Clinical trial NCT03868059
Conditions: Hypogonadism, Male
Sponsor: Lipocine Inc.
Start date: 2018-04-30; Completion date: 2019-02-21
Enrollment: 138 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, multi-center, single arm study evaluating the blood pressure (BP) changes from baseline (Visit 3) to post-treatment (Visit 5) assessed by ambulatory blood pressure monitoring (ABPM) in LPCN 1021 treated adult hypogonadal male subjects.

Detailed description:
This is an open-label, multi-center, single arm study evaluating the blood pressure (BP) changes from baseline (Visit 3) to post-treatment (Visit 5) assessed by ambulatory blood pressure monitoring (ABPM) in LPCN 1021 treated adult hypogonadal male subjects.

The study is comprised of six scheduled visits: Visit 1 and 2 are for screening, Visit 3 is to assess subject's baseline BP and pulse rate (PR) via ABPM. Visit 4 is to enroll subjects, and to provide subjects with study medication for the start of dosing. Visit 5 is to assess subject's post-treatment BP and PR via ABPM. Visit 6 is to perform exit visit procedures.

Arms: arm 1: LPCN 1021 at a 225 mg dose taken twice daily (total daily dose of 450 mg taken as 225 mg in the morning and 225 mg in the evening),
Interventions: intervention 1: LPCN 1021
Intervention descriptions: intervention 1: LPCN 1021 is gelatin capsule product provided as 112.5 mg testosterone undecanoate per capsule.

Protocol documents:
Prot_000.pdf: 
Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 1 of 50 
1.0 
TITLE PAGE 
Clinical Study Protocol: LPCN 1021-18-001 
Ambulatory Blood Pressure Monitoring in Oral Testosterone Undecanoate (TU, LPCN 
1021) Treated Hypogonadal Men. 
 
Investigational Product : Testosterone Undecanoate (TU, LPCN 1021) 
Date of Protocol 
: 19 February 2019 
FDA IND No. 
: 106476 
Development Phase 
: Phase 3 
Indication 
: 
Testosterone replacement therapy in adult, 18 years or older, males for 
conditions associated with a deficiency or absence of endogenous 
testosterone – primary hypogonadism (congenital or acquired) or 
secondary hypogonadism (congenital or acquired) 
Investigator 
: Multi-Center, US 
Sponsor 
: Lipocine Inc. 
675 Arapeen Drive, Suite 202, Salt Lake City, Utah – 84108 
Tel: +1-801-994-7383 
Fax: +1-801-994-7388 
Sponsor /  
Emergency Contact 
: Nachiappan Chidambaram 
675 Arapeen Drive, Suite 202,  
Salt Lake City, Utah – 84108 
Tel: +1-801-994-7383, Ext 2188 
Fax: +1-801-994-7388 
Email: nc@lipocine.com  
Protocol Version 
: 06 
Confidentiality Statement 
This document is a confidential communication of Lipocine Inc. Acceptance of this document signifies 
agreement by the recipient that no unpublished information contained within will be published or 
disclosed to a third party without prior written approval, except that this document may be disclosed to 
an Institutional Review Board under the same conditions of confidentiality. 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 2 of 50 
2.0 
SUMMARY OF CHANGES TO PROTOCOL VERSION 2 
Version 02 of the LPCN 1021-18-001 study protocol was developed to make the following 
changes to the study: 
• Added sexual desire and sexual distress questions to pre-treatment and post-treatment 
phases of the study. 
• Clarified that subjects with chronic conditions requiring medication should be under 
stable treatment, with the same medication and dosage for at least 3 months prior to 
dosing. 
• Added a list of prohibited concomitant medications. 
• Clarified that a digital rectal exam (DRE) is not part of screening procedures. 
• Clarified that adverse events will be collected from the time of informed consent. 
• Adopted the changes from Protocol Clarification Letter 1 
o Screens for Drugs of Abuse and Alcohol: A urine drug and alcohol screen will be 
performed at Visit 2, and not as part of study exit.  
o Screening Procedures (Visits 1 and 2): Vital signs (single measurement of body 
temperature, triplicate measurement of pulse rate, systolic and diastolic blood 
pressure) will be performed at Visit 2 of Screening, not at Visit 1 of Screening.   
o Vital Signs: Vital signs (single measurement of body temperature, triplicate 
measurement of pulse rate, systolic and diastolic blood pressure) will be 
performed at Visit 2, Visit 3, Visit 5 and study exit, not at Visit 1 and Visit 4.  
o Ambulatory Blood Pressure Monitoring: Clarified the ambulatory blood pressure 
monitoring (ABPM) Data Criteria. 
• Minor editorial changes for protocol consistency.  
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 3 of 50 
3.0 
SUMMARY OF CHANGES TO PROTOCOL VERSION 3 
Version 03 of the LPCN 1021-18-001 study protocol was developed to make the following 
changes to the study: 
• 
The study size was increased to 140 subjects. 
• The duration of treatment increased to 4 months, with ABPM measurements at baseline 
and 4 months.  A study drug resupply was added to accommodate the updated study 
duration. 
• Added a blood draw at the end of study for pharmacokinetic sampling. 
• Added exclusion criteria for subjects with screening systolic BP or diastolic BP above 
160 mmHg or 100 mmHg, respectively. 
• Added instruction for sites to ask each subject if he found the baseline ABPM 
measurement tolerable, and if he is willing to complete the ABPM measurements after 4 
months. 
• Duration of confinement at Visit 5 increased from about 33 hours to up to 45 hours. 
• Statistical section added with calculation of ability of the study to identify changes in BP 
that can be ruled out based on the new sample size.  
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 4 of 50 
4.0 
SUMMARY OF CHANGES TO PROTOCOL VERSION 4 
Version 04 of the LPCN 1021-18-001 study protocol was developed to make the following 
changes to the study: 
• The timing of the Visit 5 ambulatory blood pressure monitoring (ABPM) measurement 
was changed from Day 120 to Day 107.  Subjects will be instructed to continue taking 
study medication after Visit 5 to provide the option for subjects to repeat the ABPM 
measurement if there are issues with the Visit 5 ABPM reading. 
• Added Visit 6 to schedule the exit procedures that were formerly performed at Visit 5. 
• Additional tests were added to assess subjects at baseline (prior to Visit 4) and post-
treatment (following Visit 5): 
o Added baseline Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-
PDFF) between Visit 2 and Visit 4, and a post-treatment MRI-PDFF between 
Visit 5 and Visit 6 (study exit). 
o Added additional clinical laboratories tests at baseline Visit 2 and Visit 6. 
• Added instruction for sites to query subjects on specific aspects of their Medical History 
(smoking status and history of hypertension).  
• Minor editorial changes for protocol consistency.  
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 5 of 50 
5.0 
SUMMARY OF CHANGES TO PROTOCOL VERSION 5 
Version 05 of the LPCN 1021-18-001 study protocol was developed to make the following 
changes to the study: 
• Added an interim MRI-PDFF (MRI-2) between Visit 4 and Visit 5, to occur between Day 
56 and Day 76, inclusive. 
• Minor editorial changes for protocol consistency.  
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 6 of 50 
6.0 
SUMMARY OF CHANGES TO PROTOCOL VERSION 6 
Version 06 of the LPCN 1021-18-001 study protocol was developed to make the following 
changes to the study: 
• The primary endpoint of the study was changed from change in average daytime systolic 
blood pressure to change in average 24-hour systolic blood pressure based on the recent 
Food and Drug Administration (FDA) public workshop on ambulatory blood pressure 
monitoring studies (“Evaluating the Pressor Effects of Drugs and Ambulatory Blood 
Pressure Monitoring Studies”).  The public workshop noted that the primary endpoint for 
ABPM studies should be the change in 24-hour average blood pressure. 
• Changed the Development Phase of the study protocol from Phase 1 to Phase 3.  The 
FDA’s Division of Bone, Reproductive and Urologic Products noted that although 
Protocol LPCN 1021-18-001 listed the Development Phase of the study as Phase 1, the 
study design is not consistent with the definition of a Phase 1 study in 
21 CFR Part 312.21.  The Division requested that Lipocine change the designated 
Development Phase to be consistent with the CFR.  Based on the CFR study descriptions, 
the Development Phase for Protocol LPCN 1021-18-001 was changed to Phase 3. 
• Minor editorial changes for protocol consistency.  
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 7 of 50 
7.0 
SYNOPSIS 
Sponsor 
:  Lipocine Inc.   
Protocol Number 
: LPCN 1021-18-001 
Study Drug Name 
:  Testosterone Undecanoate Capsule  
Phase of Development 
:  Phase 3 
Active Ingredient 
:  Testosterone Undecanoate 
 
Protocol Title:  
  
Ambulatory Blood Pressure Monitoring in Oral Testosterone Undecanoate (TU, LPCN 1021) 
Treated Hypogonadal Men. 
Objective:  To assess average daytime (7:00 AM to 11:00 PM), nighttime (11:00 PM to 7:00 
AM), and average 24-hour blood pressure (BP) and pulse rate (PR) by ambulatory blood 
pressure monitoring (ABPM) at baseline (Visit 3) and post-treatment (Visit 5).  
Study Population: Hypogonadal males, aged 18–80 years (inclusive). 
Number of Subjects: 140 
Study Endpoints:  
 
Primary Endpoint:   
The primary endpoint is the change in ABPM-measured average 24-hour systolic BP from 
Visit 3 to Visit 5.   
Other Measures:   
Change in average daytime and nighttime systolic BP assessed by ABPM from Visit 3 to Visit 5.  
Change in average daytime, nighttime, and average 24-hour diastolic BP and PR assessed by 
ABPM from Visit 3 to Visit 5.  
Change in morning systolic and diastolic BP and PR measured in triplicate at the clinic (“Clinic 
BP and PR”) from Visit 3 to Visit 5.  
Change in patient reported sexual desire and sexual distress from baseline to Visit 5. 
Change in Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) from MRI-1 
(baseline) to MRI-2 (interim) and to MRI-3 (post-treatment) in all subjects with baseline, 
interim, and post-treatment MRI-PDFF measurements, those with a MRI-PDFF measurement of 
>5% at baseline, and those with a MRI-PDFF measurements of >10% at baseline. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 8 of 50 
Methodology: 
  
This is an open-label, multicenter, single arm study evaluating the BP changes from baseline 
(Visit 3) to post-treatment (Visit 5) assessed by ABPM in LPCN 1021 treated adult hypogonadal 
male subjects.  
The study is comprised of six scheduled visits: Visit 1 and 2 are for screening, Visit 3 is 
scheduled on Day -4 (±2 day) to assess subject’s baseline BP and PR via ABPM.  Visit 4 is to 
enroll subjects, and to provide subjects with study medication for the start of dosing. Visit 5 is to 
assess subject’s post-treatment BP and PR via ABPM.  Visit 6 is to perform exit procedures. 
There are two confinement visits during the study of approximately 30 hours each (prior to start 
of the dosing and at the end of the study). The study visits are described below. 
Visit 1 & 2: Subjects will undergo a screening period to complete the pre-study examinations 
and to confirm their hypogonadal status. Serum total testosterone (T) below lab normal range 
based on two consecutive blood samples obtained between 6 and 10 AM, on two separate days at 
approximately the same time of day, following an appropriate washout of current androgen 
replacement therapy will be used for screening T levels.  
MRI-1 (Window: any time between Visit 2 and Visit 4): The MRI-1 baseline MRI-PDFF 
measurement will be performed between Visit 2 and Visit 4 in a subset of study subjects 
(approximately 20 or more subjects).  Following confirmation of a subject’s hypogonadal status 
at Visit 2, sites will schedule a MRI-1 at a local MRI facility for the subject.  MRI-1 will be 
performed for all subjects reaching Visit 4 after implementation of Protocol Version 04 until 
target enrollment is reached.  MRI-1 will not be performed for subjects who have already 
progressed past Visit 4 at the time of Version 04 implementation. 
Visit 3: The morning of Visit 3 (Day -4), hypogonadal men meeting the inclusion criteria and 
none of the exclusion criteria will be confined for approximately 26 hours in the clinic for BP 
assessments by ABPM. In the morning, about 2 hours prior to start of the ABPM, sites will 
measure each subject’s vital signs (oral temperature, Clinic BP and PR), with the subject seated 
at rest with back support for at least 10 minutes prior to vital sign measurement. Following this 
measurement, subjects will be started on the 24-hour ABPM portion of the study, starting at 
7:00 AM. During the 24-hour ABPM portion of the study, the site will provide the subject with a 
meal, and then affix a validated, 510(k) cleared, portable ABPM device to the subject’s arm; the 
device will record the subject’s BP and PR over 24-hours.  At the end of confinement period, 
sites will upload the ABPM data from the device to the web upload, and a central reader will 
evaluate if a subject’s ABPM data are valid based on the ABPM Data Criteria provided in 
Section Ambulatory Blood Pressure Monitoring.  Subjects with valid recorded ABPM data will 
proceed to Visit 4; subjects who do not have valid ABPM data may choose to repeat Visit 3 or 
they will not be enrolled into the study.  Further, subjects will be asked if they are able to tolerate 
the ABPM component of the study and if they are willing to complete another 24 hour ABPM 
visit. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 9 of 50 
Visit 4: Subjects with valid ABPM data will return to the clinic for study enrollment.  The 
morning (6 – 10 AM) of Visit 4 (Day 1 of treatment), eligible subjects will return to the clinic, 
where staff will dispense study drug.   
Investigation Drug Product Resupply (Day 60; Window Day 30 to Day 60): subjects will return 
to the clinic for a resupply of study drug.  Sites will record the day of the study drug resupply, 
and batch number of the study drug provided to the subject. 
MRI-2 (Window: any time between Day 56 and Day 76, inclusive): The MRI-2 interim MRI-
PDFF measurement will be performed between Visit 4 and Visit 5 in subjects who had a baseline 
MRI-PDFF measurement (MRI-1).  Sites will schedule MRI-2 at the same local MRI facility that 
performed the subject’s MRI-1. 
Visit 5: The Visit 5 (Day 107, window ± 7 days) schedule involves collecting a blood sample, 
providing meals to subjects, dosing the study medication and ABPM measurements. 
The visit starts on Day 106 with confinement lasting for up to 45 hours. Subjects will enter the 
clinic on Day 106 after taking their study medication in the morning. The site will collect a 
single blood sample from the subjects (at approximately 3 hours post-morning dose on Day 106). 
Following the blood sample collection, subjects will remain at the site until completion of 
ABPM on Day 108 (on site duration: ~45 hours). For subjects who are not able to remain in the 
site for the 45-hour duration, blood sample may be collected at approximately 3 hours after the 
evening dose of Day 106 (on site duration at least 33 hours).  
On the morning of Day 107 prior to start of the ABPM, vital signs (oral temperature, Clinic BP 
and PR) will be measured when seated at rest with back support for 10 minutes. Subjects will 
then be provided with the study medication approximately 30 minutes after a meal.  Following 
the administration of study drug, subjects will be started on the 24-hour ABPM portion of the 
study, starting at 7:00 AM. For the 24-hour ABPM portion of the study, the site will affix a 
validated, 510(k) cleared portable ABPM device to the subject’s arm; the device will record the 
subject’s BP and PR over 24-hours. During the ABPM confinement visit, the subjects will be 
administered study drug every 12 hours with meal (evening of Day 106, morning and evening of 
Day 107, morning of Day 108 prior to exiting site). Following the 24-hour ABPM period, 
subjects will exit the clinic.  All subjects will be instructed to continue taking their study 
medication.  Subjects with valid recorded ABPM data at Visit 5 will proceed to Visit 6 for exit 
procedures after completing the MRI-2 measurement described below; subjects who do not have 
valid ABPM data may choose to repeat Visit 5. 
MRI-3 (Window: any time between Visit 5 and Visit 6): Following the second ABPM 
measurement at Visit 5, subjects who had a baseline MRI-PDFF measurement (MRI-1) will have 
a post-treatment MRI-PDFF (MRI-3).  Sites will schedule MRI-3 at the same local MRI facility 
that performed the subject’s MRI-1. 
Visit 6: The Visit 6 (Day 110, window ± 10 days) schedule involves exit procedures, including 
return of study medication, vital signs measurement (oral temperature, Clinic BP and PR), a 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 10 of 50 
blood sample for clinical laboratory tests, adverse event (AE) reporting, and a review of the 
subject’s Medical History, including specific querying if the subject has a history of diabetes, 
hypertension (never diagnosed, diagnosed but treated, diagnosed but not treated), and the 
subject’s smoking status (never smoked, former smoker, current smoker) to ensure that this 
information is included in the subject’s Medical History.  Sites will collect the blood sample for 
clinical laboratory tests in the morning prior to meals and study drug administration. 
The total duration of the study will be approximately 110 days not including the screening 
period. 
Inclusion Criteria 
A subject will be eligible for study participation if he meets the following criteria. 
 
1. Voluntarily sign and date the study consent form(s) which have been approved by an 
Institutional Review Board (IRB). Written consent must be obtained prior to the 
initiation of any study procedures. 
2. Male between 18 and 80 years of age, inclusive, with documented onset of 
hypogonadism prior to age 65. 
3. Subjects should be diagnosed to be primary (congenital or acquired) or secondary 
hypogonadal (congenital or acquired). 
4. Serum total T below lab normal value (300 ng/dL) based on two consecutive blood 
samples obtained between 6 and 10 AM, on two separate days at approximately the 
same time of day, following an appropriate washout of current androgen replacement 
therapy, if required. 
5. Naïve to androgen replacement or has discontinued current treatment and completed 
adequate washout of prior androgen therapy. Washout must be completed prior to 
collection of baseline serum T samples to determine study eligibility. 
6. Judged to be in good general health as determined by the investigator at screening. 
Exclusion Criteria 
A subject will not be eligible for study participation if he meets any of the following criteria. 
1. History of significant sensitivity or allergy to androgens, or product excipients. 
2. Clinically significant abnormal laboratory value, in the opinion of the investigator, in 
serum chemistry, hematology, or urinalysis including but not limited to: 
a. Hemoglobin < 11.5 g/dL or > 16.5 g/dL 
b. Hematocrit < 35% or > 54% 
c. Serum transaminases > 2.5 times upper limit of normal 
d. Serum bilirubin > 2.0 mg/dL  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 11 of 50 
e. Creatinine > 2.0 mg/dL 
f. PSA > 4 ng/mL  
g. Prolactin > 17.7 ng/mL. 
3. Clinically significant findings in the pre-study examinations including abnormal 
breast examination requiring follow-up. 
4. Subjects with screening systolic BP or diastolic BP above 160 mmHg or 100 mmHg, 
respectively.  
5. Subjects with symptoms of moderate to severe benign prostatic hyperplasia. 
6. History of seizures or convulsions occurring after age 5, including alcohol or drug 
withdrawal seizures. 
7. History of gastric surgery, cholecystectomy, vagotomy, bowel resection or any 
surgical procedure that might interfere with gastrointestinal motility, pH or 
absorption. 
8. History of any clinically significant illness, infection, or surgical procedure within 1 
month prior to study drug administration. 
9. Known tolerability issues with ABPM devices. 
10. History of stroke, myocardial infarction, transient ischemic attack, or acute coronary 
syndrome within the past 5 years. 
11. History of long QT syndrome (or QTcB > 450) or unexplained sudden death 
(including cardiac death) or history of long QT syndrome in a first degree relative 
(parent, sibling, or child). 
12. Subjects who are not on stable dose of current medication (no changes in medication 
in the last 3 months).  
13. History of current or suspected prostate or breast cancer.  
14. History of untreated obstructive sleep apnea or not compliant with sleep apnea 
treatment.  
15. Active alcohol or any drug substance abuse, or history of abuse that will interfere 
with the subject’s ability to participate in the study in the judgement of the 
investigator. 
16. Use of known inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone, 
phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 
days prior to study drug administration and through the end of the study.  A list of 
prohibited medications is provided in Appendix C. 
17. Use of any investigational drug within 5 half-lives of the last dose in the past 6 
months prior to Study Day –2 without principal investigator and/or sponsor approval.   
18. Receipt of any investigational drug by injection within 30 days or 10 half-lives 
(whichever is longer) prior to study drug administration without principal investigator 
and/or sponsor approval. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 12 of 50 
19. Subject who is not willing to use adequate contraception for the duration of the study.  
20. Any contraindications to a MRI scan (i.e. subjects with non-removable ferromagnetic 
implants, pacemakers, aneurysm clips or other foreign bodies), and/or subjects with 
claustrophobic symptoms and/or inability to fit into an MRI scanner. 
21. Inability to understand and provide written informed consent for the study. 
22. Considered by the investigator or the sponsor-designated physician, for any reason, 
that the subject is an unsuitable candidate to receive LPCN 1021 (exact reason should 
be specified by the investigator). 
Investigational Product: Testosterone Undecanoate (TU) Oral Capsules, 112.5 mg TU per 
capsule. 
Doses:  The study involves a 225 mg dose of LPCN 1021. The dose is administered as 225 mg 
TU (two capsules of 112.5 mg) twice daily (BID) approximately 12 hours apart with meal (total 
daily dose of 450 mg taken as 225 mg in the morning and 225 mg in the evening).  
Administration Route: Oral. 
Study Duration:  Study duration will be up to 110 days excluding screening. 
Stopping Criteria:  
All subjects are free to withdraw from the study at any time during the study. In addition, 
subjects may be withdrawn from the study at the discretion of the investigator if they meet any of 
the following criteria: 
• Any event, in the judgment of the investigator, where continuation of the subject in the 
trial could put the subject at health risk. 
• Significant noncompliance with the protocol requirements. 
• Lost to follow-up. 
 
