Clinical trial NCT03242590
Conditions: Hypogonadism, Male
Sponsor: Lipocine Inc.
Start date: 2016-12-01; Completion date: 2017-07-01
Enrollment: 95 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Multicenter, open-label, one treatment study evaluating the efficacy of LPCN 1021 in adult hypogonadal male subjects.

Detailed description:

Arms: arm 1: Oral testosterone undecanoate, LPCN 1021 225 mg TU two times a day.
Interventions: intervention 1: LPCN 1021
Intervention descriptions: intervention 1: Oral testosterone undecanoate

Protocol documents:
Prot_SAP_000.pdf: 
Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 1 of 39 
1.0 
TITLE PAGE 
Clinical Study Protocol: LPCN 1021-16-002 
Validation of Dosing Regimen of Oral Testosterone Undecanoate (TU, LPCN 1021) in 
Hypogonadal Men. 
 
Investigational Product : Testosterone Undecanoate (TU, LPCN 1021) 
Date of Protocol 
: January 24th 2017 
FDA IND No. 
: 106476 
Development Phase 
: Phase 1 
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 
: 03 
Amendments 
: N/A 
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agreement by the recipient that no unpublished information contained within will be published or 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 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 2 of 39 
2.0 
SUMMARY OF CHANGES TO PROTOCOL IN VERSION 02 
Version 02 of the LPCN1021-16-002 study protocol was developed to make the following changes 
to the study: 
 The protocol was updated to clarify that all T Cmax values that occur following morning 
and evening doses will be used to calculate Cmax proportions, and an evaluation of T 24-
hour Cmax was added. 
 Extended study duration to 25 days. 
 Increased the study size to 100 subjects. 
 Exclusion criteria 4: deleted the body mass index (BMI) exclusion criterion (BMI≥38 
kg/m2). 
 Exclusion criterion 4: added exclusion criterion for subjects with symptoms of moderate 
to severe benign prostatic hyperplasia. 
 Exclusion criterion 5a: updated baseline hemoglobin exclusion criterion from >18g/dL to 
>16.5 g/dL. 
 Exclusion criterion 7: updated history of seizures or convulsions exclusion criterion to 
specify that this criterion is applicable to seizures or convulsions occurring after age 5. 
 Exclusion criterion 13: clarified that subjects should be excluded if they have active 
alcohol/drug abuse, or a history of abuse, that the investigator determines will interfere 
with study participation. 
 Exclusion criterion 14: clarified the history of long QT syndrome exclusion criterion to 
specify QTc >450. 
 Exclusion criterion 16: clarified that this criterion is applicable to the use of investigational 
drug. 
 Exclusion criterion 17: clarified that this criterion is applicable to the use of investigational 
drug. 
 Updated the normal testosterone range for the primary endpoint so that it is based on the 
lab determined normal range. 
 Added cosyntropin stimulation testing to screening (for the first 50 subjects to undego Visit 
2) and exit (for enrolled subjects who had test at screening) procedures. 
 Clarified that urine alcohol testing will be performed at screening and exit. 
 Clarified that a physical examination will be performed at screening and exit. 
 Removed cotinine from the screening and exit drug panel. 
 Removed the standard meal, meal fat and carbohydrate specifications. 
 Added alcohol restriction, and caffeine intake limitation during confinement. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 3 of 39 
 Clarified that primary endpoint, secondary endpoint, and additional evaluation analysis 
will be performed using all treated subjects, with missing data handled by imputation. 
 Additional minor wording corrections that with no impact to the conduct of the study.  
 
In addition, the changes described in protocol administrative change letters 1 and 2 were 
incorporated into the protocol: 
 Added an electrocardiogram at the screening visit to identify, and subsequently exclude, 
subjects with long QT syndrome. 
 The blood sample taken for pharmacokinetic (PK) analysis at each timepoint was 
changed from 8 ml to 12 ml.  The total amount of blood collected for PK analysis was 
accordingly changed from 88 ml to 132 ml.   
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 4 of 39 
3.0 
SUMMARY OF CHANGES TO PROTOCOL IN VERSION 03 
Version 03 of the LPCN1021-16-002 study protocol was developed to make the following changes 
to the study: 
 On Visit 4, added pharmacokinetic (PK) sampling at hour 3, 5, 15, and 17 post AM 
dose.  The updated protocol provides for PK blood samples at 0 (pre-dose), 2, 3, 4, 5, 
6, 8, 12 (before evening dose), 14, 15, 16, 17, 18, 20 and 24 hours relative to morning 
dose.  The total amount of blood collected for PK analysis was changed accordingly 
from 132 ml to 180 ml.   
 Removed the note that the primary endpoint, secondary endpoints, and additional 
evaluation analyses will be performed using all treated subjects, with missing data 
handled by imputation.  The statistical analyses performed on the primary endpoint, 
secondary endpoints, and additional evaluations will be described in the 
LPCN 1021-16-002statisitical analysis plan (SAP). 
In addition, the following change described in protocol clarification letter 1 was incorporated into 
the protocol: 
 The Cosyntropin test will be performed on 50 subjects during Visit 2, regardless of 
the order of the subjects undergoing Visit 2.   
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 5 of 39 
5.0 
SYNOPSIS 
Sponsor 
:  Lipocine Inc.   
Protocol Number 
: LPCN 1021-16-002 
Study Drug Name 
:  Testosterone Undecanoate Capsule  
Phase of Development 
:  Phase 1 
Active Ingredient 
:  Testosterone Undecanoate 
 
