study 
drug.  During phone calls and in-person visits throughout the study, subjects will be asked 
specific questions pertaining to the possible occurrence of SAEs, adverse events of special 
interest (AESI), adverse events as well as the collection of additional information related 
to ongoing AE(s).
Any change in antihypertensive medication(s), antihypertensive medication(s) dose 
increase and/or initiation of antihypertensive medication(s) will be documented 
throughout the study. 
An analysis to estimate the standard deviation (SD) of change from Baseline in SBP 
average 24-hour recording will be conducted in a blinded fashion when approximately 
70% of the planned subjects in the per protocol population (i.e., 120 subjects) have 
completed the EOT Visit.  The objective of this analysis is to re-estimate sample size if 
needed.  
The schematic of the study is shown in Figure 1.
 


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Figure 1.
Study Schematic
ABPM = ambulatory blood pressure monitoring; BP = blood pressure; EOT = End of Treatment; 
PK = pharmacokinetics; QD = once a day; SV1 = Screening Visit 1; SV2 = Screening Visit 2
2.3
Treatment Assignment and Blinding
This is a single-arm open-label study; therefore, there will not be a randomization to 
treatment assignment.  All subjects will be assigned a unique identification number by the 
IRT at SV1.  For subjects who rescreen, the screening number assigned by the IRT at the 
SV1 should be used.  
Subjects will be categorized in IRT by ongoing medical history of hypertension (Yes/No) 
at Baseline to ensure that 35% to 50% of subjects with an ongoing medical history of 
hypertension are enrolled.  
The study team, study statistician, study sites, and subjects will remain masked to the 
Week 16 ABPM data until the end of the Treatment Period of the last subject.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.4
Sample Size Determination
A sample size of 171 subjects will provide 90% power for a paired t-test with 
0.025 one-sided significance level to show that the EOT average 24-hour SBP is not 
greater than the Baseline average 24-hour SBP with a non-inferiority margin of 3 mmHg, 
assuming the mean difference between EOT and Baseline is an increase of 0.5 mmHg and 
the SD of the difference is 10 mmHg.  The power for the primary analysis using linear 
regression with covariate adjustment for baseline will be as least as high as that from the 
paired t-test.  Assuming a 10% loss of subjects from the per protocol population due to 
premature discontinuation, invalid ABPM at the Baseline or EOT visit, or non-adherence 
to study drug, approximately 190 subjects will be enrolled to reach a minimum of 
171 subjects who are at least 85% compliant to study drug and have valid ABPM data 
from Baseline and the EOT visits.
If the dropout, non-evaluable ABPM, or non-adherence rates are higher than expected, 
enrollment will continue until the required number of evaluable subjects in the per 
protocol population is reached.  If the SD is higher than the expected SD, an evaluation 
will be made to adjust the number of evaluable subjects if necessary.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is the mean change in 24-hour average SBP from Baseline to EOT.
3.2
Other Endpoints
●
Change from Baseline to EOT in average daytime (09:00 – 21:00 h) mean 
arterial pressure (MAP), SBP, diastolic blood pressure (DBP), pulse pressure 
(PP), and heart rate (HR)
●
Change from Baseline to EOT in average nighttime (01:00 – 06:00 h) MAP, 
SBP, DBP, PP, and HR
●
Change from Baseline to EOT in average 24-hour MAP, DBP, PP, and HR
 


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●
Change from Baseline to EOT in MAP, SBP, DBP, PP, and HR at the time of 
maximum observed T concentration (Tmax) by 24-hour recordings
●
Change from Baseline over time (hourly average) by nominal clock time for 
MAP, SBP, DBP, PP, and HR by 24-hour recordings at EOT  
●
Change from Baseline over time (hourly average) by time after dose for MAP, 
SBP, DBP, PP, and HR by 24-hour recordings at EOT
●
Subjects with new concomitant antihypertensive medication(s) during the 
Treatment Period
●
Subjects with dose increases in antihypertensive medication(s) during the 
Treatment Period
●
Subjects and observations meeting the following BP thresholds separately by 
24-hour average and by hourly average by 24-hour recordings:
○
≥ 160 mmHg SBP at EOT
○
≥ 100 mmHg DBP at EOT
○
≤ 90 mmHg SBP at EOT
○
≤ 60 mmHg DBP at EOT
○
≥ 20 mmHg increase from Baseline to EOT in SBP
○
≥ 15 mmHg increase from Baseline to EOT in DBP 
3.3
Safety Endpoint(s)
Safety will be assessed by the incidence of serious adverse events (SAEs), AESI, study 
procedure related nonserious AEs and SAEs, and AEs that lead to study drug 
discontinuation.  In addition, changes from Baseline in laboratory and vital sign 
parameters to each specified timepoint will be summarized. 
3.4
Additional Endpoint(s)
The analyses of pharmacokinetic endpoints will not be covered in this SAP.
4.0
Analysis Populations
The following population sets will be used for the analyses.  
 