Criteria for Evaluation: 
Changes from baseline in average daytime, average night time and average 24-hour BP as 
measured by ABPM in LPCN 1021 treated subjects. If the upper limit of the two-sided 95% 
confidence interval (CI) for the change from baseline in average 24-hour systolic BP is 
≤ 4.9 mmHg, the change will be considered as not clinically significant. 
Statistical Methods: Statistical analyses will be described in the statistical analysis plan (SAP). 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 13 of 50 
8.0 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
8.1. 
Abbreviations 
AE  
Adverse event 
ALT (SGPT)  
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ABPM 
Ambulatory blood pressure monitoring 
AST (SGOT)  
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BID 
Twice daily 
BMI  
Body mass index 
BP 
Blood pressure 
BPH  
Benign prostate hypertrophy 
BUN  
Blood urea nitrogen 
CI 
Confidence interval 
CRF  
Case Report Form 
CRO 
Clinical research organization 
DEA  
Drug Enforcement Agency 
DHT  
Dihydrotestosterone 
DHTU  
Dihydrotestosterone undecanoate 
E2  
Estradiol 
ECG  
Electrocardiogram 
EDC 
Electronic data capture 
eCRF  
Electronic Case Report Form 
FAS 
Full analysis set 
FSH  
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
HAV-IgM  
Hepatitis A virus immunoglobulin M 
HBsAg  
Hepatitis B surface antigen 
HCT  
Hematocrit 
HCV Ab  
Hepatitis C virus antibody 
HDL 
High-density lipoprotein 
HDPE  
High-density polyethylene 
Hgb  
Hemoglobin 
HIV Ab  
Human immunodeficiency virus antibodies 
ICH  
International Conference on Harmonization 
IEC  
Independent Ethics Committee 
I-PSS  
International Prostate Symptom Score 
IRB  
Institutional Review Board 
LDL 
Low-density lipoprotein 
LH  
Luteinizing hormone 
MedDRA  
Medical Dictionary for Regulatory Activities 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 14 of 50 
PD  
Pharmacodynamic 
PI 
Principal investigator 
PK  
Pharmacokinetic 
PSA  
Prostate-specific antigen 
RBC  
Red blood cell 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SHBG  
Sex hormone binding globulin 
SOC  
System organ class 
WBC  
White blood cell 
T  
Testosterone 
TU 
Testosterone undecanoate 
 
 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 15 of 50 
9.0 
TABLE OF CONTENTS 
1.0 
Title Page ...................................................................................................................1 
2.0 
Summary of Changes to Protocol Version 2 ..........................................................2 
3.0 
Summary of Changes to Protocol Version 3 ..........................................................3 
4.0 
Summary of Changes to Protocol Version 4 ..........................................................4 
5.0 
Summary of Changes to Protocol Version 5 ..........................................................5 
6.0 
Summary of Changes to Protocol Version 6 ..........................................................6 
7.0 
Synopsis......................................................................................................................7 
8.0 
List of Abbreviations and Definition of Terms ....................................................13 
8.1. 
Abbreviations .............................................................................................................................. 13 
9.0 
Table of Contents ....................................................................................................15 
10.0 
Introduction .............................................................................................................17 
11.0 
Study Objectives .....................................................................................................19 
11.1. Primary Objective ....................................................................................................................... 19 
11.2. Study Endpoints .......................................................................................................................... 19 
11.2.1. 
Primary Endpoint .............................................................................................................. 19 
11.2.2. 
Other Measures ................................................................................................................. 19 
12.0 
Investigational Plan ................................................................................................19 
12.1. Overall Study Design .................................................................................................................. 19 
12.2. Selection of Study Population ..................................................................................................... 22 
12.2.1. 
Inclusion Criteria .............................................................................................................. 22 
12.2.2. 
Exclusion Criteria ............................................................................................................. 23 
13.0 
Study Procedures ....................................................................................................24 
13.1. Screening Procedures (Visits 1 and 2) ........................................................................................ 25 
13.2. MRI-1 (Window: between Visit 2 and Visit 4) ........................................................................... 25 
13.3. Baseline ABPM (Visit 3) ............................................................................................................ 25 
13.4. Treatment Phase (Visit 4 through Visit 6) .................................................................................. 26 
13.5. Clinical Procedures ..................................................................................................................... 27 
13.6. Dosage Administration ............................................................................................................... 33 
13.7. Subject Discontinuation .............................................................................................................. 33 
13.7.1. 
Exit Evaluation ................................................................................................................. 33 
13.8. Study Discontinuation ................................................................................................................. 34 
13.9. Drug Product ............................................................................................................................... 34 
13.9.1. 
Packaging and Labeling .................................................................................................... 34 
13.9.2. 
Storage and Disposition of Study Drug ............................................................................ 34 
13.9.3. 
Treatment Compliance and Drug Accountability ............................................................. 34 
13.10. Missed Dose ................................................................................................................................ 35 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
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675 Arapeen Drive, Suite 202 
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Date: 19 February 2019 
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14.0 
Adverse Events ........................................................................................................35 
14.1. Definition of an Adverse Event .................................................................................................. 35 
14.2. Serious Adverse Events .............................................................................................................. 36 
14.3. Adverse Event Severity ............................................................................................................... 36 
14.4. Relationship to Study Drug ......................................................................................................... 37 
14.5. Adverse Event Collection Period ................................................................................................ 37 
14.6. Serious Adverse Event Reporting ............................................................................................... 37 
14.7. Pregnancy Reporting ................................................................................................................... 37 
15.0 
Protocol Deviations .................................................................................................37 
16.0 
Statistical Analysis ..................................................................................................38 
16.1. Determination of Sample Size .................................................................................................... 38 
16.2. Study Populations ....................................................................................................................... 38 
16.3. Statistical Analysis ...................................................................................................................... 38 
16.4. Endpoint Analysis ....................................................................................................................... 39 
16.5. Other Safety Endpoints ............................................................................................................... 39 
17.0 
Ethics ........................................................................................................................40 
17.1. Institutional Review Board (IRB) ............................................................................................... 40 
17.2. Ethical Conduct of the Study ...................................................................................................... 40 
17.3. Subject Information and Consent ................................................................................................ 40 
18.0 
Source Documents and Case Report Form Completion .....................................40 
18.1. Source Documents ...................................................................................................................... 41 
18.2. Case Report Forms ...................................................................................................................... 41 
19.0 
Data Quality Assurance..........................................................................................42 
20.0 
Use of Information ..................................................................................................42 
21.0 
Completion of the Study .........................................................................................43 
Appendix A. 
Schedule of Events: ........................................................................................44 
Appendix B. 
Investigator's Agreement ..............................................................................45 
Appendix C. 
LPCN 1021-Prohibited Concomitant Medications .....................................47 
Appendix D. 
Sexual Desire and Distress Questions ..........................................................50 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
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10.0 
INTRODUCTION 
LPCN 1021 (TU) is an oral capsule developed for use in the proposed indication of replacement 
therapy in males for conditions associated with a deficiency or absence of endogenous T due to 
primary or hypogonadotropic hypogonadism.  
Testosterone is an endogenous androgen that is responsible for normal growth and development 
of the male sex organs and for maintenance of secondary sex characteristics. Testosterone has 
effects that include the growth and maturation of the prostate, seminal vesicles, penis, and 
scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; 
laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat 
distribution. Dihydrotestosterone is another androgen endogenously produced in the body. 
Testosterone and DHT are necessary for the normal development of secondary sex 
characteristics. 
The Endocrine Society defines hypogonadism in men as “a clinical syndrome that results from 
failure of the testis to produce physiological levels of T (androgen deficiency) and a normal 
number of spermatozoa due to disruption of one or more levels of the hypothalamic pituitary-
testicular axis.”1  Male hypogonadism, a clinical syndrome resulting from insufficient secretion 
of T, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as 
Klinefelter's Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of 
the hypothalamus (or pituitary) to produce sufficient gonadotropins (i.e., follicle stimulating 
hormone [FSH] and luteinizing hormone [LH]). The 2010 Endocrine Society guidelines 
recommends replacement therapy for symptomatic men with androgen deficiency to induce and 
maintain secondary sex characteristics and to improve bone mineral density, sexual function, 
sense of well-being, and muscle mass and strength. 
There are various routes of T preparation administration available in the US. Each of the routes 
of delivery and formulations are approved to provide T replacement therapy, although each has 
unique pharmacokinetic properties, limitations, risks, and safety concerns. 
Oral administration of native T generally results in low bioavailability as it is extensively 
metabolized through pre-systemic first-pass metabolism.2  The only oral product currently used 
is a 17--alkyl androgens (methyl testosterone), and this product has been associated with 
serious hepatic adverse effects including life-threatening or fatal complications.  
To date, there is no FDA approved oral T replacement therapy product that is not 17--alkylated. 
Availability of an oral product may confer benefits over existing T replacement products 
                                                 
 
1  Bhasin S, Cunningham G, Hayes F, Matsumoto AM, Snyder PJ, Swerdloff RS, 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 
2  Daggett PR, Wheeler MJ, Nabarro JD.  Oral testosterone, a reappraisal. Horm Res  1978;9(3):121-9. 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 18 of 50 
including absence of transfer risk, absence of the need for transdermal application, absence of 
application site reactions or need for self-injections/doctor’s office visit for injections, and an 
improved safety profile compared with 17--alkylated androgens.3 
LPCN 1021 is an oral capsule product 112.5 mg of TU employing a proprietary formulation 
composed of lipids. LPCN 1021 oral product is designed to enable absorption of TU via the 
intestinal lymphatic pathway. Testosterone undecanoate, is a straight chain fatty acid ester of T, 
which is not alkylated at the 17-alpha position. Testosterone undecanoate is converted to T by 
non-specific esterases that are abundantly present in the body. Currently, TU is available as an 
injectable product in the US (brand name, Aveed®). Oral TU is not available in the US, but has 
been marketed for more than 20 years outside of the US and is available in more than 80 
countries, including Canada (as Andriol), for the treatment of male hypogonadism.4  
The LPCN 1021 clinical development program included eight Phase 1 studies and three Phase 3 
studies.  In previous clinical studies (Study LPCN 1021-05-001 and Study LPCN 1021-09-001), 
various oral TU formulations were evaluated. All formulations increased T concentrations in 
postmenopausal female and hypogonadal male subjects. Two formulations (07 and 10) were 
further evaluated in a single ascending dose study in hypogonadal males (Study S361.1.001). 
Single doses administered ranged from 75 mg to 225 mg, and all doses for both formulations 
achieved T Cmax values at or slightly above the eugonadal range. In a multiple ascending dose 
study (Study M12-778), LPCN 1021 was administered at doses ranging from 75 to 300 mg as a 
single dose on Day 1 and twice daily from Day 2 to 14 or 28 days with a normal-fat diet. 
Effect of food and food-fat content were evaluated on LPCN 1021 product in a clinical study 
LPCN 1021-14-001.  Food affects the rate and extent of TU absorption from the LPCN 1021 
drug product with higher absorption occurring when the product is taken with food compared to 
fasting.  However, systemic exposure of T following administration of LPCN 1021 with varying 
fat contents was evaluated and the data demonstrated that there was no significant influence of 
varying fat content on T levels.  
The Phase 3 Study LPCN 1021-13-001 provides safety, efficacy, and pharmacokinetic for a 
titrated dose of LPCN 1021 as a T replacement therapy in men with primary and secondary 
hypogonadism.  Results indicate that a starting dose of 225 mg BID, with titration to 150 mg or 
300 mg LPCN 1021 based on a pharmacokinetic algorithm, was effective in restoring T levels of 
hypogonadal men to the eugonadal range when taken with a meal. 
The Phase 3 Study LPCN 1021-16-002 provides safety, efficacy, and pharmacokinetic data for a 
fixed dose of LPCN 1021 as a T replacement therapy in men with primary and secondary 
hypogonadism.  Results indicate that a twice daily fixed dose of 225 mg taken with a meal is 
                                                 
 
3  Lowdell CP, Murray-Lyon IM. Reversal of liver damage due to long-term methyltestosterone and safety of non-17-a-alkylated 
androgens.  Brit Med J 1985;291(6496):637. 
4 Andriol product information. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a9758bea-b15b-42e5-
938c-03e3f042b290. Accessed on 08 August 2015 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 19 of 50 
effective in restoring T levels of hypogonadal men to the eugonadal range. 
Further discussion of the preclinical toxicology, metabolism, and pharmacology can be found in 
the Investigator's Brochure. 
11.0 
STUDY OBJECTIVES 
11.1. 
Primary Objective 
To assess average daytime (7:00 AM to 11:00 PM), nighttime (11:00 PM to 7:00 AM), and 
average 24-hour BP and PR by ABPM at baseline (Visit 3) and post-treatment (Visit 5).  
11.2. 
Study Endpoints 
 
11.2.1. 
Primary Endpoint   
The primary endpoint is the change in ABPM-measured average 24-hour  systolic BP from Visit 
3 to Visit 5.     
11.2.2. 
Other Measures  
Change in average daytime and nighttime systolic BP assessed by ABPM from Visit 3 to Visit 5.  
Change in average daytime, nighttime, and average 24-hour diastolic BP and PR assessed by 
ABPM from Visit 3 to Visit 5.  
Change in morning systolic and diastolic BP and PR measured in triplicate at the clinic (“Clinic 
BP and PR”) from Visit 3 to Visit 5.  
Change in patient reported sexual desire and sexual distress from baseline to Visit 5. 
Change in Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) from MRI-1 
(baseline) to MRI-2 (interim) and to MRI-3 (post-treatment) in all subjects with baseline, 
interim, and post-treatment MRI-PDFF measurements, those with a MRI-PDFF measurement of 
>5% at baseline, and those with a MRI-PDFF measurements of >10% at baseline. 
12.0 
INVESTIGATIONAL PLAN 
12.1. 
Overall Study Design 
This is an open-label, multicenter, single arm study evaluating the BP changes from baseline 
(Visit 3) to post-treatment (Visit 5) assessed by ABPM in LPCN 1021 treated adult hypogonadal 
male subjects.  
The study is comprised of six scheduled visits: Visit 1 and 2 are for screening, Visit 3 is 
scheduled on Day -4 (±2 day) to assess subject’s baseline BP and PR via ABPM.  Visit 4 is to 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 20 of 50 
enroll subjects, and to provide subjects with study medication for the start of dosing. Visit 5 is to 
assess subject’s post-treatment BP and PR via ABPM.  Visit 6 is to perform exit visit procedures. 
There are two confinement visits during the study, one prior to start of the dosing and another at 
the end of the study.  The study visits are described below. 
Visit 1 & 2: Subjects will undergo a screening period to complete the pre-study examinations and 
to confirm their hypogonadal status. Serum total testosterone (T) below 300 ng/dL based on two 
consecutive blood samples obtained between 6 and 10 AM, on two separate days at approximately 
the same time of day, following an appropriate washout of current androgen replacement therapy 
will be used for screening T levels.  At the end of Visit 2, sites will provide subjects with a 7-day 
sexual desire question printout, with instructions to answer the question each day for 7 days leading 
up to Visit 3.  Sites will remind subjects to complete the sexual desire question printout when 
scheduling Visit 3 for eligible subjects; ineligible subjects will be informed that they will not be 
able to participate in the study, and they do not need complete the printout. 
MRI-1 (Window: between Visit 2 and Visit 4): The MRI-1 baseline MRI-PDFF measurement 
will be performed between Visit 2 and Visit 4 in a subset of study subjects (approximately 20 or 
more subjects).  Following confirmation of a subject’s hypogonadal status at Visit 2, sites will 
schedule MRI-1 at a local MRI facility for the subject.  A local MRI facility capable of 
performing the MRI-PDFF test will be pre-identified by the Medpace Core Lab within the 
geographic location of the site.  Alternatively, if the site has a preferred MRI facility, the site can 
use their preferred facility following confirmation by the Medpace Core Lab. 
MRI-1 will be performed for all subjects reaching Visit 4 after implementation of Protocol 
Version 04 until target enrollment is reached.  MRI-1 will not be performed for subjects who 
have already progressed past Visit 4 at the time of Version 04 implementation.   
Visit 3: The morning of Visit 3 (Day -4), hypogonadal men meeting the inclusion criteria and none 
of the exclusion criteria will be confined for approximately 26 hours in the clinic for BP 
assessments by ABPM.  Upon clinic entry, sites will collect the 7-day sexual desire question 
printout from subjects and give subjects a sexual distress question printout to answer.  About 2 
hours prior to start of the ABPM, vital sign measurements will be recorded to include oral 
temperature, Clinic BP PR. For proper measurement of Clinic BP and PR, the following 
procedures should be followed: 
• An appropriately sized cuff for the size of the subject’s arm circumference should be 
utilized to minimize inaccurate readings.   
• No smoking or exercise for at least 30 minutes before a blood pressure measurement 
• Subjects should sit in a chair with a back support and the arm supported at heart level 
with feet flat on the floor. The subject should void prior to the measurement. 
• Blood pressure and PR will be measured in triplicate over a minimum of approximately 
10 minutes after the subject has rested in a sitting position for at least 10 minutes.  The 
three measurements will each be recorded in the CRF and a mean value for that visit will 
be calculated. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
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Following this measurement, subjects will be started on the 24-hour ABPM portion of the study, 
starting at 7:00 AM. During the 24-hour ABPM portion of the study, the site will provide the 
subject with a meal, and then affix a validated, 510(k) cleared portable ABPM device to the 
subject’s arm; the device will record the subject’s BP and PR over 24-hours.  Sites will set the 
ABPM device to record BP and PR every 15 minutes during daytime hours (7 AM to 11 PM), 
and every 20 minutes during nighttime hours (11 PM to 7 AM).  At the end of confinement 
period, sites will upload the ABPM data from the device to the web upload, and a central reader 
will evaluate if a subject’s ABPM data are valid based on the ABPM Data Criteria provided in 
Section Ambulatory Blood Pressure Monitoring.  Subjects with valid ABPM data will proceed to 
Visit 4; subjects who do not have valid ABPM data may choose to repeat Visit 3 or they will not 
be enrolled into the study.  Subjects will be asked if they were able to tolerate the ABPM 
component of the study and if they are willing to participate in the ABPM visit at the end of the 
study. 
Visit 4: Subjects with valid ABPM data will return to the clinic for study enrollment.  The 
morning (6 – 10 AM) of Visit 4 (Day 1 of treatment), eligible subjects will return to the clinic, 
where staff will dispense study drug.  At the end of the visit, sites will provide subjects with a 7-
day sexual desire question printout, with instructions to answer the question each day for 7 days 
leading up to Visit 5.  Sites will contact subjects 7 days in advance of Visit 5 to remind subjects 
to complete the sexual desire question printout. 
Investigation Drug Product Resupply (Day 60; Window Day 30 to Day 60): subjects will return 
to the clinic for a resupply of study drug.  Sites will record the day of the study drug resupply, 
and batch number of the study drug provided to the subject. 
MRI-2 (Window: any time between Day 56 to Day 76, inclusive): The MRI-2 interim MRI-
PDFF measurement will be performed between Visit 4 and Visit 5 in subjects who had a baseline 
MRI-PDFF measurement (MRI-1).  Sites will schedule MRI-2 at the same local MRI facility that 
performed the subject’s MRI-1. 
The Visit 5 (Day 107, window ± 7 days) schedule involves collecting a blood sample, providing 
meals to subject, dosing the study medication and ABPM measurements. 
The visit starts on Day 106 with confinement lasting for up to 45 hours. Subjects will enter the 
clinic on Day 106 after taking their study medication in the morning. The site will collect a 
single blood sample from the subjects (at approximately 3 hours post-morning dose on Day 106). 
Following the blood sample collection, subjects will remain at the site until completion of 
ABPM on Day 108 (confinement duration of about 45 hours). For subjects who are not able to 
remain in the site for the 45-hour duration, blood sample may be collected at approximately 3 
hours after the evening dose of Day 106 (confinement duration of at least 33 hours).  
Sites will collect the 7-day sexual desire question printout from subjects and give subjects a 
sexual distress question printout to answer. Then, on the morning of Day 107, prior to start of the 
ABPM, vital signs (oral temperature, Clinic BP and PR) will be measured. Subjects will then be 
provided with the study medication approximately 30 minutes after a meal.  Following the 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 22 of 50 
administration of study drug, subjects will be started on the 24-hour ABPM portion of the study, 
starting at 7:00 AM. During the 24-hour ABPM portion of the study, the site will affix a valid, 
510(k) cleared portable ABPM device to the subject’s arm; the device will record the subject’s 
BP and PR over 24-hours.  Sites will set the ABPM device to record BP and PR every 15 
minutes during daytime hours (7 AM to 11 PM), and every 20 minutes during nighttime hours 
(11 PM to 7 AM).  During the ABPM confinement visit, the subjects will be administered study 
drug every 12 hours with a meal (evening of Day 106, morning and evening of Day 107, 
morning of Day 108 prior to exiting site). Following the 24-hour ABPM portion of the study, the 
subjects will exit the clinic. All subjects will be instructed to continue taking their study 
medication.  Subjects with valid recorded ABPM data at Visit 5 will proceed to Visit 6 for exit 
procedures after completing the MRI-2 measurement described below; subjects who do not have 
valid ABPM data may choose to repeat Visit 5. 
MRI-3 (Window: between Visit 5 and Visit 6): Following the second ABPM measurement at 
Visit 5, subjects who had the MRI-1 baseline MRI-PDFF will have a post-treatment MRI-PDFF, 
MRI-3.  Sites will schedule MRI-3 at the same local MRI facility that performed the subject’s 
MRI-1.  
Visit 6: The Visit 6 (Day 110, window ± 10 days) schedule involves exit procedures including 
weight measurement, physical exam, vital signs, return of study medication, a blood sample for 
clinical laboratory tests, review of concomitant medication, AE reporting, and a review of the 
subject’s Medical History, including specific querying if the subject has a history of diabetes, 
hypertension (never diagnosed, diagnosed but treated, diagnosed but not treated), and the 
subject’s smoking status (never smoked, former smoker, current smoker) to ensure that this 
information is included in the subject’s Medical History.  Sites will collect the blood sample for 
clinical laboratory tests in the morning prior to meals; the subject will not take study drug the 
morning of Visit 6.   
The total duration of the study will be approximately 110 days not including the screening 
period. 
12.2. 
Selection of Study Population 
Subjects will undergo screening procedures within approximately 60 days prior to the start of 
treatment. Adult hypogonadal male subjects will be eligible for enrollment in the study based on 
the following inclusion and exclusion criteria. 
12.2.1. 
Inclusion Criteria 
A subject will be eligible for study participation if he meets the following criteria: 
1. Voluntarily sign and date the study consent form(s) which have been approved by an 
Institutional Review Board (IRB). Written consent must be obtained prior to the 
initiation of any study procedures. 
2. Male between 18 and 80 years of age, inclusive, with documented onset of 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 23 of 50 
hypogonadism prior to age 65. 
3. Subjects should be diagnosed to be primary (congenital or acquired) or secondary 
hypogonadal (congenital or acquired). 
4. Serum total T below lab normal range (300 ng/dL) based on two consecutive blood 
samples obtained between 6 and 10 AM, on two separate days at approximately the 
same time of day, following an appropriate washout of current androgen replacement 
therapy, if required. 
5. Naïve to androgen replacement or has discontinued current treatment and completed 
adequate washout of prior androgen therapy. Washout must be completed prior to 
collection of baseline serum T samples to determine study eligibility. 
6. Judged to be in good general health as determined by the investigator at screening. 
12.2.2. 
Exclusion Criteria 
A subject will not be eligible for study participation if he meets any of the following criteria. 
1. History of significant sensitivity or allergy to androgens, or product excipients. 
2. Clinically significant abnormal laboratory value, in the opinion of the investigator, in 
serum chemistry, hematology, or urinalysis including but not limited to: 
a. Hemoglobin < 11.5 g/dL or > 16.5 g/dL 
b. Hematocrit < 35% or > 54% 
c. Serum transaminases > 2.5 times upper limit of normal 
d. Serum bilirubin > 2.0 mg/dL  
e. Creatinine > 2.0 mg/dL 
f. PSA > 4 ng/mL  
g. Prolactin > 17.7 ng/mL. 
3. Clinically significant findings in the pre-study examinations including abnormal 
breast examination requiring follow-up. 
4. Subjects with screening systolic BP or diastolic BP above 160 mmHg or 100 mmHg, 
respectively.  
5. Subjects with symptoms of moderate to severe benign prostatic hyperplasia.  
6. History of seizures or convulsions occurring after age 5, including alcohol or drug 
withdrawal seizures. 
7. History of gastric surgery, cholecystectomy, vagotomy, bowel resection or any 
surgical procedure that might interfere with gastrointestinal motility, pH or 
absorption. 
8. History of any clinically significant illness, infection, or surgical procedure within 1 
month prior to study drug administration. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 24 of 50 
9. Known tolerability issues with ABPM devices. 
10. History of stroke, myocardial infarction, transient ischemic attack, or acute coronary 
syndrome within the past 5 years. 
11. History of long QT syndrome (or QTcB > 450) or unexplained sudden death 
(including cardiac death) or history of long QT syndrome in a first degree relative 
(parent, sibling, or child). 
12. Subjects who are not on stable dose of current medication (no changes in medication 
in the last 3 months).  
13. History of current or suspected prostate or breast cancer.  
14. History of untreated obstructive sleep apnea or not compliant with sleep apnea 
treatment.  
15. Active alcohol or any drug substance abuse, or history of abuse that will interfere 
with the subject’s ability to participate in the study in the judgement of the 
investigator. 
16. Use of known inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone, 
phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 
days prior to study drug administration and through the end of the study.  A list of 
prohibited medications is provided in Appendix C. 
17. Use of any investigational drug within 5 half-lives of the last dose in the past 6 
months prior to Study Day –2 without principal investigator and/or sponsor approval.   
18. Receipt of any investigational drug by injection within 30 days or 10 half-lives 
(whichever is longer) prior to study drug administration without principal investigator 
and/or sponsor approval. 
19. Subject who is not willing to use adequate contraception for the duration of the study.  
20. Any contraindications to a MRI scan (i.e. subjects with non-removable ferromagnetic 
implants, pacemakers, aneurysm clips or other foreign bodies), and/or subjects with 
claustrophobic symptoms and/or inability to fit into an MRI scanner. 
21. Inability to understand and provide written informed consent for the study. 
22. Considered by the investigator or the sponsor-designated physician, for any reason, 
that the subject is an unsuitable candidate to receive LPCN 1021 (exact reason should 
be specified by the investigator). 
13.0 
STUDY PROCEDURES 
The following study procedures will be performed periodically during the study. Please refer to 
the schedule of events for the study schedule (Appendix A). 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
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Date: 19 February 2019 
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13.1. 
Screening Procedures (Visits 1 and 2) 
Screening procedures will be performed within approximately 60 days preceding study drug 
administration. Subjects must provide written informed consent prior to initiation of any 
screening procedures. The consent to perform some general screening procedures may be 
obtained on a consent document other than the Informed Consent Form (ICF) specific to the 
study. The study-specific ICF must be signed and dated by the subject before participation to 
study-specific procedures. 
Screening procedures will be conducted over two scheduled visits: Visit 1 and Visit 2. Visit 1 
screening procedures will include: informed consent, demographic data, medical and medication 
histories, physical examination and the first screening testosterone sample. 
In Visit 2, sites will perform sampling for additional laboratory analysis including a second 
screening testosterone sample, electrocardiogram, a blood sample for clinical laboratory tests, 
and drug and alcohol screen.  At the end of the visit, sites will provide subjects with a 7-day 
sexual desire question printout, with instructions to answer the question each day for 7 days 
leading up to Visit 3 (sites will collect at Visit 3).  Sites will remind subjects to complete the 
sexual desire question printout when scheduling Visit 3 for eligible subjects; ineligible subjects 
will be informed that they will not be able to participate in the study, and they do not need 
complete the printout. 
13.2. 
MRI-1 (Window: between Visit 2 and Visit 4) 
The MRI-1 baseline MRI-PDFF measurement will be performed between Visit 2 and Visit 4 in a 
subset of study subjects (approximately 20 or more subjects).  Following confirmation of a 
subject’s hypogonadal status at Visit 2, sites will schedule MRI-1 at a local MRI facility for the 
subject.  A local MRI facility capable of performing the MRI-PDFF test will be pre-identified by 
the Medpace Core Lab within the geographic location of the site.  Alternatively, if the site has a 
preferred MRI facility, the site can use their preferred facility following confirmation by the 
Medpace Core Lab. 
MRI-1 will be performed for all subjects reaching Visit 4 after implementation of Protocol 
Version 04 until target enrollment is reached.  MRI-1 will not be performed for subjects who 
have already progressed past Visit 4 at the time of Version 04 implementation.   
13.3. 
Baseline ABPM (Visit 3) 
Hypogonadal men meeting the inclusion criteria and none of the exclusion criteria will be return 
to the clinic on the morning of Day -4 (±2) for a confinement visit of approximately 26 hours.  
During this confinement visit, subjects will have their BP measured by ABPM for 24 hours 
starting at 7:00 AM.  Upon clinic entry, sites will collect the 7-day sexual desire question 
printout from subjects and give subjects a sexual distress question printout.  In the morning, prior 
to start of the ABPM, vital signs (oral temperature, Clinic BP and PR) will be measured. 
Following this measurement, subjects will be started on the 24-hour ABPM portion of the study 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 26 of 50 
starting at 7:00 AM. The site will provide the subject with a meal, and then affix a validated, 
510(k) cleared portable ABPM device to the arm of the subject, and the device will record BP 
and PR for 24-hours.  At the end of confinement period, sites will upload the ABPM data from 
the device to the web upload, and a central reader will evaluate if subjects had valid ABPM 
results. For the 24-hour ABPM results to qualify as valid, the data must meet ABPM Data 
Criteria provided in Section Ambulatory Blood Pressure Monitoring. 
Subjects with valid 24-hour ABPM results proceed to study enrollment (Visit 4).  Subjects who 
do not have valid ABPM data based on the ABPM criteria can choose to repeat Visit 3 or they 
will not be enrolled into the study. Subject will be asked by the clinic staff if the subject was able 
to tolerate the ABPM component of the study and if they are able to participate in the ABPM 
visit at the end of the study. 
13.4. 
Treatment Phase (Visit 4 through Visit 6) 
Treatment Phase of the study consists of approximately 107 days starting at Visit 4 and ending at 
Visit 5. 
Visit 4: Sites will enroll subjects with valid 24-hour ABPM data from Visit 3 into the study.  The 
morning of study Visit 4 (Day 1 of treatment), eligible subjects will return to the clinic.  Sites 
will dispense study drug, review the concomitant medications of the subject, review any AEs.  
Sites will instruct subjects to take LPCN 1021 225 mg twice daily, with a meal (approximately 
30 minutes following meal), for 107 days (± 7 days).  Sites will schedule subjects for the 
confinement visit (Visit 5, starting on Day 106).  At the end of the visit, sites will provide 
subjects with a 7-day sexual desire question printout, with instructions to answer the question 
each day for 7 days leading up to Visit 5.  Sites will contact subjects 7 days in advance of Visit 5 
to remind them to answer the question as instructed. 
Investigation Drug Product Resupply (Day 60; Window Day 30 to Day 60): subjects will return 
to the clinic for a resupply of study drug.  Sites will record the day of the study drug resupply, 
and batch number of the study drug provided to the subject. 
MRI-2 (Window: any time between Day 56 to Day 76, inclusive): The MRI-2 interim MRI-
PDFF measurement will be performed between Visit 4 and Visit 5 in subjects who had a baseline 
MRI-PDFF measurement (MRI-1).  Sites will schedule MRI-2 at the same local MRI facility that 
performed the subject’s MRI-1. 
The Visit 5 (Day 107, window ± 7 days) schedule involves collecting a blood sample, providing 
meals to subject, dosing the study medication and ABPM measurements. 
The visit starts on Day 106 with confinement lasting for up to 45 hours. Subjects will enter the 
clinic on Day 106 after taking their study medication in the morning. The site will collect a 
single blood sample from the subjects (at approximately 3 hours post-morning dose on Day 106). 
Following the blood sample collection, subjects will remain at the site until completion of 
ABPM on Day 108 (on site duration: ~45 hours). For subjects who are not able to remain in the 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 27 of 50 
site for the 45-hour duration, blood sample may be collected at approximately 3 hours after the 
evening dose of Day 106 (on site duration at least 33 hours). 
Sites will collect the 7-day sexual desire question printout from the subjects, and the subjects will 
be given a question to assess their sexual distress. On the morning of Day 107, prior to start of 
the ABPM, vital signs (oral temperature, Clinic BP and PR) will be measured. Subjects will then 
be provided with the study medication approximately 30 minutes after a meal.  Following the 
administration of study drug, subjects will be started on the 24-hour ABPM portion of the study 
starting at 7:00 AM. During the 24-hour ABPM portion of the study, the site will affix a valid, 
510(k) cleared portable ABPM device to the subject’s arm; the device will record the subject’s 
BP and PR over 24-hours. During the ABPM confinement visit, the subjects will be administered 
study drug every 12 hours with meal (evening of Day 106, morning and evening of Day 107, 
morning of Day 108 prior to exiting site). At the end of 24-hours, subjects will exit the clinic.  
Clinic staff will return study medication to the subject and instruct the subject to continue taking 
their study medication until Visit 6.  Subjects with valid recorded ABPM data at Visit 5 will 
proceed to Visit 6 for exit procedures after completing the MRI-2 measurement described below; 
subjects who do not have valid ABPM data may choose to repeat Visit 5. 
MRI-3 (Window: between Visit 5 and Visit 6): Following the second ABPM measurement at 
Visit 5, subjects who had the MRI-1 baseline MRI-PDFF will have a post-treatment MRI-PDFF, 
MRI-3.  Sites will schedule a MRI-PDFF measurement at the same local MRI facility that 
performed the baseline MRI-PDFF.   
Visit 6: The Visit 6 (Day 110, window ± 10 days) schedule involves exit procedures including 
weight measurement, physical exam, vital signs, return of study medication, a blood sample for 
clinical laboratory tests, review of concomitant medication, AE reporting, and a review of the 
subject’s Medical History, including specific querying if the subject has a history of diabetes, 
hypertension (never diagnosed, diagnosed but treated, diagnosed but not treated), and the 
subject’s smoking status (never smoked, former smoker, current smoker) to ensure that this 
information is included in the subject’s Medical History. Sites will collect the blood sample for 
clinical laboratory tests in the morning prior to meals; the subject will not take study drug the 
morning of Visit 6. 
13.5. 
Clinical Procedures 
The following sections help define the requirements of medical / clinical information to be 
obtained as a part of the study. 
13.5.1.1. 
Medical and Medication History 
The subject’s medical history (key events) during the past 5 years will be obtained and recorded 
on the Medical History Electronic Case Report Form (eCRF). Any new information / changes 
should be documented during the study. If a clinical event concerns a chronic disorder, which 
means it started in the past and it is still present at the screening visit, it should also be recorded 
on the Medical History eCRF. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 28 of 50 
All subjects should be instructed to use adequate contraception for the duration of the study, 
acceptable methods of birth control include the following methods: abstinence, barrier methods, 
hormonal contraception, intrauterine devices, fallopian tube occlusion devices, and sterilization 
either of the male or female partner.  
Medication use (prescription or over-the-counter, including vitamins and herbal supplements) 
from 3 months prior to study drug administration through the end of the study will be recorded in 
the eCRF.  If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplement or if administration becomes necessary from 3 months prior to study 
drug administration through the end of the study, the name of the medication, dosage information 
including dose, route, frequency, date(s) of administration including start and end dates, and 
reason for use must be recorded.   
Subjects participating in the trial should be naive to androgen replacement or has discontinued 
current therapy and completed an adequate washout. Recommended adequate washout is 
12 weeks following intramuscular androgen injections; 4 weeks following topical or buccal 
androgens; 3 weeks following oral androgens, or, in the judgement of the investigator, the 
subject has had an adequate washout window to be eligible. 
Subjects with a chronic condition requiring medication must: 
• Be under stable treatment, with the same medication and dosage for at least 3 months 
prior to first dosing.  
• Have no expected change to medication planned throughout the study. 
• The subject’s medication should have no interaction with the pharmacokinetics of the 
study drug or the bioanalytical methods. 
Concomitant Medication for Hypertension 
Given that the objective of this study is to assess changes in blood pressure after LPCN  1021 
treatment, sites should document the medical and medication history associated with 
hypertension. Subjects should be queried on medication for hypertension, start date, current 
medication, last change in medication prior to the start of the study. During the study, changes in 
hypertensive medication should be driven only by the requirement due to change in hypertensive 
status. Any such changes should be documented with a reason for change. 
Any addition of medication should be documented including the indication for which the 
medication was added. This will be coded per WhoDrug dictionary.  
13.5.1.2. 
Electrocardiogram 
An electrocardiogram will be performed at the screening to identify, and subsequently exclude, 
subjects with long QT syndrome. Subjects with QTcB > 450 msec will not be enrolled into the 
trial. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 29 of 50 
13.5.1.3. 
Physical Examination 
A physical examination will be performed at screening and exit.  The examination will include at 
minimum an examination of head/eyes/ears/nose/throat. Any changes during the study will be 
documented. Subject's height and weight will be used to calculate BMI.  
13.5.1.4. 
Vital Signs 
Sites will measure oral temperature (single measurement), and Clinic BP and PR on Visit 3, 
Visit 5, and at Visit 6/study exit. Vital signs must be measured after the subject has been sitting at 
rest for at least 10 minutes with a back support, using automated digital blood pressure devices 
(the device used should be current with respect to calibration, the exact make and model of the 
device used to record blood pressure should be documented).  The average of the three BP and PR 
measurements will be used in statistical analyses. 
13.5.1.5. 
Ambulatory Blood Pressure Monitoring 
Sites will measure subject ABPM on Visit 3 and Visit 5.  Sites will affix a validated, 510(k) 
cleared portable ABPM device to the arm of the subject, and the device will record BP and PR.  
Sites will set the ABPM device to record BP and PR every 15 minutes during daytime hours (7 
AM to 11 PM), and every 20 minutes during nighttime hours (11 PM to 7 AM).  At the end of 
24-hours, sites will evaluate if subjects had valid ABPM results. Site staff will be trained in the 
usage of the device. At the end of the 24-hour measurements, sites will upload the data to a 
central web upload tool. A central reader of the data will qualify the data as valid or not. If data 
are not valid at Visit 3 or Visit 5, a repeat measurement may be allowed at the discretion of study 
medical monitor. For the 24-hour ABPM results to qualify as valid, the data must meet the 
following ABPM Data Criteria: 
• Minimum of 1 valid reading per hour, including during sleep.  
• Valid data for at least 22 out of 24 hours in the day.   
13.5.1.6. 
Clinical Laboratory Tests 
13.5.1.6.1. 
Hematology, Chemistries, and Urinalysis 
For all subjects, blood samples will be taken at screening Visit 2 (refer to Table 1 and Appendix 
A) for clinical laboratory tests (hematology, clinical chemistry, and hormones). Sites will collect 
samples for serum chemistry tests in the morning prior to meals.  
Table 1: Listing of Clinical Laboratory Tests for all Subjects at Visit 2 
Hematology 
Clinical Chemistry  
Hormones 
Hematocrit 
Hemoglobin 
 