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The Full Analysis Set (FAS) includes all subjects who received at least 1 dose of study 
drug.  The FAS will be used for baseline analyses and certain sensitivity analyses.
The per protocol population (PP) includes all subjects who received at least 1 dose of 
study drug, are at least 85% compliant to study drug, and have valid Baseline and EOT 
systolic ABP data.  The per protocol population will be used for all analyses on endpoints 
based on 24-hour recording from ABPM device, including the primary endpoint, except 
for certain sensitivity analyses of the primary endpoint and the BP outlier analysis.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  
The Safety Analysis Set will be used for BP outlier analysis and all other safety analyses 
not related to 24-hour collection from ABPM device.
5.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for all enrolled subjects:
●
Subjects enrolled in the study.
●
Subjects who took at least one dose of study drug.
●
Subjects who completed protocol-specified treatment.
●
Subjects who completed study.
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason).
●
Subjects who prematurely discontinued study (all reasons and primary reason).
●
Subjects in each analysis population, as applicable. 
6.0
Study Drug Duration and Compliance
For the FAS and per protocol population, duration of treatment will be summarized.  
Duration of treatment is defined for each subject as last dose date minus first dose 
date + 1.  Duration of treatment will be summarized using the number of subjects treated, 
 


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mean, standard deviation, median, minimum and maximum.  In addition, the number and 
percentage of subjects in each treatment duration interval (0 to < 16 weeks, and 
≥16 weeks) will be summarized. 
Compliance
Treatment compliance will be summarized for the entire treatment period for the FAS and 
per protocol population, separately.  Treatment compliance is defined as the weight of the 
drug actually utilized divided by the weight of the drug that should have been utilized.  
Percent compliance will be summarized.
Step 1: Calculate the number of days between visits and possible titration dates
To calculate compliance for each subject, let D0, D1, D2, D3, D4, D5 and D6 be defined as:
 = 	
     1    2 
 2   − 1   + 1
 = 	
     2    2  
 2    − 2   + 1
! = 	
     2     4 
 4   − 2    + 1
# = 	
     4    4  
 4    − 4   + 1
$ = 	
     4    %&  
%&    − 4    + 1
If there is no titration between Week 2 and Week 4 visits, then
' = 	
     2    4 
 4   − 2   + 1
If there is no titration between Week 4 and EOT visits, then
( = 	
     4   %&  
%&    − 4   + 1
Step 2: Calculate weight of the prescribed dose (A) and Pavg
 


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Let P0, P1, P2, P3 and P4 be the study drug actuations assigned at the Day 1 visit date, 
Week 2 visit date, Week 2 Titration date, Week 4 visit date, and Week 4 Titration date, 
respectively.
a.
Case 1:  there is titration after Week 2 visit and after Week 4 visit
The weight of the prescribed actuations (A) is defined by:
) = *( ∗- +  ∗- + ! ∗-! + # ∗-# + $ ∗-$) ∗ 1.251 mg
The average actuations, Pavg, over the treatment period is defined as:
-234 =  ∗- +  ∗- + ! ∗-! + # ∗-# + $ ∗-$
 +  + ! + # + $
b. Case 2:  there is titration after Week 2 visit but NOT after Week 4 visit
A is defined by:
) = (( ∗- +  ∗- + ! ∗-! + ( ∗-#) ∗ 1.25) mg
The average actuations, Pavg, over the treatment period drug duration is defined as:
-234 =  ∗- +  ∗- + ! ∗-! + ( ∗-#
 +  + ! + (
c.
Case 3: there is titration after Week 4 visit but NOT after Week 2 visit
A is defined by:
) = (( ∗- + ' ∗- + # ∗-# + $ ∗-$) ∗ 1.25) mg
The average actuations, Pavg, over the treatment period is defined as:
-234 =  ∗- + ' ∗- + # ∗-# + $ ∗-$
 + ' + # + $
d. Case 4:  there is NO titration after Week 2 visit nor after Week 4 visit
 


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A is defined by:
) = (( ∗- + ' ∗- + ( ∗-#) ∗ 1.25) mg
The average actuations, Pavg, over the treatment period is defined as:
-234 =  ∗- + ' ∗- + ( ∗-#
 + ' + (
Step 3: Calculate weight of the utilized study drug (B) 
Define the following:
n0:  number of bottles utilized and returned
n1:  number of missing bottles completely used (never returned)
n2:  number of missing bottles partially used (never returned)
x:  number of days the partially used missing bottles are used in total
W0:  total weight of the n0 bottles that were utilized and returned
B1:  the weight of the study drug utilized in returned bottles
B2: the weight of the drug utilized after adjusting for the missing bottles completely used
B: the weight of all study drug utilized by the subject (adjusting for missing bottles 
completely or partially used)
The weight of the study drug utilized from returned bottles = B1 = n0 *131 – W0.
If n1 = 0, B2 = B1; if n1 > 0, B2 = B1 + (n1 * 75) assuming 75 mg used in every completely 
used never returned bottle.
 


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If n2 = 0, B = B2; if n2 > 0, B = B2 + ((n2*Pavg) * 1.25) assuming that the average number 
of actuations used in the rest of the bottles was used in each partially used and never 
returned bottle.
Step 4: Calculate compliance over the treatment period
Compliance percentage (C) over the treatment period is defined as:
5 = 6
) ∗100
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics and baseline characteristics will be summarized for the FAS and per 
protocol population.  Medical history and prior and concomitant medications will be 
summarized for the FAS only.  Categorical variables will be summarized with the number 
and percentage of subjects; percentages will be calculated based on the number of non-
missing observations.  Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean and standard deviation, median, minimum 
and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, body mass index (BMI), 
and arm circumference.  Categorical demographic variables include ethnicity 
[Hispanic/Latino, Not Hispanic/Latino], race, age (18 years – < 45 years, 45 years –
< 65 years, ≥ 65 years), BMI (< 25 or ≥ 25 kg/m2), tobacco user (current, former, never, 
unknown), and alcohol user (current, former, never, unknown).
Continuous baseline characteristics include testosterone value, PSA, hematocrit, office 
SBP, office DBP, heart rate (HR), respiratory rate (RR), oral body temperature, creatinine, 
hemoglobin A1c.  Categorical baseline characteristics include ongoing medical history of 
 


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hypertension (Yes/No), diabetes status at Baseline (Yes/No), anti-hypertensive medication 
at Baseline (Yes/No), ongoing medical history with anti-hypertensive medication at 
Baseline (medical history of hypertension with medication, medical history of 
hypertension without medication, no medical history of hypertension without medication), 
ECG (normal/abnormal), DRE (normal/abnormal), PSA (≤ 3 ng/mL and > 3 ng/mL) and 
hemoglobin A1c (< 6.5% and ≥6.5%). 
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized.  The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).  No statistical comparison will be performed on medical history. 
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized separately by generic name.  
Hypertensive medications, both prior and concomitant medications, will be summarized 
separately by generic name.
A prior medication is defined as any medication taken prior to the first dose of study drug.  
This includes medications with a start date before the first study drug administration date, 
regardless of the end date of these medications.  In cases where incomplete or missing 
medication dates are collected, a conservative approach will be taken such that if a 
medication could have been a prior medication, it will be counted as a prior medication.
A concomitant medication is defined as any medication, other than the study drug, that 
started prior to the date of the first dose of study drug and continued to be taken after the 
first dose of study drug or any medication that started on or after the date of the first dose 
 