Creatinine 
Bilirubin 
Serum glutamic-pyruvic transaminase (SGPT/ALT) 
Serum glutamic-oxaloacetic transaminase (SGOT/AST) 
Prolactin 
Prostate specific 
antigen 
For subjects reaching Visit 2 after Protocol Version 04, additional clinical laboratory tests (refer 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 30 of 50 
to Table 2) will be performed at Visit 2.  The additional tests will be performed for all subjects 
reaching Visit 2 following the implementation of Protocol Version 04 until target enrollment is 
reached.  
 
Table 2: Listing of Additional Clinical Laboratory Tests for Subjects for Reaching Visit 2 after 
Protocol Version 04 
Clinical Chemistry 
Hematology/Coagulation 
Albumin  
Alkaline phosphatase (ALP) 
Blood urea nitrogen (BUN) 
Gamma-glutamyltransferase (GGT)  
Cholesterol  
Triglycerides  
High density lipoprotein (HDL) cholesterol  
Low density lipoprotein (LDL) cholesterol  
Free fatty acid 
Prothrombin 
time 
(PT) 
and 
international 
normalized ratio (INR) 
Hemoglobin A1C (HBA1C) 
For all subjects, blood samples will be taken at screening Visit 6 (refer to Table 3 and Appendix 
A) for clinical laboratory tests. Sites will collect samples for serum chemistry tests in the 
morning prior to meals.   
Table 3: Listing of Clinical Laboratory Tests for Subjects at Visit 6 
Clinical Chemistry 
Hematology/Coagulation 
Creatinine 
Bilirubin 
Serum glutamic-pyruvic transaminase 
(SGPT/ALT) 
Serum 
glutamic-oxaloacetic 
transaminase 
(SGOT/AST) 
Albumin  
Alkaline phosphatase (ALP) 
Blood urea nitrogen (BUN) 
Gamma-glutamyltransferase (GGT)  
Cholesterol  
Triglycerides  
High density lipoprotein (HDL) cholesterol  
Low density lipoprotein (LDL) cholesterol  
Free fatty acid 
 
Prothrombin 
time 
(PT) 
and 
international 
normalized ratio (INR) 
Hemoglobin A1C (HBA1C) 
 
Clinical laboratory testing must be performed by appropriately credentialed laboratories. 
Certified central laboratories will process and provide results for the tests conducted at screening 
and throughout the study. The certified study laboratories for sample shipment and contact 
information will be provided in lab manual. 
13.5.1.6.2. 
Residual Serum Sample Testing Performed by Medpace 
For subjects who progressed past Visit 2 prior to Protocol Version 04, the following additional 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 31 of 50 
tests will be performed by Medpace using residual serum sample (no additional blood sampling 
is required by study sites). 
 
Table 4: Listing of Clinical Laboratory Tests Performed on Residual Serum Sample 
Clinical Chemistry 
Albumin  
Alkaline phosphatase (ALP) 
Blood urea nitrogen (BUN) 
Gamma-glutamyltransferase (GGT)  
Cholesterol  
Triglycerides  
High density lipoprotein (HDL) cholesterol  
Low density lipoprotein (LDL) cholesterol  
13.5.1.6.3. 
Screens for Drugs of Abuse and Alcohol 
Sites will collect urine samples to screen for drugs of abuse and alcohol at screening. The panel 
for drugs of abuse will minimally include cannabinoids, opiates, barbiturates, amphetamines, 
cocaine, and benzodiazepines. Analyses will be performed by a certified laboratory. 
13.5.1.6.4. 
Prostate-Specific Antigen (PSA) 
Sites will collect samples for PSA at screening.  A digital rectal exam (DRE) is not part of 
screening procedures.  If the investigator conducts a DRE outside of protocol requirement, the 
PSA samples should be collected prior to the DRE. 
13.5.1.6.5. 
Serum Testosterone  
At screening, serum total T must be below lab normal range based on two consecutive blood 
samples obtained between 6 and 10 AM, on two separate days at approximately the same time of 
day, following washout of any prior androgen replacement therapy. Refer to the Schedule of 
Events (Appendix A) for sample collection days and times. 
13.5.1.6.6. 
Blood Sample Collection – Serum TU 
On Day 106 (approximately 3 hours post-morning dose on Day 106), when subjects enter the 
clinic, a single blood sample of 8 mL blood will be collected in a serum separator tube (gold top 
tube), at approximately 3 hours post-morning dose on Day 106.  For subjects who are not able to 
remain in the site for the 45-hour duration, blood sample may be collected at approximately 3 
hours after the evening dose. 
The collected sample will be processed for serum separation and stored at -20C. The samples 
will be shipped in dry ice to PPD bioanalytical laboratory. The serum samples will be analyzed 
for TU levels. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 32 of 50 
13.5.1.7. 
Confinement 
There are two confinement visits for each subject.  During Visit 3 and Visit 5, subjects will 
return to the clinic for 24-hour ABPM.  During the confinement, sites will provide meals and 
snacks to subjects; during confinement visits. Also, the study drug administration during Visit 5 
confinement will be carried out by the site. Strenuous activity during confinement will not be 
permitted.  
13.5.1.8. 
Meals and Dietary Requirements 
Throughout the study, subjects will be advised to maintain a diet that provides a total daily 
caloric content of approximately 2400 calories (total per day).  
During the confinement periods, the subjects will be provided with meals.  Breakfast, lunch, a 
snack, and dinner will be provided during confinement.  Subjects with special meal requirements 
may be accommodated accordingly at the clinic. Study medication in the morning and evening 
will be administered 30 minutes after the meal. Alcohol is prohibited during the confinement, 
and caffeine intake should be limited. Administration of water with meals is permitted.  
13.5.1.9. 
Patient Reported Sexual Desire and Distress 
Subjects will be asked two questions to assess the patient reported outcomes before and after 
treatment: 
(A) Sexual desire: Seven-day questionnaire  
(B) Sexual distress: One day questionnaire  
For the sexual desire question, sites will give subjects a printout of a sexual desire question 
(provided in Appendix D) repeated on 7 pages at Visit 2, with instructions to answer the question 
each day for 7 days.  Sites will remind subjects to complete the sexual desire question printout 
when scheduling Visit 3 for eligible subjects; ineligible subjects will be informed that they will 
not be able to participate in the study, and they do not need complete the printout.  Sites will 
collect the printout from the subjects upon entry for Visit 3.   
For the sexual distress question, sites will provide subjects with a printout of a question to assess 
sexual distress (provided in Appendix D) upon clinic entry at Visit 3.   
Subjects will be asked the same two questions at the end of treatment.  For the sexual desire 
question, sites will give subjects a printout of the sexual desire question (provided in Appendix 
D) repeated on 7 pages at Visit 4, with instructions to answer the question each day for 7 days 
leading up to Visit 5.  Sites will contact subject’s 7 days in advance of Visit 5 to remind them to 
answer the sexual desire question.  Sites will collect the printout from the subjects upon entry for 
Visit 5.  For the sexual distress question, sites will provide subjects with a printout of a question 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 33 of 50 
to assess sexual distress (provided in Appendix D) upon clinic entry at Visit 5. 
13.5.1.10. 
Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF)  
A MRI-PDFF measurement will be performed at baseline between Visit 2 and Visit 4 (MRI-1), 
at an interim point between Day 56 and Day 76, inclusive, (MRI-2) and post-treatment between 
Visit 5 and Visit 6 (MRI-3). MRI-1 will be performed for all subjects reaching Visit 4 after 
implementation of Protocol Version 04 until target enrollment is reached (approximately 20 or 
more subjects).  MRI-1 will not be performed for subjects who have already progressed past 
Visit 4 at the time of Version 04 implementation.  The MRI-2 and MRI-3 measurements will be 
performed for all subjects who complete MRI-1. 
13.6. 
DOSAGE ADMINISTRATION  
All subjects will receive 225 mg BID (two capsules of 112.5 mg) taken twice daily (total daily 
dose of 450 mg taken as 225 mg in the morning and 225 mg in the evening), approximately 12 
hours apart, approximately 30 minutes after morning and evening meals, with water.    
13.7. 
Subject Discontinuation  
All the subjects are free to withdraw from the study at any time; additionally, subjects may be 
withdrawn from the study at the discretion of the investigator if they meet any of the following 
criteria: 
• Any event, in the judgment of the investigator, where continuation of the subject in the 
trial could put the subject at health risk. 
• Significant noncompliance with the protocol requirements. 
• Lost to follow-up. 
Subjects who withdraw from the study will not be replaced. In the event that a subject withdraws 
or is discontinued from the study, the reason(s) for the discontinuation from the study will be 
recorded and the study exit evaluation should be performed. For consent withdrawn subjects, 
sites should query the specific reason for withdrawal and document it. For subjects who are lost 
to follow-up sites should make at least three documented attempts to contact the subject prior to 
terminating from study.  If a subject is discontinued from the study with an ongoing AE or an 
unresolved laboratory result that is significantly outside of the reference range, the investigator 
will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result or 
AE is achieved. 
13.7.1. 
Exit Evaluation 
Exit evaluation occurs during Visit 6 for subjects who complete the study. For subjects who 
withdraw from the study or discontinued early exit evaluation should be conducted.   


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 34 of 50 
13.8. 
Study Discontinuation 
The sponsor may terminate this study prematurely, either 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 sponsor in advance of the intended termination.  Advance notice 
is not required by either party if the study is stopped due to safety concerns. If Lipocine 
terminates the study for safety reasons, Lipocine will immediately notify the investigators. 
13.9. 
Drug Product 
LPCN 1021 is gelatin capsule product that will be provided as 112.5 mg TU per capsule.  
13.9.1. 
Packaging and Labeling 
LPCN 1021 will be provided in high-density polyethylene (HDPE) bottles containing 
120 capsules in each bottle. Each HDPE bottle will be labeled with the information required by 
regulatory authorities. Adequate supplies of study drug will be provided to the study center.  
13.9.2. 
Storage and Disposition of Study Drug 
The study drug must be stored at room temperature 15°C to 25°C (59°F to 77°F). LPCN 1021 
capsules are listed as Drug Enforcement Administration (DEA) Schedule CIII drugs in the 
United States and must be handled according to applicable federal and local regulations. The 
study drugs are for investigational use only and are to be used only within the context of this 
study. The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or returned to 
sponsor. 
13.9.3. 
Treatment Compliance and Drug Accountability 
The investigator or his/her designated and qualified representatives will dispense study drug only 
to subjects enrolled in the study in accordance with the protocol. The study drug must not be 
used for reasons other than that described in the protocol. During the confinement periods for 
LPCN 1021-treated subjects, study-site personnel will ensure ingestion of each dose. Subjects 
must return all unused medication and empty bottles to the study center. The number of capsules 
returned will be counted and entered into the eCRF.  
Treatment compliance is calculated as follows:  
% compliance = [(number of capsules dispensed – number of capsules returned)/ number of 
capsules expected to be used] * 100 
The investigator must agree to comply with all applicable DEA laws and regulations regarding 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 35 of 50 
controlled substances as outlined in 21 CFR 1300-1321. 
A current (running) and accurate inventory of study drug will be kept by the investigator and will 
include shipping invoices and the date on which study drug is dispensed to the subject. An 
overall accountability of the study drug will be performed and verified by sponsor monitor 
throughout the study and at the study site closeout visit. Upon completion or premature 
discontinuation of the study, all original containers (empty or containing unused study drug) will 
be returned to sponsor (or a designee), according to instructions from sponsor and according to 
local regulations. Labels must remain attached to the containers. 
13.10. 
MISSED DOSE 
Subjects who miss a dose and recall the missed dose within 4 hours of their usual dose time 
should take their dose with a meal.  If more than 4 hours have elapsed after their usual dosing 
time, they should skip that dose and resume their normal schedule with the following dose. 
14.0 
ADVERSE EVENTS 
The investigator will monitor each subject for clinical and laboratory evidence of AEs on a 
routine basis throughout the study. The investigator will assess and record any AE in detail 
including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course, 
duration, outcome, relationship of the AE to study drug, and any action(s) taken. For serious AEs 
not considered "related" to study drug, the investigator will provide an “Other” cause of the 
event. For AEs to be considered intermittent, the events must be of similar nature and severity. 
Adverse events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded. All AEs will be followed to a satisfactory 
resolution. 
14.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, 
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 accidental or intentional overdose, drug abuse, or drug withdrawal. 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 AEs 
only if they result in discontinuation from the study, necessitate therapeutic medical intervention, 
and/or if the investigator considers them to be AEs. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 36 of 50 
14.2. 
Serious Adverse Events 
If an AE meets any of the following criteria, it is to be reported to the sponsor/PI as an SAE 
within 24 hours of the site being made aware of the SAE: 
Event 
Description of Event 
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 in 
the female partner of a study subject. 
 
Persistent or 
Significant 
Disability/Incapacity 
An event that results in a condition that substantially interferes with the 
activities of daily living of a study subject. Disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle). 
 