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of study drug, but not after the date of the last dose of study drug.  In the situation where 
an incomplete or missing medication date is collected, a conservative approach will be 
taken such that if a medication could have been a concomitant medication, it will be 
counted as a concomitant medication.  A medication will be considered a concomitant 
medication where one of the following three cases occurs (1) the start date is missing and 
the end date is either after or on the first study drug dose date; (2) the start date is prior to 
or on the last dose of study drug and the end date is missing; (3) both the start date and the 
end date are missing.
Note that a medication can be considered both a prior and concomitant medication if it 
started prior to the first dose of study drug and continued after the first dose of study drug.
The number and percentage of subjects in the FAS population taking medications will be 
summarized by generic drug name based on the World Health Organization (WHO) Drug 
Dictionary for both prior and concomitant medications.
Prior and concomitant medications for hypertension will be summarized separately. 
8.0
Efficacy Analyses
Efficacy will not be evaluated in this study. 
9.0
Safety Analyses
9.1.1
Primary Safety Endpoint
The primary endpoint is the change in 24-hour average SBP from Baseline to EOT.
9.1.2
Handling of Missing Data for the Primary Safety Endpoint
The ABPM data will be collected for 24 hours both at Baseline and EOT.  The ABPM 
data will be considered valid if at least 50% measurements are recorded during the 
24-hour period, daytime period (09:00 – 21:00), and nighttime period (01:00 – 06:00), 
i.e., at least 24 measurements of SBP during the 24-hour period, at least 12 SBP 
 


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measurements between 9:00 to 21:00, and at least 5 measurements between 1:00 and 6:00.  
If the above criteria are not met, the ABPM collection will not be considered as valid. 
For the primary analysis of the primary safety endpoint, subjects in the per protocol 
population will have both valid Baseline ABPM collection as well as valid EOT ABPM 
collection.  For the primary analysis, average 24-hour SBP will be used and no missing 
data imputation will be performed for the missing ABPM measurements within a valid 
ABPM collection. 
Sensitivity analyses 1 and 2 using all individual ABPM measurements using multiple 
imputation will be performed on subjects in the FAS population who are at least 85% 
compliant to the study drug and in the per protocol population, respectively.  Missing 
ABPM measurements within the 24-hour duration at both Baseline and EOT will be 
imputed with multiple imputation.  Missing data mechanism of Missing at Random 
(MAR) is assumed in these analyses.
Sensitivity analysis 3 will be performed on subjects in the FAS population who are at 
least 85% compliant to the study drug.  A mixed model with repeated measures analysis 
using average 24-hour SBP (including both valid EOT and Baseline collections) as the 
outcome variable will be performed. In this analysis, no missing data imputation will be 
performed for the missing ABPM measurements within a valid ABPM collection. 
A supportive analysis examining effect of day of the week will be performed on subjects 
in the per protocol population.  Average 24-hour SBP will be used and no missing data 
imputation will be performed for the missing ABPM measurements within a valid ABPM 
collection.
9.1.3
Primary Safety Analysis
The hypothesis for the primary safety analysis is,
H0:  Change in 24-hour average SBP from Baseline to EOT ≥3 mmHg
 


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Vs.
H1:  Change in 24-hour average SBP from Baseline to EOT < 3 mmHg 
The primary endpoint of change from Baseline to EOT in average 24-hour SBP will be 
evaluated using a linear regression model with change in average 24-hour SBP from 
Baseline to EOT as the dependent variable, centralized baseline average 24-hour SBP, 
ongoing medical history of hypertension, and pooled study center as covariates in the per 
protocol population.
Denote: 
y = change from Baseline to EOT in average 24-hour SBP
x = average 24-hour SBP at Baseline
µx = mean of the average 24-hour SBP at Baseline
C = pooled study center indicator, c = 1, 2, ..., m
µc = coefficient of pooled study center indicator for pooled study center c
H = stratum of ongoing medical history of hypertension indicator, h = Y, N
µh = coefficient of ongoing medical history of hypertension indicator for stratum h
N = total sample size
Nc = sample size for center c
Nh = sample size for stratum h
α = intercept
β = coefficient of the centralized Baseline average 24-hour SBP
ε = error term
 


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The model could be represented as,
 =  : +  ;(< − =>) + ?
=@
A
@B
 C(5 = D) + ?
=E
!
EB
 C(F = ℎ) +  H
The primary endpoint will be evaluated by least squares estimate and 1-sided 97.5% 
confidence interval (CI) of mean change in the average 24-hour SBP from Baseline to 
EOT (i.e., α + ∑
(J@/J)=@ + ∑
(JE/J)=E
!
EB
A
@B
 ).  If the upper confidence limit of the 
1-sided CI is less than 3 mmHg, this will establish that the baseline average 24-hour SBP 
at EOT is not greater than Baseline with a non-inferiority margin of 3 mmHg. 
Pooled Study Center
To define pooled study centers, the study sites will first be pooled by geographic 
locations.  Table 1 displays the states that are included in the four regions of the United 
States according to the Unites States Census Bureau.1
 


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Table 1.
Regions of the United States
Region 1:
Northeast
Region 2:
Midwest
Region 3:
South
Region 4:
West
Connecticut
Maine
Massachusetts
New Hampshire
Rhode Island
Vermont
New Jersey
New York
Pennsylvania
Indiana
Illinois
Michigan
Ohio
Wisconsin
Iowa
Kansas
Minnesota
Missouri
Nebraska
North Dakota
South Dakota
Delaware
District of Columbia
Florida
Georgia
Maryland
North Carolina
South Carolina
Virginia
West Virginia
Alabama
Kentucky
Mississippi
Tennessee
Arkansas
Louisiana
Oklahama
Texas
Arizona
Colorado
Idaho
New Mexico
Montana
Utah
Nevada
Wyoming
Alaska
California
Hawaii
Oregon
Washington
If a pooled geographic region has more than 25% of the study subjects, then the sites in 
this pooled study center will be randomly separated into two pooled centers in that region.
9.1.3.1
Sensitivity Analyses of the Primary Safety Endpoint
Sensitivity Analysis 1
This sensitivity analysis will use all ABPM observations on subjects in FAS population 
who are at least 85% compliant to study drug. 
1.
Missing ABPM measurements (timepoints 1, 2, 3, ..., 47, 48) at both Baseline and 
EOT will be imputed by multiple imputation in the following 3 steps. Multiple 
Imputation:  (a) 30 "complete" datasets of ABPM measurements (48 timepoints) 
at Baseline will be generated via MCMC IMPUTE = FULL option using SAS 
PROC MI.2  The strata of ongoing medical history of hypertension and pooled 
 


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study center will be included in the imputation model as covariates.  Random seed 
12345 will be used; (b) For each subject, Baseline ABPM measurements will be 
calculated by taking the average over 30 "complete" datasets obtained in (a); (c) 30
"complete" datasets of ABPM measurements (48 timepoints) at EOT will be 
generated via MCMC IMPUTE = FULL option using PROC MI2 in SAS.  The 
imputation model will include Baseline ABPM measurements obtained in (b), 
ongoing medical history of hypertension, and pooled study center as covariates.  
Random seed 34567 will be used.
2.
Analysis:  each of the 30 imputed datasets will be analyzed separately using the 
same linear regression model as in the primary safety analysis.  
3.
Pooling:  estimates from step 2 will be combined into one overall pooled estimate 
using PROC MIANALYZE3 in SAS. 
Sensitivity Analysis 2
This sensitivity analysis will repeat the analysis using multiple imputation as described in 
Sensitivity Analysis 1 in the per protocol population. 
Sensitivity Analysis 3
This sensitivity analysis will be performed on subjects in FAS population who are at least 
85% compliant to study drug. 
A repeated measures analysis model will be used with the 24-hr average SBP (including 
both valid EOT and Baseline collections) as outcome variable, fixed effects of visit (EOT, 
Baseline), fixed covariates of strata of ongoing medical history of hypertension and 
pooled study center, and the interaction effects of visit*strata and visit*center. The 
REPEATED statement will be used for visit in PROC MIXED. An unstructured 
covariance structure will be used.  If the model fails to converge, a simplified covariance 
structure will be explored.
 