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome 
An important medical event that may not be immediately life-threatening or 
result in death or hospitalization, but based on medical judgment may jeopardize 
the subject and may require medical or surgical intervention to prevent any of 
the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate eCRF.  
14.3. 
Adverse Event Severity 
The investigator will use the following definitions to rate the severity of each AE: 
Mild 
The AE is transient and easily tolerated by the subject. 
Moderate 
The AE causes the subject discomfort and interrupts the subject's usual 
activities. 
Severe 
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life-threatening. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 37 of 50 
14.4. 
Relationship to Study Drug 
The investigator will use the following definitions to assess the relationship of the AE to the use 
of study drug: 
Related 
An AE where there is evidence to suggest a causal relationship between the 
study drug and the AE. 
Not Related 
An AE where there is no evidence to suggest a causal relationship between the 
study drug and the AE. 
For causality assessments, events assessed as having a reasonable possibility of being related to 
the study drug will be considered “related”. Events assessed as having no reasonable possibility 
of being related to study drug will be considered “not related”. If an investigator's opinion of no 
reasonable possibility of being related to study drug is given, an “other” cause of event must be 
provided by the investigator for the SAE. 
14.5. 
Adverse Event Collection Period 
All AEs in the subject and pregnancies that occur in subject’s partner reported from the time of 
informed consent until completion of the last visit after the last dose of study drug will be 
collected, whether solicited or spontaneously reported by the subject.  
14.6. 
Serious Adverse Event Reporting 
In the event of an SAE in the subject, whether related to study drug or not, the investigator will 
notify the sponsor or representative within 24 hours of the site being made aware of the SAE.  
For SAE Reporting or subject safety concerns, please contact: 
Anthony DelConte, MD, Office: 610-660-3182, Mobile: 862-432-9036, E-mail: 
ad@lipocine.com 
14.7. 
Pregnancy Reporting 
In the event of a pregnancy in a subject’s partner, the investigator will notify the sponsor or 
representative within 24 hours of the site being made aware of the pregnancy.   
15.0 
PROTOCOL DEVIATIONS 
The investigator should not implement any deviation from the protocol without prior review and 
agreement by the sponsor and in accordance with the IRB and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects. When a deviation from the 
protocol is deemed necessary for an individual subject, the investigator must alert the following 
contact(s): 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 38 of 50 
Primary Contact 
Dr. Nachiappan (Chidu) Chidambaram, PhD  
nc@lipocine.com 
(801) 534-6807 
Alternate Contact 
Dr. Anthony DelConte, 
ad@lipocine.com 
(862) 432-9036 
Such contact must be made as soon as possible to permit a review by the sponsor to determine 
the impact of the deviation on the subject and/or the study. Any significant protocol deviations 
affecting subject eligibility and/or safety must be reviewed and/or approved by the IRB, as 
applicable, prior to implementation. 
16.0 
STATISTICAL ANALYSIS 
The primary endpoint and associated analyses are described in this section. Details of the 
analyses to be performed will be given in a statistical analysis plan 
16.1. 
Determination of Sample Size 
The final sample size of 135 was chosen for the study based on the recommendations of FDA. 
This sample size is higher than the originally proposed 75 subject sample size and should meet 
the scientific objective of ruling out a change from baseline of 4.9 mmHg.  
16.2. 
Study Populations 
Statistical analyses will be performed on the full analysis set (FAS), and safety set.  
Safety Set (SS): The safety set includes all subjects who received a dose of study drug. All 
safety analyses will be conducted in the SS. 
Full Analysis Set (FAS): The FAS consists of all subjects enrolled into the study with valid 
ABPM data at Visit 3 and Visit 5. All analyses of blood pressure will be conducted in the FAS. 
16.3. 
Statistical Analysis 
Demographic parameters will be summarized descriptively. Treatment-emergent AEs will be 
summarized descriptively for all subjects who were dosed (safety population).  
Descriptive statistics (arithmetic and geometric means, standard deviation (SD), coefficient of 
variation (CV [%]), minimum, maximum, and median) of Clinic BP and PR measurements will 
be summarized descriptively for all subjects who were dosed (SS population).  
Descriptive statistics (arithmetic and geometric means, SD, CV [%], minimum, maximum, and 
median) of daytime (7:00 AM to 11:00 PM), nighttime (11:00 PM to 7:00 AM), and 24-hour 
ABPM parameters (heart rate, systolic blood pressure, and diastolic blood pressure) from Visit 3 
and Visit 5 will be summarized descriptively for all subjects who were dosed and have valid 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 39 of 50 
ABPM data (FAS population).  
In addition, the following analyses and data presentation will be included: 
• Central tendency analysis and outlier analysis for the 24-hour average and for the hourly 
average. Outliers will be defined in the SAP (i.e., systolic BP exceeding 160 mmHg or a 
change in systolic BP > 20 mmHg, or a diastolic BP exceeding 100 mmHg or a change in 
diastolic BP > 15 mmHg). 
• Graphical display of hourly ABPM averages that include standard deviation bars for both 
systolic BP and diastolic BP at baseline and at endpoint (mid-trial data optional). 
• Cumulative distribution curves of 24-hour average systolic BP and diastolic BP at 
baseline and at each of the timepoints in which ABPM studies are performed. 
• Forest plots of daytime, nighttime, and 24-hour change from baseline with 95% 
confidence interval displays for systolic BP and diastolic BP. 
Sensitivity analyses: 1) the above four sub-bullets grouped for subjects without hypertension, 
with hypertension untreated, and with hypertension treated; 2) the above four sub-bullets for 
subjects with/without diabetes mellitus. 
A complete description of the statistical analyses to be performed will be presented in the SAP.  
16.4. 
Endpoint Analysis 
Details of the analyses to be performed will be described in detail in the SAP. Study primary 
endpoints are briefly discussed below.  Primary endpoint analysis will be performed using data 
from all subjects with valid ABPM data at baseline (Visit 3) and post-treatment (Visit 5).  
The objective of the study is to rule out a clinically meaningful increase in 24-hour average 
systolic BP, as measured by ABPM.  The primary endpoint is the change from Visit 3 to Visit 5 
of the average 24-hour systolic BP.  If the upper limit of the two-sided 95% CI for the change 
from Visit 3 to Visit 5 in average 24-hour systolic BP is ≤ 4.9 mm Hg, then the change will be 
considered not clinically significant. 
16.5. 
Other Safety Endpoints 
Other key safety endpoints are AEs and physical examination. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). An AE is considered treatment emergent if the event begins or worsens in severity 
after initiation of treatment. The number and percentage of subjects with treatment-emergent 
AEs will be tabulated by system organ class (SOC) and preferred term. A summary of the 
number of subjects with treatment-emergent AEs will be provided by severity and by 
relationship to study drug. Subjects reporting more than 1 AE for a given MedDRA preferred 
term will be counted only once for that term using the most severe incident. Subjects reporting 
more than 1 type of event within a SOC will be counted only once for that SOC. Incidence of 
treatment-emergent AEs, serious treatment-emergent AEs, treatment-emergent AEs resulting in 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 40 of 50 
discontinuation. Listings will be provided for all AEs, SAEs, AEs resulting in discontinuation, 
and target AEs. 
17.0 
ETHICS 
17.1. 
Institutional Review Board (IRB) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent and all other forms of subject information related 
to the study (e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IRB. The IRB will review the ethical, scientific and medical appropriateness of 
the study before it is conducted. IRB approval of the protocol, informed consent and subject 
information and/or advertising, as relevant, will be obtained prior to the authorization of drug 
shipment to a study site.  Any amendments to the protocol will require IRB approval prior to 
implementation of any changes made to the study design. The investigator will be required to 
submit, maintain and archive study essential documents according to International Conference on 
Harmonization (ICH). 
Serious adverse events that meet the reporting criteria, as dictated by local regulations, will be 
reported to both IRB and Regulatory Agencies as required by local regulations. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports or any additional reports required by local regulations) to the IRB of any 
changes that affect the conduct of the study and/or increase the risk to subjects. Written 
documentation of the submission to the IRB should also be provided to sponsor/PI. 
17.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH GCP guidelines, applicable 
regulations and guidelines governing clinical study conduct and ethical principles that have their 
origin in the Declaration of Helsinki. Responsibilities of the clinical investigator are specified in 
Appendix B. 
17.3. 
Subject Information and Consent 
Prior to the initiation of any screening or study-specific procedures, the investigator or his/her 
representative will explain the nature of the study to the subject and answer all questions 
regarding this study. Each informed consent will be reviewed, signed and dated by the subject, 
the person who administered the informed consent, and any other signatories according to local 
requirements. A copy of each informed consent will be given to the subject and each original 
will be placed in the subject's medical record. An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy. 
18.0 
SOURCE DOCUMENTS AND CASE REPORT FORM 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 41 of 50 
COMPLETION 
18.1. 
Source Documents 
Source documents are defined as original documents, data and records. These may include 
hospital records, clinical and office charts, laboratory data/information, subject questionnaires or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. 
Source document data may be transcribed onto eCRFs as required. Data collected during this 
study must be recorded on the appropriate source document. 
The investigator/institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspection(s), providing direct access to source data documents. 
18.2. 
Case Report Forms 
Case report forms (CRF) must be completed for each subject who receives study medication in 
this study. These forms will be used to transmit information collected during the study to 
sponsor/PI and regulatory authorities, as applicable. The CRF data for this study will be collected 
with an electronic data capture (eEDC) system. The EDC system and the study-specific eCRFs 
will comply with Title 21 CFR Part 11. The documentation related to the validation of the EDC 
system is available through the system vendor, while the validation of the study-specific eCRFs 
will be conducted by the clinical research organization (CRO) and will be maintained in the Trial 
Master File at the CRO. 
The investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
investigative site personnel in the EDC system. All data entered into the eCRF will be supported 
by source documentation.  
The investigator or an authorized member of the investigator's staff will make any necessary 
corrections to the eCRF. All change information, including the date and person performing the 
corrections, will be available via the audit trail, which is part of the EDC system. For any 
correction, a reason for the alteration will be provided. The eCRFs will be reviewed periodically 
for completeness, legibility, and acceptability by CRO personnel (or their representatives). The 
CRO (or their representatives) will also be allowed access to all source documents pertinent to 
the study in order to verify eCRF entries. The investigator will review the eCRFs for 
completeness and accuracy and provide his or her electronic signature and date to eCRFs as 
evidence thereof. 
The CRO will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access. Such access will be removed from investigator 
sites at the end of the site's participation in the study. Data from the EDC system will be archived 
on appropriate data media (e.g., CD-ROM) and provided to the investigator at that time as a 
durable record of the site's eCRF data. It will be possible for the investigator to make paper 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 42 of 50 
printouts from that media. 
19.0 
DATA QUALITY ASSURANCE 
Prior to enrolling any subject in the study, an initiation meeting will be held with CRO 
personnel, the investigator(s), and the study coordinators/project manager(s). This meeting will 
include a detailed discussion and review of the protocol and essential documents, performance of 
study procedures, eCRF completion and specimen collection methods. 
The CRO monitor will monitor the study site throughout the study. Source document verification 
will be performed. A quality assurance check will be performed to ensure that the investigator is 
complying with the protocol and regulations. In addition, after the eCRFs are submitted, a review 
of the data will be conducted by a representative at CRO. 
Computer logic checks will be run to identify such items as inconsistent study dates. Any 
necessary corrections will be made to the database via the eCRF. 
Routine hematology, serum chemistry, and urinalysis tests will be conducted using a certified 
clinical laboratory. Laboratory reference ranges will be obtained prior to the initiation of the 
study. A review of all laboratory results will be conducted by the CRO monitor, the investigator 
and other appropriate personnel from CRO. 
20.0 
USE OF INFORMATION 
All information concerning LPCN 1021 and Lipocine operations, such as Lipocine patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by Lipocine and not previously published is considered confidential 
information. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by Lipocine in connection with the development of LPCN 1021. 
This information may be disclosed as deemed necessary by Lipocine to other clinical 
investigators, other pharmaceutical companies, and to governmental agencies. To allow for the 
use of the information derived from this clinical study and to ensure complete and thorough 
analysis, the investigator is obligated to provide Lipocine with complete test results and all data 
developed in this study and to provide direct access to source data/documents for study-related 
monitoring, audits, IRB review, and regulatory inspection. 
This confidential information shall remain the sole property of Lipocine, shall not be disclosed to 
others without the written consent of Lipocine, and shall not be used except in the performance 
of this study. 
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone number and 
emergency contact information. This list will be maintained at the study site with other study 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 43 of 50 
records under adequate security and restricted access, and will not be retrieved by 
Lipocine/CRO. 
21.0 
COMPLETION OF THE STUDY 
The investigator will provide a final report to the IRB following conclusion of the study, and will 
forward a copy of this report to Lipocine or their representative. 
The investigator must retain any records related to the study according to local requirements. If 
the investigator is not able to retain the records, he/she must notify Lipocine/CRO to arrange 
alternative archiving options.  
The end of study is defined as the date of the last subject's last visit. If, on the date of the last 
subject’s last visit, the subject is experiencing an ongoing AE, the event will be followed until 
satisfactory resolution occurs. 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 44 of 50 
Appendix A. 
SCHEDULE OF EVENTS:  
Visit 
Visit 1 Visit 2 
MRI-PDFF 
Investigational 
Drug Resupply 
MRI-PDFF 
Visit 5 
MRI-PDFF 
Visit 6 
Exit1 
Baseline 
Interim 
Post- Treatment 
Visit 3 
Visit 4 
 
 
Day (Relative to start of dosing) 
Screen Screen 
Screen (Day -4 [±2 day]) 
Time relative to ABPM 
on morning of Day -4 
Day 1 
Day 60 
(Window Day 
30 to Day 60) 
(Window 
Day 56 to 
Day 76) 
Day 107 (Window: ± 7 days) Time relative to 
time of dosing on morning of Day 107. 
(Window Between  
Visit 5 and Visit 6) 
Day 110 
(Window: ± 
10 days) 
Time on the Day 
 
 
-2 hour 
0 to 24 hour 
 
 
 
-21 hour -12 hour 0 hour 12 hour 24 hour 
 
 
Informed consent 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight, body mass index (BMI)2 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
 
 
✓ 
Medical history3 
✓ 
Physical examination 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
Electrocardiogram 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (Clinic  BP and PR, and oral temperature) 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
✓ 
24-hour Ambulatory BP Measurement 
 
 
 
✓ 
 
 
 
 
 
✓ 
 
 
Sample collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Testosterone (6-10 AM) 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
Study clinical laboratory tests (all subjects) 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
✓ 
Additional clinical laboratory tests (subset of study subjects) 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
✓ 
Drug screen 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
AE Reporting 
✓ 
Blood sample collection for TU measurement4 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
Prior and Concomitant medication5  
✓ 
✓ 
✓ 
 
✓ 
 
 
✓ 
 
 
 
 
 
✓ 
Confinement begins 
 
 
✓ 
 
 
 
 
✓ 
 
 
 
 
 
 
Study enrollment 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
Study drug dispensed 
 
 
 
 
✓ 
✓ 
 
 
 
 
 
✓ 
 
 
Study drug returned 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
✓ 
Meal provided 
 
 
 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
Study drug administered 
 
 
 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
Sexual distress question upon clinic entry 
 
 
✓ 
 
 
 
 
✓ 
 
 
 
 
 
 
Collect sexual desire question printout (completed for 7 days prior 
to visit) 
 
 
✓ 
 
 
 
 
✓ 
 
 
 
 
 
 
MRI-PDFF measurement 
 
 
MRI-1* 
 
MRI-2* 
 
MRI-3* 
 
* Schedule the MRI-1 baseline MRI-PDFF any time between Visit 2 and Visit 4.  Schedule the MRI-2 interim MRI-PDFF any time between Day 56 and Day 76, inclusive. Schedule the MRI-3 post-treatment MRI-
PDFF to occur any time between Visit 5 and Visit 6. 
                                                 
 
1 Study exit can be conducted at Visit 6 or when subject discontinues the study 
2 Height and BMI at screening only 
3 Medical history for the past 5 years will be collected at screening, changes will be documented at subsequent visits  
4 Blood sample collected ~ 3 hours post-morning dose on Day 106. For subjects who cannot come post-morning dose, sample ~3 hours post-evening dose may be collected. 
5 Full medication history will be collected at screening; changes will be documented at subsequent visits 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 45 of 50 
Appendix B. 
INVESTIGATOR'S AGREEMENT 
Study Title: 
Ambulatory Blood Pressure Monitoring in Oral Testosterone 
Undecanoate (TU, LPCN 1021) Treated Hypogonadal Men. 
Study Number: 
LPCN 1021-18-001 
Final Date: 
19 February 2019 
Clinical research studies sponsored by Lipocine are subject to the Good Clinical Practices (GCP) 
and local regulations and guidelines governing the study at the site location. In signing below, 
the investigator is agreeing to the following: 
1. Conducting the study in accordance with the current protocol, making changes to a 
protocol only after obtaining approval from Lipocine, except when necessary to 
protect the safety, rights or welfare of subjects. 
2. Personally, conducting or supervising the described investigation(s). 
3. Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and institutional review board [IRB] review and approval of the protocol and 
amendments). 
4. Reporting adverse experiences that occur in the course of the investigation(s) to 
Lipocine/ PI and the site director. 
5. Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s). 
6. Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments. 
7. Maintaining adequate and accurate records of the conduct of the study, making those 
records available for inspection by representatives of Lipocine/CRO and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from Lipocine. 
8. Maintaining records demonstrating that an ethics committee reviewed and approved 
the initial clinical investigation and all amendments. 
9. Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and Lipocine/PI. 
10. Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate hazards 
to human subjects 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 46 of 50 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
1. I have received and reviewed the Investigator's Brochure for LPCN 1021. 
2. I have read this protocol and agree that the study is ethical. 
3. I agree to conduct the study as outlined in the protocol and in accordance with all 
applicable regulations and guidelines. I will not deviate from the protocol without 
prior written approval from the sponsor or designee. 
4. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
Signature of the Investigator 
 
Date 
 
 
 
 
 
 
Name of the Investigator (Printed or Typed) 
 
 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 47 of 50 
Appendix C. 
LPCN 1021-PROHIBITED CONCOMITANT MEDICATIONS 
Concurrent treatment with medications that may impact the absorption, distribution, metabolism 
or excretion of TU or place the subject at risk for treatment with testosterone within 30 days 
prior to study drug administration and through the end of the study without sponsor approval. 
Examples of prohibited concurrent medications include lipase inhibitors, saw palmetto, 
androgenic or androgenic-modifying supplements, anti-androgens, estrogens, oral CYP3A4 
inducers or inhibitors, and long-acting opioid analgesics. All such medications, including but not 
limited to those listed below, are prohibited without sponsor approval. 
1. Medications that affect SHBG metabolism (levels) 
• 
Phenobarbital  
• 
Phenytoin (Dilantin)  
• 
Carbamazepine (Tegretol)  
• 
Spironolactone (Aldactone)  
• 
Flutamide (Drogenil)  
• 
Cyproterone acetate (Androcur)  
• 
Ketoconazole (Nizoral) 
2. Medications that affect Prolactin metabolism (levels)  
• 
Risperidone (Risperdal)  
• 
Olanzapine (Zyprexa)  
• 
Clozapine (Clozaril) 
• 
Haloperidol (Haldol)  
• 
Ramelton (Rozerem)  
• 
Methyldopa (Aldomet)  
• 
Reserpine 
3. Androgenic and androgenic modifying supplements (may include other supplements)  
• 
Saw palmetto  
• 
ZMA (zinc monomethionine aspartate) 
• 
NatraSterone (Natural Anabolic Androgen)  
• 
Natadrol 
4. GnRH (Gonadotropin-releasing hormone) analogues  
• 
Leuprolide (Lupron)  
• 
Buserelin (Suprefact)  
• 
Decapeptyl 
• 
Clomiphene citrate (Clomid)  
• 
Tamoxifen citrate (Nolvadex)  
• 
Valproic acid 
5. Other Antiandrogens 
• 
Casodex (bicalutamide)  
• 
Eulexin (flutamide)  
• 
Nilandron (nilutamide)  
• 
Xtandi (enzalutamide)  
• 
Goserelin 
• 
Abarelix  
• 
Flutamide  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 48 of 50 
• 
Nilutamide  
• 
Bicalutamide  
• 
Cyproterone acetate  
• 
Medroxyprogesterone  
• 
Spironolactone 
6. Opioid analgetics-  
Any of various sedative narcotics containing opium or one or more of its natural or synthetic derivatives.  
• 
Heroin  
• 
Methadone  
• 
Opium   
7. Lipase inhibitors  
• 
Orlistat (alli, Xenical)   
8. Estrogens  
• 
Amnestrogen® (esterified estrogens) 
• 
Cenestin® (conjugated synthetic A estrogens)  
• 
Enjuvia® (conjugated synthetic B estrogens)  
• 
Estrace® Tablets (estradiol)  
• 
Estratab® (esterified estrogens)  
• 
Evex® (esterified estrogens) 
• 
Femogen® (esterified estrogens) 
• 
Menest® (esterified estrogens)  
• 
Ogen® Tablets (estropipate)  
• 
Ortho-est® (estropipate)  
• 
Premarin® Tablets (conjugated estrogens)  
• 
Covaryx® (containing Esterified Estrogens, Methyltestosterone)  
• 
Essian® (containing Esterified Estrogens, Methyltestosterone)  
• 
Estratest® (containing Esterified Estrogens, Methyltestosterone)  
• 
Femtest® (containing Esterified Estrogens, Methyltestosterone)   
 
• 
Menogen® (containing Esterified Estrogens, Methyltestosterone)  
• 
Menrium® (containing Chlordiazepoxide, Esterified Estrogens)¶  
• 
Milprem® (containing Conjugated Estrogens, Meprobamate)¶  
• 
PMB® (containing Conjugated Estrogens, Meprobamate)¶  
• 
Premarin® with Methyltestosterone (containing Conjugated Estrogens, Methyltestosterone)  
• 
Syntest® (containing Esterified Estrogens, Methyltestosterone)   
9. CYP3A4 inhibitors  
• 
Clarithromycin  
• 
Clotrimazole   
• 
Delavirdine  
• 
Diltiazem  
• 
Erythromycin  
• 
Fluconazole  
• 
Fluvoxamine  
• 
Itraconazole  
• 
Ketoconazole 
• 
Lorazepam 
• 
Nefazodone  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 49 of 50 
• 
Nelfinavir  
• 
Quinupristin/dalfopristin (Synercid)  
• 
Ritonavir (Norvir)  
• 
Saquinavir (Invirase)  
• 
Troleandomycin (TAO)  
• 
Verapamil (Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Covera-HS)  
• 
Indinavir (Crixivan)   
10. CYP3A4 inducers   
• 
Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, mazepine, Carbamaz, CBZ)  
• 
Dexamethasone (Decadron)  
• 
Efavirenz (Sustiva, Stocrin, Efavir, EFV)  
• 
Nevirapine (Viramune)   
• 
Oxcarbazepine (Trileptal)  
• 
Phenobarbital  
• 
Phenytoin  
• 
Primidone  
• 
Rifampin 
• 
St. John’s wort (Hypericum perforatum)  
• 
Troglitazone (Rezulin, Resulin, Romozin, Noscal) 
11. Medications that may impact absorption, distribution, metabolism or excretion of TU  
• 
Atropine 
• 
Activated charcoal  
• 
Lactulose,  
• 
Sodium phosphate  
• 
Sodium biphosphate  
• 
Magnesium sulfate  
• 
Magnesium hydroxide  
• 
Bisacodyl 
• 
Phenolphthalein 
• 
Castor oil 
• 
Petroleum products 
• 
Acepromazine 
• 
Ipecac syrup  
• 
Magnesium hydroxide  
• 
Aluminum/magnesium hydroxide 
12. 5 alpha-reductace inhibitors  
• 
Finasteride 
• 
Dutasteride  
• 
Bexlosteride  
• 
Epristeride  
• 
Izonsteride  
• 
Lapisteride  
• 
Turosteride 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-18-001 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: 19 February 2019 
Confidential  
Page 50 of 50 
 
Appendix D. 
SEXUAL DESIRE AND DISTRESS QUESTIONS 
 
PROVIDE A 7-PAGE PRINTOUT OF THE FOLLOWING QUESTION FOR SUBJECTS 
TO COMPLETE PRIOR TO VISIT 3 AND VISIT  5. 
Sexual Desire Question: Daily Rating 
Instructions: Please read the item below carefully and circle the number that best describes how 
you feel.  Circle only one number.   
 