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9.1.3.2
Supportive Analyses of the Primary Safety Endpoint
1.
Analysis examining effect of collection day of the week
An analysis will be conducted on the per protocol population to assess the effect of 
conducting the ABPM collection on weekdays vs. on weekends.  If the ABPM 
collection started on Saturdays or Sundays, it is considered as a weekend 
collection, otherwise, it is considered as a weekday collection. 
A repeated measures analysis model will be used with the 24-hr average SBP 
(including both valid EOT and Baseline collections) as outcome variable, fixed 
effects of visit (EOT, Baseline), day effect (Weekend, Weekday), the interaction 
effect (visit * day effect), and fixed covariates of strata of ongoing medical history 
of hypertension and pooled study center.  Test for the interaction effect will be 
conducted to see if the day of collection has any effect on the change from Baseline 
to EOT in ABPM data.
2.
Association between Data Missingness and Baseline Variables.
A stepwise logistic regression analysis will be conducted in the FAS to assess the 
association between the data missingness and key baseline clinical and
demographic variables.  The dependent variable will be whether the subject had 
valid ABPM data of SBP or not at EOT.  Continuous independent variables will 
include baseline age, BMI, testosterone value, PSA, hematocrit, creatinine, 
hemoglobin A1c, average 24-hour SBP, and average 24-hour DBP.  Categorical 
independent variables will include ethnicity, race, tobacco use, alcohol use, 
ongoing medical history of hypertension, anti-hypertensive medication at Baseline, 
and pooled study center.  Additional variables may be added if deemed clinically 
meaningful.
 


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9.2
Other Safety Endpoints and Analyses
9.2.1
Handling of Missing Data for Other Safety Endpoints
For the summary of other safety endpoints in Section 9.2.2, the average SBP, DBP, MAP, 
PP, and HR will be calculated separately for the 24-hour period, daytime, nighttime, and 
hourly using available data.  The analyses will be performed on the per protocol 
population, except the BP outlier analysis.  No missing data imputation will be performed 
for missing measurements within an ABPM collection. 
9.2.2
Other Safety Endpoints
The continuous endpoints, for example, change from Baseline to EOT in average daytime, 
nighttime, 24-hour period, and measurement at Tmax for DBP, SBP, MAP, PP and HR, 
will be summarized by mean, median, standard deviation, minimum and maximum.
The same linear regression model as in the primary analysis of the primary safety 
endpoint will be performed on the change from Baseline to EOT in average daytime 
SBP/DBP/MAP, nighttime SBP/DBP/MAP, and 24-hour DBP/MAP.  The linear 
regression model will be evaluated with change from Baseline to EOT in the 
corresponding variable as the dependent variable, and corresponding centralized baseline 
value, strata of ongoing medical history of hypertension, and pooled study center as 
covariates in the per protocol population.
Change from Baseline to EOT for hourly average of MAP, SBP, DBP, PP and HR will 
also be summarized by mean, median, standard deviation, minimum and maximum by 
both nominal clock time and by time after dose.
The categorical endpoints (e.g., subjects with new concomitant anti-hypertensive 
medications and subjects with dose increase in anti-hypertensive medication during the 
treatment period) will be summarized with n and percentage.
Subjects meeting the following BP thresholds separately by 24-hour average and by 
hourly average by 24-hour recordings will also be summarized categorically.
 


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●
≥ 160 mmHg SBP at EOT
●
≥ 100 mmHg DBP at EOT
●
≤ 90 mmHg SBP at EOT
●
≤ 60 mmHg DBP at EOT
●
≥ 20 mmHg increase from Baseline to EOT in SBP
●
≥ 15 mmHg increase from Baseline to EOT in DBP
Listings of subjects with the BP categories as above will also be provided.  The BP outlier 
analysis as described above will be performed on the Safety analysis set.
The following additional analysis will be performed:
●
Graphical display of hourly ABPM averages by time after dose that include 
standard deviation bars for both SBP and DBP at the Baseline and EOT Visits.
●
Cumulative distribution curves of 24-hour average SBP and DBP at the 
Baseline and EOT Visits.
●
Forest plots of daytime, nighttime, and 24-hour average change from Baseline 
to EOT with 95% CI displays for SBP and DBP.
Summary of frequency of data completeness of ABPM measurement data of SBP (0,1 or 
2) both at Baseline and EOT will be provided by hour over the 24-hour time frame.
9.3
Safety Subgroup Analyses
All the analyses for the primary (except supplementary and sensitivity analyses) and other 
safety endpoints will also be provided by the following subgroups:
●
Subjects without an ongoing medical history of hypertension and without any 
antihypertensive medication(s) at Baseline;
●
Subjects with an ongoing medical history of hypertension with any 
antihypertensive medication(s) at Baseline;
●
Subjects with an ongoing medical history of hypertension without any 
antihypertensive medication(s) at Baseline.
 


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The primary safety analysis will be performed at each subgroup level for the following 
subgroup variables:
●
Race; 
●
Ongoing medical history of hypertension;
●
Diabetes status. 
10.0
Additional Safety Analyses
10.1
General Considerations
Additional safety data including adverse events, clinical laboratory data, and vital signs 
will be summarized for the Safety Analysis Set. 
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
Treatment-emergent Adverse Event (TEAE)
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose 
of study drug.  AEs starting more than 30 days following discontinuation of study drug 
will not be included in summaries related to treatment-emergent AEs.  Events where the 
onset date is the same as the study drug start date are assumed to be treatment-emergent.  
 


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10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent SAE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent AE of hypertension
●
All deaths
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment emergent AESI, AEs leading to study drug discontinuation and SAEs will be 
summarized in descending order of overall frequency by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, as well as by system organ class (SOC) 
and MedDRA preferred term (PT).  The SOCs will be presented in alphabetical order, and 
the PTs will be presented in alphabetical order within each SOC.  Treatment-emergent 
SAEs leading to study drug discontinuation will also be summarized by SOC and PT. 
Treatment emergent AESI and SAEs will also be summarized by maximum relationship 
to study drug as assessed by the investigator (e.g., reasonable possibility or no reasonable 
possibility) and SOC and PT; by maximum severity and SOC and PT; and by subject 
number and SOC and PT.  Specific adverse events will be counted once for each subject 
for calculating percentages, unless stated otherwise.  In addition, if the same adverse event 
occurs multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.  The following listings of AEs will be prepared:
●
Listing of treatment-emergent serious adverse events.
●
Listing of treatment-emergent AESI. 
●
Listing of treatment-emergent adverse events leading to discontinuation of 
study drug.
 


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●
Listing of treatment-emergent serious adverse events leading to 
discontinuation of study drug.
●
Listing of all deaths. 
10.2.4
Adverse Events of Special Interest
Treatment-emergent adverse events of special interest will be summarized as described in 
Section 10.2.3 and will be based on standardized MedDRA queries (SMQ).  Adverse 
events of special interest in this study are:  
●
Hypertension
Detailed information about the search criteria are provided in Appendix B.
10.3
Analysis of Laboratory Data
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests listed in Table 2 will be summarized. 
 


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Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Laboratory Tests
Hematocrit
Hemoglobin
Red blood cell count
White blood cell count
Platelet count (estimate not 
acceptable)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Gamma-glutamyl transferase
Sodium
Potassium
Calcium
Cholesterol
Low-density lipoprotein 
cholesterol
High-density lipoprotein 
cholesterol
Glucose
Triglycerides
Prostate specific antigen
Sex Steroids
Testosterone
Each laboratory variable listed above will be summarized for all time points (starting with 
Baseline) with the number of non-missing observations, mean and standard deviation, 
median, minimum and maximum.  Mean change from baseline to each applicable post-
baseline visit will be summarized for laboratory variables listed above, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
deviation, and 95% confidence interval will be presented.
Changes in laboratory parameters will be tabulated using shift tables by categorization of 
low, normal, or high based on the normal ranges of the laboratory used for each sample.  
A shift table from baseline to minimum and maximum value (based on normal range), 
will be created.  A similar shift table will be provided to summarize shifts from baseline to 
the final post-baseline value.
 


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10.4
Analysis of Vital Signs
Vital sign variables include, but are not limited to, SBP and DBP by office measurement, 
HR, respiratory rate (RR), and oral body temperature.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  The change from baseline mean, standard deviation, and 
95% confidence interval will be presented. 
11.0
Interim Analyses
With a sample size of 171 subjects in the per protocol population, the study is powered at 
90% if the SD of the change from baseline in average 24-Hour SBP is 10 mmHg.  
In order to ensure the assumption of SD holds for the study, a review and estimate of the 
SD of the change from Baseline to EOT in average SBP from 24-hour recording will be 
conducted in a blinded fashion when approximately 70% of the planned subjects in the 
per protocol population (i.e., 120 subjects) have completed the EOT visit.  The objective 
of analysis is to re-estimate sample size if needed.  A study database snapshot will be 
performed for this analysis.  The sample size will be re-estimated with updated 
assumption of SD if necessary.  The blinded sample size re-estimation (BSSR) analysis 
will be performed by an AbbVie statistician external to the study team who has access to 
unmasked Week 16 ABPM data.
Since the study team is masked to the ABPM data during the study and only SD is used in 
the sample size re-estimation, no multiplicity adjustment is needed for the BSSR.
Detailed Methodology for BSSR
The initial sample size J  is determined by 
 