How would you rate your level (degree) of sexual desire today? 
0 
1 
2 
3 
4 
5 
None at all 
Very low 
Low 
Moderate 
High 
Very high 
 
 
PROVIDE A SINGLE PAGE PRINTOUT OF THE FOLLOWING QUESTION FOR 
SUBJECTS TO COMPLETE AT VISIT 3 AND VISIT  5. 
Sexual Distress Question: Weekly Rating 
Instructions: Please read the item below carefully and circle the number that best describes how 
you feel.  Circle only one number. Rate how much the problem listed below has bothered you over 
the past 7 days, including today.  
 
How often did you feel: Bothered by low sexual desire? 
Past 7 Days 
0 
1 
2 
3 
4 
Never 
Rarely 
Occasionally 
Frequently 
Always 
 
 
 

SAP_001.pdf: 
Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
STATISTICAL ANALYSIS PLAN 
 
Investigational Product : Testosterone Undecanoate (TU, LPCN 1021) 
Clinical Study Protocol : LPCN 1021-18-001 
Protocol Title 
: Ambulatory Blood Pressure Monitoring in Oral Testosterone 
Undecanoate (TU, LPCN 1021) Treated Hypogonadal Men 
Date of SAP 
: January 23, 2019 
Development Phase 
: Phase 3 
Indication 
: 
Testosterone replacement therapy in adult, 18 years or older, males for 
conditions associated with a deficiency or absence of endogenous 
testosterone – primary hypogonadism (congenital or acquired) or 
secondary hypogonadism (congenital or acquired) 
Protocol Version 
: Version 6 
SAP Version 
: 02 
Previous Version (# 
and Date) 
: 01, September 15, 2018 
 
 
 
Confidentiality Statement 
This document is a confidential communication of Lipocine Inc. Acceptance of this document signifies 
agreement by the recipient that no unpublished information contained within will be published or 
disclosed to a third party without prior written approval, except that this document may be disclosed to 
an Institutional Review Board under the same conditions of confidentiality. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
1. 
SUMMARY OF CHANGES 
The purpose of LPCN 1021-18-001 Statistical Analysis Plan Version 2 is to incorporate changes 
summarized below: 
• The primary endpoint of the study was changed from change in average daytime blood 
systolic blood pressure to change in average 24-hour systolic blood pressure based on the 
recent Food and Drug Administration (FDA) public workshop on ambulatory blood 
pressure monitoring studies (“Evaluating the Pressor Effects of Drugs and Ambulatory 
Blood Pressure Monitoring Studies”).  The public workshop noted that the primary 
endpoint for ABPM studies should be the change in 24-hour average blood pressure. 
• Added change in daytime systolic blood pressure to the secondary endpoints, and revised 
secondary endpoints for consistency. 
• Added details for blood pressure analysis. 
• Added details for subgroup analysis.  
• Changed the Development Phase from Phase 1 to Phase 3.  The FDA’s Division of Bone, 
Reproductive and Urologic Products noted that although Protocol LPCN 1021-18-001 
listed the Development Phase of the study as Phase 1, the study design is not consistent 
with the definition of a Phase 1 study in 21 CFR Part 312.21.  The Division requested 
that Lipocine change the designated Development Phase to be consistent with the CFR.  
Based on the CFR study descriptions, the Development Phase for Protocol LPCN 1021-
18-001 was changed to Phase 3. 
• Updated to reflect other changes made to Protocol LPCN 1021-18-001. 
• Minor editorial changes for consistency.  
  
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
2. 
TABLE OF CONTENTS 
1. 
SUMMARY OF CHANGES ....................................................................................2 
2. 
Table of contents .......................................................................................................3 
3. 
List of Abbreviations and Definition of Terms ......................................................6 
3.1. 
Abbreviations ................................................................................................................................ 6 
3.2. 
6 
4. 
Introduction ...............................................................................................................7 
4.1. 
Responsibilities ............................................................................................................................. 7 
4.2. 
Timings of Analyses ..................................................................................................................... 7 
5. 
Brief Description .......................................................................................................7 
5.1. 
Selection of Study Population ....................................................................................................... 9 
5.1.1. 
Inclusion Criteria ................................................................................................................ 9 
5.1.2. 
Exclusion Criteria ............................................................................................................. 10 
5.1.3. 
Stopping Criteria ............................................................................................................... 11 
5.2. 
Determination of Sample Size .................................................................................................... 12 
5.3. 
Treatment Assignment & Blinding ............................................................................................. 12 
5.4. 
Administration of Study Medication ........................................................................................... 12 
5.5. 
Study Procedures ........................................................................................................................ 12 
6. 
Analysis Sets ............................................................................................................12 
7. 
Endpoints .................................................................................................................13 
7.1. 
Efficacy Endpoint ....................................................................................................................... 13 
7.2. 
Primary Efficacy Endpoint .......................................................................................................... 13 
7.3. 
Secondary Efficacy Endpoints .................................................................................................... 13 
7.4. 
Additional Evaluations ................................................................................................................ 13 
7.5. 
Efficacy Endpoints Calculation .................................................................................................. 14 
7.5.1. 
ABPM Data Validity ........................................................................................................ 14 
7.5.2. 
ABPM Data Selection ....................................................................................................... 14 
7.5.3. 
Weighted Average of Blood Pressure ............................................................................... 14 
7.5.4. 
Hourly Average of Blood Pressure ................................................................................... 15 
7.5.5. 
Mean Average of Blood Pressure ..................................................................................... 15 
7.5.6. 
Blood Pressure Dip ........................................................................................................... 15 
7.6. 
Pharmacokinetic Analyses .......................................................................................................... 15 
7.7. 
Safety Endpoints ......................................................................................................................... 16 
8. 
General Aspects for Statistical Analysis ...............................................................16 
8.1. 
General Methods ......................................................................................................................... 16 
8.2. 
Missing Data ............................................................................................................................... 16 
8.3. 
Visit Windows ............................................................................................................................ 17 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
9. 
Demographic, Other Baseline Characteristics and Medication .........................17 
9.1. 
Subject Disposition and Withdrawals ......................................................................................... 17 
9.2. 
Demographic and Other Baseline Characteristics ....................................................................... 17 
9.3. 
Medical History and Concomitant Diseases ............................................................................... 17 
9.3.1. 
Prior and Concomitant Medication ................................................................................... 17 
9.4. 
Protocol Deviations ..................................................................................................................... 18 
10. 
Analysis of Efficacy .................................................................................................18 
10.1. Analysis of Primary Efficacy Endpoint ...................................................................................... 18 
10.2. Analysis of Secondary Efficacy Endpoints ................................................................................. 19 
10.2.1. 
Hourly Average of Blood Pressure ................................................................................... 19 
10.2.2. 
Analysis of Other Secondary Efficacy Endpoints ............................................................. 20 
10.3. Analysis by Subgroup ................................................................................................................. 20 
10.4. Handling of Missing Data ........................................................................................................... 20 
10.5. Presentation of Data and Additional Analysis ............................................................................ 21 
11. 
Analysis of Serum Concentration Data ................................................................22 
11.1. Data Sets Analyzed ..................................................................................................................... 22 
11.2. Sample Collection ....................................................................................................................... 22 
11.2.1. 
Handling of Missing Data and Values Below the Quantification Limit ........................... 22 
11.2.2. 
Serum Concentration Summarization ............................................................................... 22 
11.3. PK Parameters ............................................................................................................................. 22 
12. 
Patient Reported Questionnaire ............................................................................22 
12.1. Data Collection ........................................................................................................................... 22 
12.2. Questionnaire Data Analysis and Reporting ............................................................................... 23 
13. 
Liver Fat Assessments ............................................................................................23 
14. 
Safety ........................................................................................................................24 
14.1. Extent of Exposure ...................................................................................................................... 24 
14.2. Treatment Compliance ................................................................................................................ 24 
14.3. Adverse Events ........................................................................................................................... 24 
14.4. Laboratory Evaluations ............................................................................................................... 26 
14.5. Vital Signs ................................................................................................................................... 26 
14.6. Abbreviated Physical Examination ............................................................................................. 26 
15. 
Changes from the Protocol.....................................................................................26 
16. 
Programming Considerations ................................................................................26 
16.1. General Considerations ............................................................................................................... 26 
16.2. Table, Listing, and Figure Format .............................................................................................. 27 
16.2.1. 
General .............................................................................................................................. 27 
16.2.2. 
Headers ............................................................................................................................. 27 
16.2.3. 
Display Titles .................................................................................................................... 28 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
16.2.4. 
Column Headers ............................................................................................................... 28 
16.2.5. 
Body of the Data Display .................................................................................................. 28 
16.2.6. 
Footnotes ........................................................................................................................... 30 
17. 
Quality Control .......................................................................................................31 
18. 
Index of Tables, Listings and Figures ...................................................................31 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
3.1. 
Abbreviations 
AE  
Adverse event 
ABPM 
Ambulatory blood pressure monitoring 
AUC 
Area under the curve 
BMI  
Body mass index 
BP 
Blood pressure 
CI 
Confidence interval 
CRO 
Clinical research organization 
DBP 
Diastolic blood pressure 
eCRF  
Electronic Case Report Form 
FAS 
Full analysis set 
HDL 
High-density lipoprotein 
ICH  
International Conference on Harmonization 
IRB  
Institutional Review Board 
LDL 
Low-density lipoprotein 
MedDRA  
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MRI-PDFF 
Magnetic Resonance Imaging-Proton Density 
Fat Fraction 
PK  
Pharmacokinetic 
PR 
Pulse rate 
PSA  
Prostate-specific antigen 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC  
System organ class 
SS 
Safety Set 
T  
Testosterone 
TU 
Testosterone undecanoate 
 
 
3.2. 
 
 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
4. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary 
tables and figures which will be produced, and the statistical methodologies that will be used, are 
complete and appropriate to allow valid conclusions regarding the study objectives in accordance 
with the study protocol.   
4.1. 
Responsibilities 
Study conduct,  data management,  statistical analyses, and the production and quality control of 
all tables, figures and listings are the responsibilities of Medpace and Softworld, as assigned. 
4.2. 
Timings of Analyses 
The final analysis is planned after all subjects have completed Visit 6 or discontinued early from 
the study.    
5. 
BRIEF DESCRIPTION 
This is an open-label, multicenter, single arm study evaluating the blood pressure (BP) changes 
from baseline (Visit 3) to post-treatment (Visit 5)assessed by ambulatory blood pressure 
monitoring (ABPM) in LPCN 1021 treated adult hypogonadal male subjects.  
The study is comprised of six scheduled visits: Visit 1 and 2 are for screening, Visit 3 is 
scheduled on Day -4 (±2 day) to assess subject’s baseline BP and pulse rate (PR) via ABPM.  
Visit 4 is to enroll subjects, and to provide subjects with study medication for the start of dosing. 
Visit 5 is to assess subject’s post-treatment BP and PR via ABPM.  Visit 6 is to perform exit 
procedures. 
There are two confinement visits during the study of approximately 30 hours each (prior to start 
of the dosing and at the end of the study). The study visits are described below. 
Visit 1 & 2: Subjects will undergo a screening period to complete the pre-study examinations 
and to confirm their hypogonadal status. Serum total testosterone (T) below lab normal range 
based on two consecutive blood samples obtained between 6 and 10 AM, on two separate days at 
approximately the same time of day, following an appropriate washout of current androgen 
replacement therapy will be used for screening T levels.  
MRI-1 (Window: any time between Visit 2 and Visit 4): The MRI-1 baseline Magnetic 
Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) measurement will be performed 
between Visit 2 and Visit 4 in a subset of study subjects (approximately 20 or more subjects).  
Following confirmation of a subject’s hypogonadal status at Visit 2, sites will schedule a MRI-1 
at a local MRI facility for the subject.  MRI-1 will be performed for all subjects reaching Visit 4 
after implementation of Protocol Version 04 until target enrollment is reached.  MRI-1 will not 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
be performed for subjects who have already progressed past Visit 4 at the time of Version 04 
implementation. 
Visit 3: The morning of Visit 3 (Day -4), hypogonadal men meeting the inclusion criteria and 
none of the exclusion criteria will be confined for approximately 26 hours in the clinic for BP 
assessments by ABPM. In the morning, about 2 hours prior to start of the ABPM, sites will 
measure each subject’s vital signs (oral temperature, Clinic BP and PR), with the subject seated 
at rest with back support for at least 10 minutes prior to vital sign measurement. Following this 
measurement, subjects will be started on the 24-hour ABPM portion of the study, starting at 
7:00 AM. During the 24-hour ABPM portion of the study, the site will provide the subject with a 
meal, and then affix a validated, 510(k) cleared, portable ABPM device to the subject’s arm; the 
device will record the subject’s BP and PR over 24-hours.  At the end of confinement period, 
sites will upload the ABPM data from the device to the web upload, and a central reader will 
evaluate if a subject’s ABPM data are valid based on the ABPM Data Criteria provided in 
Section Data Validity. Subjects with valid recorded ABPM data will proceed to Visit 4; subjects 
who do not have valid ABPM data may choose to repeat Visit 3 or they will not be enrolled into 
the study.  Further, subjects will be asked if they are able to tolerate the ABPM component of the 
study and if they are willing to complete another 24 hour ABPM visit. 
Visit 4: Subjects with valid ABPM data will return to the clinic for study enrollment.  The 
morning (6 – 10 AM) of Visit 4 (Day 1 of treatment), eligible subjects will return to the clinic, 
where staff will dispense study drug.   
Investigation Drug Product Resupply (Day 60; Window Day 30 to Day 60): subjects will return 
to the clinic for a resupply of study drug.  Sites will record the day of the study drug resupply, 
and batch number of the study drug provided to the subject. 
MRI-2 (Window: any time between Day 56 and Day 76, inclusive): The MRI-2 interim MRI-
PDFF measurement will be performed between Visit 4 and Visit 5 in subjects who had a baseline 
MRI-PDFF measurement (MRI-1). Sites will schedule MRI-2 at the same local MRI facility that 
performed the subject’s MRI-1. 
Visit 5: The Visit 5 (Day 107, window ± 7 days) schedule involves collecting a blood sample, 
providing meals to subjects, dosing the study medication and ABPM measurements. 
The visit starts on Day 106 with confinement lasting for up to 45 hours. Subjects will enter the 
clinic on Day 106 after taking their study medication in the morning. The site will collect a 
single blood sample from the subjects (at approximately 3 hours post-morning dose on Day 106). 
Following the blood sample collection, subjects will remain at the site until completion of 
ABPM on Day 108 (on site duration: ~45 hours). For subjects who are not able to remain in the 
site for the 45-hour duration, blood sample may be collected at approximately 3 hours after the 
evening dose of Day 106 (on site duration at least 33 hours).  
On the morning of Day 107 prior to start of the ABPM, vital signs (oral temperature, Clinic BP 
and PR) will be measured when seated at rest with back support for 10 minutes. Subjects will 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
then be provided with the study medication approximately 30 minutes after a meal.  Following 
the administration of study drug, subjects will be started on the 24-hour ABPM portion of the 
study, starting at 7:00 AM. For the 24-hour ABPM portion of the study, the site will affix a 
validated, 510(k) cleared portable ABPM device to the subject’s arm; the device will record the 
subject’s BP and PR over 24-hours. During the ABPM confinement visit, the subjects will be 
administered study drug every 12 hours with meal (evening of Day 106, morning and evening of 
Day 107, morning of Day 108 prior to exiting site). Following the 24-hour ABPM period, 
subjects will exit the clinic.  All subjects will be instructed to continue taking their study 
medication.  Subjects with valid recorded ABPM data at Visit 5 will proceed to Visit 6 for exit 
procedures after completing the MRI-3 measurement described below; subjects who do not have 
valid ABPM data may choose to repeat Visit 5. 
MRI-3 (Window: any time between Visit 5 and Visit 6): Following the second ABPM 
measurement at Visit 5, subjects who had a baseline MRI-PDFF measurement (MRI-1) will have 
a post-treatment MRI-PDFF (MRI-3).  Sites will schedule MRI-3 at the same local MRI facility 
that performed the subject’s MRI-1. 
Visit 6: The Visit 6 (Day 110, window ± 10 days) schedule involves exit procedures, including 
return of study medication, vital signs measurement (oral temperature, Clinic BP and PR), a 
blood sample for clinical laboratory tests, adverse event (AE) reporting, and a review of the 
subject’s Medical History, including specific querying if the subject has a history of diabetes, 
hypertension (never diagnosed, diagnosed but treated, diagnosed but not treated), and the 
subject’s smoking status (never smoked, former smoker, current smoker) to ensure that this 
information is included in the subject’s Medical History.  Sites will collect the blood sample for 
clinical laboratory tests in the morning prior to meals and study drug administration. 
The total duration of the study will be approximately 110 days not including the screening 
period. 
5.1. 
Selection of Study Population 
Subjects will undergo screening procedures prior to the start of treatment. Adult hypogonadal 
male subjects will be eligible for enrollment in the study based on the following inclusion and 
exclusion criteria. 
5.1.1. 
Inclusion Criteria 
A subject will be eligible for study participation if he meets the following criteria. 
 