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J  =
[ MN O(1 −:) +  MN O(1 −;)]!
(= −6)!
QRS
!
Where T(γ) is the γ-quantile of the t-distribution with degree of freedom n. : is the 
one-sided type I error, 1 −; is the power,  6 is the non-inferiority margin, = is assumed 
true change in average 24-hour SBP from Baseline to EOT, and QRS
! is the variance 
estimate of the change from baseline to EOT in average 24-hour SBP.  When : = 0.025, 
1 − ; = 0.9, = = 0.5, 6 = 3, SD of change in average 24-hour SBP from Baseline to 
EOT = 10 ( QRS
! = 10! = 100 ), then J  = 171.
Interim BSSR will be conducted when change from baseline to EOT systolic ABP data 
for the first  (e.g.,  = 120) subjects are available. Variance of change from baseline 
to EOT in systolic ABP will be estimated based on   subjects with the formula below.
QRYZ
! = 
1
(  −1) ?([ −̅)!
T]
[B
where [ = change from baseline to EOT in average 24-hour SBP for subject i, ̅ is the 
mean for all [, i = 1, ....  
Then the estimated sample size will be calculated as
J  
^ =
[ M  
^O(1 −:) +  M  
^O(1 −;)]!
(= − 6)!
QRYZ
!
with : = 0.025, 1 − ; = 0.85, = = 0.5, 6 = 3.
In order to incorporate a cap of 210 on the sample size (i.e., J@2a = 210), the final 
recalculated sample size will be
JbcS@2d = min(max (J  , Jb), J@2a )
Based on the formula above, the final recalculated sample size will be always greater than 
or equal to the initial sample size of 171 evaluable subjects and less than or equal to the 
limit of 210 evaluable subjects.
 


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The final total sample size will be calculated based on the final recalculated sample size 
and the current actual rate of loss of subjects from per protocol population.
Interim Database Lock
An interim database lock will be performed to unmask the Week 16 ABPM data after the 
last subject completes a valid EOT ABPM 24-hour collection or prematurely discontinues 
from the study.
12.0
Overall Type-I Error Control
This study has one primary endpoint for which non-inferiority is tested, so no adjustment 
for multiple endpoints is needed.  Analytically and through simulations, it has been shown 
that BSSR procedures do not meaningfully affect Type I error rate.4  Therefore, no 
multiplicity adjustment is planned for the BSSR analysis.  
 


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13.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
24 Mar 2020
Original Version
2.0
14 August 2020
Model for primary safety analysis updated per FDA 
suggestion. 
Sensitivity analyses using multiple imputation added per 
FDA suggestion; sensitivity analysis using linear mixed 
model updated per FDA suggestion. 
Pooling strategy for study centers added for clarification.  
Strata of ongoing medical history of hypertension added as 
a factor to models of primary, sensitivity, and supportive 
analyses.
Analyses using linear regression model added for other 
ABPM parameters including daytime SBP/DBP/MAP, 
nighttime SBP/DBP/MAP, and 24-hour DBP/MAP, per 
FDA suggestion.
Additional subgroup analyses added per FDA suggestion. 
 


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14.0
References
1.
Available from:  https://www.census.gov/geographies/reference-
maps/2010/geo/2010-census-regions-and-divisions-of-the-united-states.html.
2.
SAS Institute Inc.  SAS/STAT® 14.1 User's Guide, The MI Procedure.  Cary, NC:  
SAS Institute Inc.  2015.
3.
SAS Institute Inc.  SAS/STAT® 14.1 User's Guide, The MIANALYZE Procedure.  
Cary, NC:  SAS Institute Inc.  2015.
4.
Kieser M, Friede T.  Simple procedures for blinded sample size adjustment that do 
not affect the type I error rate.  Stat Med.  2003;22(23):3571-81.
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
Definition of Adverse Events of Special Interest
The following AESI will be collected during the study: 
Table 4.
Adverse Event of Special Interest
Area of Safety Interest
Search Criteria
Hypertension
Narrow
Hypertension (SMQ 20000147)