1. Voluntarily sign and date the study consent form(s) which have been approved by an 
Institutional Review Board (IRB). Written consent must be obtained prior to the 
initiation of any study procedures. 
2. Male between 18 and 80 years of age, inclusive, with documented onset of 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
hypogonadism prior to age 65. 
3. Subjects should be diagnosed to be primary (congenital or acquired) or secondary 
hypogonadal (congenital or acquired). 
4. Serum total T below lab normal value (300 ng/dL) based on two consecutive blood 
samples obtained between 6 and 10 AM, on two separate days at approximately the 
same time of day, following an appropriate washout of current androgen replacement 
therapy, if required. 
5. Naïve to androgen replacement or has discontinued current treatment and completed 
adequate washout of prior androgen therapy. Washout must be completed prior to 
collection of baseline serum T samples to determine study eligibility. 
6. Judged to be in good general health as determined by the investigator at screening. 
5.1.2. 
Exclusion Criteria 
A subject will not be eligible for study participation if he meets any of the following criteria. 
1. History of significant sensitivity or allergy to androgens, or product excipients. 
2. Clinically significant abnormal laboratory value, in the opinion of the investigator, in 
serum chemistry, hematology, or urinalysis including but not limited to: 
a. Hemoglobin < 11.5 g/dL or > 16.5 g/dL 
b. Hematocrit < 35% or > 54% 
c. Serum transaminases > 2.5 times upper limit of normal 
d. Serum bilirubin > 2.0 mg/dL  
e. Creatinine > 2.0 mg/dL 
f. Prostate-specific antigen (PSA) > 4 ng/mL  
g. Prolactin > 17.7 ng/mL. 
3. Clinically significant findings in the pre-study examinations including abnormal 
breast examination requiring follow-up. 
4. Subjects with screening systolic BP or diastolic BP above 160 mmHg or 100 mmHg, 
respectively.  
5. Subjects with symptoms of moderate to severe benign prostatic hyperplasia. 
6. History of seizures or convulsions occurring after age 5, including alcohol or drug 
withdrawal seizures. 
7. History of gastric surgery, cholecystectomy, vagotomy, bowel resection or any 
surgical procedure that might interfere with gastrointestinal motility, pH or 
absorption. 
8. History of any clinically significant illness, infection, or surgical procedure within 1 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
month prior to study drug administration. 
9. Known tolerability issues with ABPM devices. 
10. History of stroke, myocardial infarction, transient ischemic attack, or acute coronary 
syndrome within the past 5 years. 
11. History of long QT syndrome (or QTcB > 450) or unexplained sudden death 
(including cardiac death) or history of long QT syndrome in a first degree relative 
(parent, sibling, or child). 
12. Subjects who are not on stable dose of current medication (no changes in medication 
in the last 3 months).  
13. History of current or suspected prostate or breast cancer.  
14. History of untreated obstructive sleep apnea or not compliant with sleep apnea 
treatment.  
15. Active alcohol or any drug substance abuse, or history of abuse that will interfere 
with the subject’s ability to participate in the study in the judgement of the 
investigator. 
16. Use of known inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone, 
phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 
days prior to study drug administration and through the end of the study.  A list of 
prohibited medications is provided in Appendix C. 
17. Use of any investigational drug within 5 half-lives of the last dose in the past 6 
months prior to Study Day –2 without principal investigator and/or sponsor approval.   
18. Receipt of any investigational drug by injection within 30 days or 10 half-lives 
(whichever is longer) prior to study drug administration without principal investigator 
and/or sponsor approval. 
19. Subject who is not willing to use adequate contraception for the duration of the study.  
20. Any contraindications to a MRI scan (i.e. subjects with non-removable ferromagnetic 
implants, pacemakers, aneurysm clips or other foreign bodies), and/or subjects with 
claustrophobic symptoms and/or inability to fit into an MRI scanner. 
21. Inability to understand and provide written informed consent for the study. 
22. Considered by the investigator or the sponsor-designated physician, for any reason, 
that the subject is an unsuitable candidate to receive LPCN 1021 (exact reason should 
be specified by the investigator). 
5.1.3. 
Stopping Criteria 
All subjects are free to withdraw from the study at any time during the study. In addition, 
subjects may be withdrawn from the study at the discretion of the investigator if they meet any of 
the following criteria: 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
• Any event, in the judgment of the investigator, where continuation of the subject in the 
trial could put the subject at health risk. 
• Significant noncompliance with the protocol requirements. 
• Lost to follow-up. 
5.2. 
Determination of Sample Size 
the final sample size of 135 was chosen for the study based on the recommendations of FDA. 
This sample size is higher than the originally proposed 75 subject sample size and should meet 
the scientific objective of ruling out a change from baseline of 4.9 mmHg.  
Assuming that the true standard deviation of the change from baseline is equal to 9.0, and that 
the assumed true mean increase from baseline is equal to zero, a sample size of 135 subjects 
provides the study with 90% power to detect an increase of 3.58 mmHg (based on the upper limit 
of the two-sided 95% CI). 
5.3. 
Treatment Assignment & Blinding 
This is an open-label, single arm study. There is no randomization and study treatment is neither 
blinded to the subject or investigator’s staff.   
5.4. 
Administration of Study Medication 
The study involves only a 225 mg dose option for LPCN 1021. The dose is administered as 225 
mg testosterone undecanoate (TU) (2 capsules of 112.5 mg) twice daily (BID) approximately 12 
hours apart (total daily dose of 450 mg taken as 225 mg in the morning and 225 mg in the 
evening).  
5.5. 
Study Procedures  
The schedule of events is provided in Appendix A of the protocol. 
 
6. 
ANALYSIS SETS 
Statistical analyses will be performed on the following analysis sets.  
Safety Set (SS): The safety set includes all subjects who received a dose of study drug. All 
safety analyses will be conducted in the SS. 
Full Analysis Set (FAS): The FAS consists of all subjects enrolled into the study with valid 
ABPM data at Visit 3 and Visit 5. All analyses of blood pressure will be conducted in the FAS. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
Pharmacokinetic Set (PK): The PK set consists of all subjects enrolled into the study with valid 
serum concentration data at Visit 5.  
MRI- Full Analysis Set (MRI-FAS): The MRI-FAS consists of all subjects enrolled into the 
study after the Protocol version 4 was implemented with valid MRI-PDFF data at baseline and 
end of the study. 
7. 
ENDPOINTS 
7.1. 
Efficacy Endpoint 
7.2. 
Primary Efficacy Endpoint 
The objective of the study is to rule out a clinically meaningful increase in 24-hour systolic blood 
pressure (SBP), as measured by ABPM.   
The primary endpoint is the change from Visit 3 to Visit 5 of the weighted average 24-hour SBP. 
If the upper limit of the two-sided 95% CI for the change from Visit 3 to Visit 5 in weighted 
average 24-hourSBP is ≤ 4.9 mmHg, then the change will be considered not clinically 
significant.  
The primary analysis will be done using the FAS.  
7.3. 
Secondary Efficacy Endpoints 
• Change in weighted average daytime and nighttime SBP, weighted average daytime 
diastolic blood pressure (DBP), weighted average nighttime DBP, and weighted average 
24-hour DBP assessed by ABPM from Visit 3 to Visit 5.  
• Change in hourly average daytime and nighttime SBP, hourly average 24-hour SBP, 
hourly average daytime DBP, hourly average nighttime DBP, and hourly average 24-hour 
DBP assessed by ABPM from Visit 3 to Visit 5.  
• Change in mean average daytime and nighttime SBP, mean average 24-hour SBP, mean 
average daytime DBP, mean average nighttime DBP, and mean average 24-hour DBP 
assessed by ABPM from Visit 3 to Visit 5.  
• 
Change in dip from Visit 3 to Visit 5.  
• Change in weighted average daytime, nighttime, and24-hour PR assessed by ABPM from 
Visit 3 to Visit 5.  
• Change in morning systolic and diastolic BP and PR measured in triplicate at the clinic 
(“Clinic BP and PR”) from Visit 3 to Visit 5.  
7.4. 
Additional Evaluations 
• Change in patient reported sexual desire and sexual distress from baseline to Visit 5. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
• Change and percent Change in MRI-PDFF to MRI-2 (interim) and to MRI-3 (post-
treatment) in all subjects with baseline, interim, and post-treatment MRI-PDFF 
measurements, those with MRI-PDFF measurement of >5% at baseline, and those with a 
MRI-PDFF measurements of >10% at baseline. 
7.5. 
Efficacy Endpoints Calculation 
7.5.1. 
ABPM Data Validity  
For the 24-hour ABPM results to qualify as valid, the data must meet the following ABPM Data 
Criteria: 
• 
Minimum of 1 valid reading per hour, including during sleep.  
• 
Valid data for at least 22 out of 24 hours in the day. 
7.5.2. 
ABPM Data Selection 
Systolic BP, diastolic BP, pulse rate and mean arterial pressure values will be obtained every 15 
minutes during the day and every 20 minutes during the night. 24-hour ABPM measurements will 
be selected as stated below, assuming a 24-hour biological cycle: 
(1) If the first measurement starts at 7 AM on ABPM Day 1, select all measurements between 7 
AM on ABPM Day 1 and 6:59 AM on ABPM Day 2. 
(2) If the last measurement ends before 7 AM on ABPM Day 2 (eg. 6:30 AM), all measurements 
in the 24-hour interval prior to the last measurement will be selected, eg. 6 AM on ABPM Day 1 
to 5:59 AM on ABPM Day 2.  
(3) If the last measurement ends after 7 AM on ABPM Day 2, select all measurements between 7 
AM on ABPM Day 1 and 6:59 AM on ABPM Day 2. 
Generally, we will select the measurements from the whole hour, if this results in less than 24-
hour measurements, we will select partial hour. For example, if the last measurement ends at 6:30 
AM on ABPM Day 2, and the first measurement is from 6:30 AM on ABPM Day 1, the 24-hour 
interval will be 6:30 AM on ABPM Day 1 to 6:29 AM on ABPM Day 2. 
7.5.3. 
Weighted Average of Blood Pressure  
For the computation of average blood pressure values, time weighted area under the curve (AUC) 
of the measured BP values (AUC of BP values divided by time duration) will be assessed and a 
time weighted average will be calculated. AUC of BP can be calculated based on the trapezoidal 
rule, then the weighted average of BP will be AUC/(time duration). 
For the purpose of computing average values, all the data for different timepoints will be used. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
Average values for daytime will start at 7:00 AM in the morning and end at 11:00 PM in the night 
[7:00 AM, 11:00 PM). Average values for night time will start at 11:00 PM and end at 7:00 AM 
[11:00 PM, 7:00AM).  
Average 24-hour ABPM will start as close as possible to 7:00 AM in the morning until the same 
time the following day. 
7.5.4. 
Hourly Average of Blood Pressure 
The hourly SBP will be calculated for each hour over 24 hours by taking the average of the readings 
taken in the corresponding hour (i.e, 7:00 AM to 7:59 AM). The Visit 3 and Visit 5 hourly daytime 
SBP is the average of the hourly SBP [7:00 AM, 11:00 PM) reviewed at Visit 3 and Visit 5, 
respectively. If there are missing measurements within the 24-hours, the hours without any 
measurements will be ignored when calculating the average. 
For the purpose of presenting graphical information on the blood pressure and pulse rate values, 
average of measure pulse and mean arterial pressure over each hour will also be computed. An 
average of SBP from 7 to 8 AM will be based on the collected data at 7:00, 7:15, 7:30 and 7:45 
AM. The data will be presented at 7 AM. 
7.5.5. 
Mean Average of Blood Pressure 
The mean average of blood pressure will be calculated as the mean of hourly average of blood 
pressure. For example, the mean average of the daytime SBP will be calculated by taking the 
average of daytime hourly average SBP.   
7.5.6. 
Blood Pressure Dip 
Optimal blood pressure fluctuates over a 24-hour sleep-wake cycle, with values rising in the 
daytime and falling after midnight. The fall in pressure, called the “dip”, is defined as the 
difference between daytime mean systolic pressure and nighttime mean systolic pressure expressed 
as a percentage of the day value. 
𝐷𝑖𝑝= (1 −𝑆𝐵𝑃𝑛𝑖𝑔ℎ𝑡𝑡𝑖𝑚𝑒
𝑆𝐵𝑃𝑑𝑎𝑦𝑡𝑖𝑚𝑒
) × 100% 
10% to 20% is considered normal. Dips less than 10%, referred to as blunted or absent, have been 
considered as predicting an adverse cardiovascular event. 
7.6. 
Pharmacokinetic Analyses 
There is no pharmacokinetic analysis in the study. However, concentrations of TU measured at 
Visit 5 will be summarized and listings presented.  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
7.7. 
Safety Endpoints  
Key safety endpoints are AEs, physical examination, clinical laboratory tests and vital signs (oral 
temperature, Clinic BP and PR). Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, version 17.1). An AE is considered treatment emergent if the 
event begins or worsens in severity after initiation of study drug.  
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.1. 
General Methods 
All relevant data will be presented in patient data listings ordered by Subject ID.  All categorical 
data will be summarized using frequency counts and percentages of subjects.  Percentage will be 
calculated using the study population as the denominator.  The continuous variables will be 
summarized using number of observations (n), mean, standard deviation (SD), median, first 
quartile, third quartile, minimum, and maximum unless otherwise specified.   All the analyses of 
safety and efficacy data for this study will be performed using SAS® statistical software 
package, version 9.3, higher or equivalent.  
8.2. 
Missing Data 
For the measurement of endpoints there will no imputation of missing data. 
If an AE has a completely missing onset date, then the AE will be considered a treatment 
emergent adverse event (TEAE).  
The following section applies to medication prior to the start of the study. A medication with a 
completely missing start date is considered a prior medication. A medication with a completely 
missing stop date is considered a concomitant medication. If an adverse event or a medication 
has a partial missing start or stop date, the following rules will be used to impute the date; then 
the imputed date will be used to determine whether it is a prior or concomitant medication. 
 
Partial Missing Start or Stop 
Date 
Imputed Start Date 
Imputed Stop Date 
Missing month and day, and 
the year is present 
January 1 of that year or first dose 
date if the year is the same as the year 
of first dose date 
December 31 of that year 
Missing day, but year and 
month are present 
 
First day of that month or first dose 
date if the year and month are the 
same as the year and month of first 
dose date 
Last day of that month 
Missing month, but year and 
day are present 
Missing month imputed as January or 
the month of the first dose date 
Missing month imputed as 
December 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
8.3. 
Visit Windows 
For visit 5, the protocol allowed visit window is Day 100 to Day 114 day.   
9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS 
AND MEDICATION 
9.1. 
Subject Disposition and Withdrawals 
The number and percentage of subjects enrolled, treated, completed, and discontinued will be 
presented.  Reasons for discontinuation will be detailed, and the number and percentage of 
subjects who discontinued for each reason will be presented. 
9.2. 
Demographic and Other Baseline Characteristics 
Subject age, race, weight and body mass index (BMI) will be summarized overall.  Age and race 
will be characterized by number and percentage of subjects who give each response (per 
Electronic Case Report Form (eCRF)). Weight and BMI will be summarized using descriptive 
statistics for continuous measures (mean, standard deviation, median, minimum, first quartile, 
third quartile, maximum).   
9.3. 
Medical History and Concomitant Diseases 
The subject’s medical history (lifetime significance including key events) during the past 5 years 
will be updated during each clinic visit and recorded on the Medical History eCRF.  
Medical history terms will be coded and summarized.  Summary of medical history will be 
presented. Subjects with a medical history of hypertension, diabetes will be presented separately. 
A subject data listing for reported medical history will be provided.  The listing will be sorted by 
study center and subject identifier.   
9.3.1. 
Prior and Concomitant Medication 
Medication use (prescription or over-the-counter, including vitamins and herbal supplements) 
from 3 months prior to study drug administration through the end of the study will be recorded 
on the Concomitant Medication eCRF. 
If a subject reports taking any over-the-counter or prescription medications, vitamins and/or 
herbal supplement or if administration becomes necessary from 3 months prior to study drug 
administration through the end of the study, the name of the medication, dosage information 
including dose and frequency, date(s) of administration including start and end dates, and reason 
for use will be recorded. For any medications taken after study drug administration and through 
the end of the study, the subject may continue to participate in the study only after the 
investigator agrees the subject may continue. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
A prior medication is any medication taken and stopped before the first dose of study medication. 
A concomitant medication is defined as any medication taken on or after the first dose day of study 
medication.  
Medications with missing stop dates and medications with a missing start date will be counted as 
concomitant.  Concomitant medications will be listed and summarized for the SS by WHO Drug 
Dictionary preferred drug name.  The number and percentage of subjects who used each 
medication will be reported.  
Medications for hypertension and diabetes will be summarized separately by class of medication. 
Changes in medication history from the start of the study through Visit 6 will be presented for 
hypertension medications.  
9.4. 
Protocol Deviations 
All deviations from the Protocol will be documented. At the end of the study, subjects who meet 
the criteria of “Major Protocol Deviations” will be identified. The basic rules for classification as 
major protocol deviations are:  
• Subjects who are enrolled but who did not meet all inclusion criteria or met any exclusion 
criteria. 
• Subjects who are significantly noncompliant with study drug administration (took more 
than 120% of anticipated dose units or less than 80% of anticipated dose units). 
• Subjects who significantly deviated from follow protocol recommended dose or dosing 
regimen. The significant deviation is defined as when a subject did not take 225 mg two 
times a day for at least 20 days preceding Visit 5. However, this does not include subjects 
who had minor deviations of a missed dose. 
10. 
ANALYSIS OF EFFICACY 
10.1. 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is the change in ABPM-measured weighted average 24-hour SBP from Visit 
3 to Visit 5. 
A linear regression model will be used with baseline SBP as a covariate to analyze the primary 
efficacy endpoint. The change in SBP from baseline to Visit 5 will be predicted at the median 
baseline level, and the predicted value, standard error and 95% confidence interval will be listed. 
The upper limit of 95% CI will be compared with 4.9 mmHg, and p-value will be calculated. 
Example SAS® code for performing this analysis is provided below: 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
 
**************************************************************** 
** chg     = change of 24-hour SBP from Visit 3 to Visit 5    ** 
** base    = hourly SBP at Visit 3                            ** 
** median  = median weighted average of SBP at baseline       ** 
**************************************************************** 
proc glm; 
 
model chg = base / clparm; 
 
estimate 'Mean Change for Median Baseline Level'  
 
 
intercept 1 base median; 
run; 
Change of 24-hour SBP from baseline will be calculated using the time weighted average of area 
under the curve (AUC divided by time duration) of SBP obtained over 24-hours. That is, the time 
weighted average of AUC of 24-hour SBP obtained at baseline (Visit 3) will be subtracted from 
corresponding time weighted average of AUC of SBP at the end of the study (Visit 5).   
Median weighted average of SBP at baseline is the sample median of the weighted average of 
AUC of SBP at baseline. 
10.2. 
Analysis of Secondary Efficacy Endpoints 
10.2.1. 
Hourly Average of Blood Pressure 
The change of hourly average SBP from baseline will be calculated by taking the difference 
between the corresponding hourly SBP at Visit 5 and Visit 3 for a given post-dosing hour.   
The change from baseline in daytime hourly SBP (hour 7, 8, 9, …, 23) will be modeled by an 
ANCOVA model for repeated measures. The factors in the ANCOVA model will include: post-
dosing daytime hour (hour 7, 8, 9, …, 23) and the baseline value as a covariate. The upper limit of 
95% CI by hour will be compared with 4.9 mmHg.  
**************************************************************** 
** chg     = change in hourly SBP from Visit 3 to Visit 5     ** 
** base    = hourly SBP at Visit 3                            ** 
** usubjid = subject id                                       ** 
** hour    = post-dosing hour                                 ** 
** median  = median weighted average of SBP at baseline       ** 
**************************************************************** 
proc mixed data=data; 
 
class hour; 
 
model chg = base hour /s; 
 
repeated hour / type=un sub=usubjid; 
Estimate "Hour=7" Intercept 1 base median age 1 /cl; 
Estimate "Hour=8" Intercept 1 base median age 0 1 /cl; 
...... 
run; 
 
As in Section , median weighted average of SBP at baseline is the sample median of the weighted 
average of AUC of SBP at baseline. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
Other change in hourly average BP endpoints will be analyzed using the same model above.  
10.2.2. 
Analysis of Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints listed below will be analyzed using the model described in 
Section : 
• Change in weighted average daytime  and nighttime SBP, weighted average daytime 
DBP, weighted average nighttime DBP, and weighted average 24-hour DBP assessed by 
ABPM from Visit 3 to Visit 5.  
• Change in mean average daytime and nighttime SBP, mean average 24-hour SBP, mean 
average daytime DBP, mean average nighttime DBP, and mean average 24-hour DBP 
assessed by ABPM from Visit 3 to Visit 5.  
• Change in dip from Visit 3 to Visit 5.  
• Change in weighted average daytime, nighttime, and24-hour PR assessed by ABPM from 
Visit 3 to Visit 5.  
• Change in morning systolic and diastolic BP and PR measured in triplicate at the clinic 
(“Clinic BP and PR”) from Visit 3 to Visit 5.  
10.3. 
Analysis by Subgroup 
The primary efficacy endpoint analysis will be repeated using the following subgroups:  
1) Excluding subjects with either SBP >140 mmHg or DBP > 90 mmHg at screening; 
2) Excluding subjects with SBP >140 mmHg and DBP > 90 mmHg at screening. 
3) Subjects with three risk levels of cardiovascular events based on the Framingham Heart 
Study:i 
• 
Low risk: age 25, total cholesterol of 161, high-density lipoprotein (HDL) of 55, 
untreated SBP of 125, nonsmoker, nondiabetic. 
• 
Moderate risk: age 40, total cholesterol of 205, HDL of 45, untreated SBP of 135, 
nonsmoker, diabetic. 
• 
High risk: age 70, total cholesterol of 225, HDL of 39, treated SBP of 150, nonsmoker, 
diabetic. 
10.4. 
Handling of Missing Data 
If a subject’s data is missing at the start or the end, the values will be considered missing for the 
computation of averages, the actual times for analyzing the average will be taken based on the 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
data available.  
If a subject’s data is missing in the middle of the data collection window, it will be considered as 
missing for the given timepoints and the average will be computed based on the area under the 
curve for the remaining timepoints.  
For a subject if there is data missing at baseline and / or at the end of the study for a complete 
hour, for the purpose of computing the average values, the corresponding times from both the 
baseline and end of study will be considered missing. For example, at baseline if a subject’s data 
is missing from 2 to 3 PM in the afternoon, however corresponding exit values are available, for 
assessing change from baseline, the average calculation will not consider the 2 to 3 PM data even 
at the end of the study.  
This approach is true only if an entire hour data is missing. If there is partial data within an hour 
missing, the all the available data will be used in computation of averages.  
10.5. 
Presentation of Data and Additional Analysis 
Descriptive statistics (arithmetic and geometric means, standard deviation (SD), coefficient of 
variation (CV [%]), minimum, maximum, and median) of Clinic BP and PR measurements will 
be summarized descriptively for all subjects who were dosed (SS population).  
Descriptive statistics (arithmetic and geometric means, SD, CV [%], minimum, maximum, and 
median) of daytime [7:00 AM, 11:00 PM), nighttime [11:00 PM, 7:00AM), and 24-hour ABPM 
parameters (pulse rate, systolic blood pressure, and diastolic blood pressure) from Visit 3 and 
Visit 5 will be summarized descriptively for all subjects who were dosed and have valid ABPM 
data (FAS population).  
In addition, the following analyses and data presentation will be included: 
• Central tendency analysis and outlier analysis for the 24-hour average and for the hourly 
average. Outliers include SBP exceeding 160 mmHg or a change in SBP > 20 mmHg, or 
a DBP exceeding 100 mmHg or a change in DBP > 15 mmHg. 
• Graphical display of hourly ABPM averages that include standard deviation bars for both 
SBP and DBP at baseline and at endpoint (mid-trial data optional). 
• Cumulative distribution curves of 24-hour average SBP and DBP at baseline and at each 
of the timepoints in which ABPM studies are performed. 
• Forest plots of daytime, nighttime, and 24-hour change from baseline with 95% 
confidence interval displays for SBP and DBP. 
Sensitivity analyses: 1) the above four sub-bullets grouped for subjects without hypertension, 
with hypertension untreated, and with hypertension treated; 2) the above four sub-bullets for 
subjects with/without diabetes mellitus. 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
 
11. 
ANALYSIS OF SERUM CONCENTRATION DATA 
11.1. Data Sets Analyzed 
The PK set as defined earlier will be used for the summarizing serum concentration data. Data 
from subjects with missing concentration values (missed blood draws, lost samples, samples 
unable to be quantified) will be considered as missing and will not be a part of PK set. Otherwise 
relevant data from these subjects will be excluded from the final analysis.  
11.2. Sample Collection 
On Day 106 (approximately 3 hours post-morning dose on Day 106), when subjects enter the 
clinic, a single blood sample of 8 mL blood will be collected in a serum separator tube (gold top 
tube), at approximately 3 hours post-morning dose on Day 106.   
11.2.1. 
Handling of Missing Data and Values Below the Quantification Limit 
Missing concentration values for subjects who were administered the scheduled study drug will 
be considered as non-informative missing. No concentration estimates will be provided for 
missing sample values.  
11.2.2. 
Serum Concentration Summarization 
Serum TU concentrations below the LLOQ in the samples will be set to zero. Descriptive 
statistics for serum concentrations including: number of observations (n), mean, standard 
deviation (SD), coefficient of variation (CV), minimum, median, and maximum will be 
calculated and presented.  
11.3. PK Parameters  
No PK parameters will be calculated in the study. 
12. 
PATIENT REPORTED QUESTIONNAIRE 
12.1. Data Collection 
Subjects will be asked two questions to assess the patient reported outcomes before and after 
treatment: 
(A) Sexual desire: Seven-day questionnaire  
(B) Sexual distress: One day questionnaire  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
For the sexual desire question, responses to a sexual desire question will be answered each day 
for 7 days preceding to Visit 3.    
For the sexual distress question, subjects will answer a sexual distress question at Visit 3.   
Responses to these questions will be repeated at the end of the study.  
12.2. Questionnaire Data Analysis and Reporting 
(A) Sexual desire: responses to the questionnaire will be given for seven continuous days at 
the start and end of the study. An average of all the responses received at baseline and 
end of the study will be computed. Change from baseline to end of the study in average 
responses for each subject will be computed. Descriptive statistics of all subject’s data 
along with subject level listing will be presented.   
(B) Sexual distress: this is a single question questionnaire that is answered by subjects once at 
Visit 3 and end of study.  Change from baseline to end of the study in the response for 
each subject will be computed. Descriptive statistics of all subject’s data along with 
subject level listing will be presented.   
Summary data and change from baseline will be presented for all subjects. Descriptive statistics 
and individual subject listing will be presented. 
13. 
LIVER FAT ASSESSMENTS 
A MRI-PDFF measurement will be performed at baseline between Visit 2 and Visit 4 (MRI-1), 
at an interim point between Day 56 and Day 76, inclusive, (MRI-2) and post-treatment between 
Visit 5 and Visit 6 (MRI-3). MRI-1 will be performed for all subjects reaching Visit 4 after 
implementation of Protocol Version 04 until target enrollment is reached (approximately 20 or 
more subjects).  MRI-1 will not be performed for subjects who have already progressed past 
Visit 4 at the time of Version 04 implementation.  The MRI-2 and MRI-3 measurement will be 
performed for all subjects who complete MRI-1. 
MRI data will be evaluated centrally by a central reader and % liver fat will be assessed. 
Changes and percent Changes in the % liver fat from baseline to end of study will be computed 
for all subjects. 
Summary data will be presented for all subjects with MRI data in the MRI-FAS dataset. Further, 
subgroup analysis will be conducted for those subjects who had baseline liver fat based on MRI-
PDFF of > 5% and also for subjects who had baseline liver fat based on MRI-PDFF of > 10%. 
Descriptive statistics and individual subject listing will be presented.  
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
 
14. 
SAFETY 
The population used for safety analyses will be the SS.  Safety will be assessed on the basis of 
adverse event (AE) reports, clinical laboratory data, physical examinations, and vital signs. 
14.1. Extent of Exposure 
Treatment exposure will be measured as number of days since first dosing day of last dosing day. 
14.2. Treatment Compliance  
Compliance will be based on the overall medication used by each subject during the study and 
will be computed as follows: 
% compliance = [(number of capsules dispensed – number of capsules returned)/ number of 
capsules expected to be consumed] ×100 
Further, treatment compliance will also include assessment of TU levels post 3 hours dosing. 
Based on the pharmacokinetic data of LPCN 1021 from prior trials, measurable levels of TU 
should be presented in these subjects.  
14.3. Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any 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 accidental or intentional overdose, drug abuse, or drug withdrawal. 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. 
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 preexisting condition and the surgery/procedure 
has been preplanned prior to study entry. However, if the preexisting 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 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
considered an AE. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and the severity of the toxicities will be graded according to the NCI 
CTCAE, v4.03, where applicable.   
Treatment emergent AEs (TEAEs) are AEs that begin or worsen in severity after initiation of 
randomized study drug and do not necessarily have a causal relationship to the use of the study 
medication.  
A Serious Adverse Event (SAE) is an AE which falls into one or more of the following 
categories: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Is a congenital anomaly/birth defect; 
• Results in persistent or significant disability or incapacity; 
• Is any other important medical event requiring medical or surgical intervention to prevent 
a serious outcome; 
The following adverse event summary tables will be generated: 
• Overall Summary of Treatment-Emergent Adverse Events(TEAE) 
• Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
• Summary of Serious Treatment-Emergent Adverse Events 
• Summary of Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation 
• Summary of Treatment-Emergent Adverse Events Resulting in Death 
The number and percentage of subjects with treatment-emergent AEs will be tabulated by system 
organ class (SOC) and preferred term. A summary of the number of subjects with treatment-
emergent AEs will be provided by severity and by relationship to study drug; a summaries based 
on event count will also be presented. Subjects reporting more than 1 AE for a given MedDRA 
preferred term will be counted only once for that term using the most severe incident. Subjects 
reporting more than 1 type of event within a SOC will be counted only once for that SOC. 
Incidence of treatment-emergent AEs, serious treatment-emergent AEs, and treatment-emergent 
AEs resulting in discontinuation will be summarized.  
Listings will be provided for all AEs, SAEs, AEs resulting in discontinuation, and AEs resulting 
in death. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
14.4. Laboratory Evaluations 
Baseline, end of study and change from baseline for the laboratory data will be presented for each 
subject. Descriptive summary statistics of all laboratory data along with individual subject listing 
will be presented.  
Laboratory tests results will include lipids, and liver enzymes. 
14.5. Vital Signs  
Sites will measure oral temperature (single measurement), and Clinic BP and PR on Visit 3, 
Visit 5, and at Visit 6/study exit. Vital signs will be measured after the subject has been sitting at 
rest for at least 10 minutes with a back support, using automated digital blood pressure devices 
(the device used should be current with respect to calibration, the exact make and model of the 
device used to record blood pressure should be documented).   
For the blood pressure and pulse rate, the average value of the three measurements will be 
computed and change from baseline to end of study will be calculated. Descriptive summary 
statistics of Clinic BP and PR along with individual subject listings will be presented. Further an 
exploratory comparison of cuff-based measurements and ABPM measurement will be carried out 
and presented.  
14.6. Abbreviated Physical Examination 
Abbreviated physical examination results will be summarized.   
15. 
CHANGES FROM THE PROTOCOL  
None. 
16. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, and figures (TLFs), and statistical analyses will be generated using SAS 
version 9.3, higher or equivalent.  Computer-generated table output will adhere to the following 
specifications. 
16.1. General Considerations 
One SAS program can create several outputs. 
Each output will be stored in a separate file. 
Output files will be delivered in Word format. 
Numbering of TFLs will follow ICH (International Council for Harmonisation) E3 guidance. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
16.2. Table, Listing, and Figure Format 
16.2.1. 
General 
All TLFs will be produced in landscape format, unless otherwise specified. 
All TLFs will be produced using the Courier New font, size 8  
The data displays for all TLFs will have a 1-inch binding margin on top of a landscape oriented 
page and a minimum 1-inch margin on the other 3 sides. 
Headers and footers for figures will be in Courier New font, size 8. 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
TLFs will be in black and white (no color), unless otherwise specified 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., Cmax, cm2) will be 
employed on a case-by-case basis. 
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied 
formats, as appropriate. 
16.2.2. 
Headers 
All outputs should have the following header at the top left of each page: 
Lipocine, Inc.  
 
 
 
 
 
 
Page X of Y 
LPCN 1021-18-001 
 
 
 
 
 
 
Draft/Final Run 
The date (date output was generated) should appear along with program name and location as the 
last footer on each page. 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
 
16.2.3. 
Display Titles 
Each TLF should be identified by the designation and a numeral (i.e., Table 14.1.1). The title 
will be centered and the analysis set should be identified on the line immediately following the 
title. The title and table designation are single spaced. A solid line spanning the margins will 
separate the display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
<Table/Listing/Figure x.y.z> 
<First Line of Title> 
<Second Line of Title if Needed> 
<Analysis Set> 
16.2.4. 
Column Headers 
Column headings should be displayed immediately below the solid line described above in initial 
upper-case characters.  
In the case of efficacy tables, the variable (or characteristic) column will be on the far left 
followed by the treatment group columns and total column (if applicable). P-values may be 
presented under the total column or in separate p-value column (if applicable). Within-treatment 
comparisons may have p-values presented in a row beneath the summary statistics for that 
treatment. 
For numeric variables, include “unit” in column or row heading when appropriate. 
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
16.2.5. 
Body of the Data Display 
16.2.5.1. 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
alphanumeric values are left-justified; 
whole numbers (e.g., counts) are right-justified; and 
numbers containing fractional portions are decimal aligned. 
16.2.5.2. 
Table Conventions 
• Units will be included where available 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category should be presented in the table, even if n=0 for all treatment groups in 
a given category that is between the minimum and maximum level for that parameter. For 
example, the frequency distribution for symptom severity would appear as: 
Severity / Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be presented and so 
any counts of 0 will be presented as 0 and not as 0 (0%). 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups should be included. 
An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more subjects.  
Unless otherwise specified, the estimated mean, median, first-, and third-quartile for a set of 
values should be printed out to 1 more significant digit than the original values, and standard 
deviations should be printed out to 2 more significant digits than the original values. The 
minimum and maximum should report the same significant digits as the original values. For 
example, for systolic blood pressure: 
N 
  XX 
Mean (SD) 
XXX.X (X.XX) 
Median 
XXX.X 
Q1, Q3 
XXX.X, XXX.X 
Minimum 
XXX 
Maximum 
XXX 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal 
places. Any p-value less than 0.001 will be presented as <0.001. Any p-value greater than 0.999 
will be presented as >0.999 
Percentage values should be printed to one decimal place, in parentheses with no spaces, one 
space after the count (e.g., 7 (12.8%), 13 (5.4%)). Values that round down to 0.0% or up to 
100.0% will be presented as such. Unless otherwise noted, for all percentages, the number of 
subjects in the analysis set for the treatment group who have an observation will be the 
denominator. Percentages after zero counts will not be displayed.  
Tabular display of data for medical history, prior / concomitant medications, and all tabular 
displays of adverse event data should be presented by the body system, treatment class, or SOC 
with the highest occurrence in the active treatment group in decreasing order, assuming all terms 
are coded. Within the body system, drug class and SOC, medical history (by preferred term), 
drugs (by ATC1 code), and adverse events (by preferred term) should be displayed in decreasing 
order. If incidence for more than 1 term is identical, they should then be sorted alphabetically. 
Missing descriptive statistics or p-values which cannot be estimated should be reported as 
“N/A”. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, a footnote (and possibly programming note) will be included to detail 
whether the subject should be included in the summary statistics for all relevant categories or just 
one (1) category and if so the criteria for selecting the criteria will be given as well. 
Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
16.2.5.3. 
Listing Conventions 
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
Missing data will be represented on subject listings as “N/A”, with the footnote “N/A = not 
applicable”. 
Dates will be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions 
of dates will be represented on subject listings as dashes (--JUL2000). Dates that are missing 
because they are not applicable for the subject are output as “N/A”, unless otherwise specified. 
All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
Units will be included where available. 
16.2.5.4. 
Figure Conventions 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment change from Baseline) values will be displayed on Y-axis. 
16.2.6. 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid 
line underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or a, b, c, etc. if 
a reference footnote. Each new footnote should start on a new line where possible. 
• Footnotes will be present on the page where they are first referenced and thereafter on 
each page of the table, unless the footnote is specific only to certain pages. Subject 
specific footnotes should be avoided. 
• Footnotes will be used sparingly and will add value to the table, figure, or data listing. If 
more than six lines of footnotes are planned, then a cover page may be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
STATISTICAL ANALYSIS PLAN 
Clinical Study LPCN 1021-18-001 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
 
page.  
• The last line of the footnote section will be a standard source line that indicates the name 
of the program used to produce the data display and the date the program was run (e.g., 
‘Program: myprogram.sas    Date: 10OCT2013’). 
17. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses. {CRO SOP Number} provide an overview of 
the development of such SAS programs. 
CRO SOP will be used for the quality control procedures that are performed for all SAS 
programs and output. Quality control is defined here as the operational techniques and activities 
undertaken to verify that the SAS programs produce the proper clinical trial output by checking 
for their logic, efficiency and commenting and by review of the produced output.  Details will be 
provided in a project-specific Quality Control Plan (QCP). 
18. 
INDEX OF TABLES, LISTINGS AND FIGURES 
{Will be updated later} 
i D’Agostino RB et al., 2008, General Cardiovascular Risk Profile for Use in Primary Care: The Framingham Heart 
Study, Circulation, 117(6):743–753.