Date of Protocol Synopsis :  January 24th 2017 
Protocol Title:  
  
Validation of dosing regimen of Oral Testosterone Undecanoate (TU, LPCN 1021) in 
Hypogonadal Men.  
Objectives:  
 
Primary Objective:  To validate the dosing regimen of LPCN 1021 to achieve therapeutic 
concentrations of T in Hypogonadal Men.  
Secondary Objectives: To assess safety and tolerability of LPCN 1021. 
Study Population: Hypogonadal males, aged 18–80 years (inclusive), with onset of 
hypogonadism diagnosed at age < 65 years. 
Number of Subjects: 100 
Study Endpoints:  
 
Primary Endpoint:   
To determine the proportion of LPCN 1021-treated subjects who achieve a 24-hour average 
serum total testosterone (T) concentration [Cavg (0-24)] within the lab determined normal range 
on Day 24.  
Secondary Endpoints:  
To determine the proportion of T Cmax below 1500 ng/dL, T Cmax between 1800 and 2500 
ng/dL, and T Cmax > 2500 ng/dL in subjects treated with LPCN 1021 on Day 24.  
Testosterone Cmax is defined as the maximum serum T concentration that occurs in the dosing 
interval (tau=12 hour for LPCN 1021). On Day 24, all Cmax values that occur following 
morning and evening doses will be used to compute the proportions. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 6 of 39 
Additional Evaluation: 
To determine the proportion of T 24-hour Cmax below 1500 ng/dL, T Cmax between 1800 and 
2500 ng/dL, and T Cmax > 2500 ng/dL in subjects treated with LPCN 1021 on Day 24. The T 
24-hour Cmax is defined as the maximum serum T concentration that occurs in a 24-hour period. 
Methodology: 
  
This is a multicenter, open-label, one treatment study evaluating the efficacy of LPCN 1021 in 
adult hypogonadal male subjects.  
The study is comprised of four scheduled visits: Visit 1 and 2 are for screening; Visit 3 is 
scheduled on Day 1 of the study for the start of dosing, and Visit 4 is for confinement of subjects 
for intensive pharmacokinetic (PK) sampling. 
Visit 1 & 2: Subjects will undergo a screening period to complete the pre-study examinations 
and to confirm their hypogonadal status. Serum total 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.  
Visit 3: A total of 100 hypogonadal men meeting inclusion criteria and none of the exclusion 
criteria will be enrolled to the study and assigned to receive 225 mg of LPCN 1021 two times a 
day for about 24 days (window of 20 to 28 days).   
Visit 4: Starting in the afternoon on Day 23, subjects will undergo confinement lasting for about 
38 hours. Subjects will enter the clinic in the afternoon of Day 23 (approximately 14 hours prior 
to anticipated dosing on the morning of Day 24) and will remain confined until the 24-hour 
blood draw on Day 25 is completed. There is one confinement visit in the study. Subjects will be 
exited from the study on Day 25.  
On Day 23, subjects will be provided with an evening meal, and study drug is administered at the 
clinic (approximately 12 hours prior to anticipated dosing on the morning of Day 24). Following 
the administration of the morning dose on Day 24 with a meal (refer to Section 11.4.1.8), 
intensive PK sampling will be carried out for up to 24 hours post AM dose. Blood samples will 
be obtained at 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12 (before evening dose), 14, 15, 16, 17, 18, 20 and 
24 hours relative to morning dose. Safety assessments will be carried out periodically during the 
study, and at exit. The total duration of the study will be about 25 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 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 7 of 39 
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 300 ng/dL based on 2 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. 
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 findings in the pre-study examinations including abnormal 
breast examination requiring follow-up.  
3. Abnormal prostate digital rectal examination (DRE) with palpable nodule(s). 
4. Subjects with symptoms of moderate to severe benign prostatic hyperplasia.  
5. Clinically significant abnormal laboratory value, in the opinion of the investigator, in 
serum chemistry, hematology, or urinalysis including but not limited to: 
a. Baseline 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 > 2 ng/mL  
g. Prolactin > 17.7 ng/mL. 
6. Positive test result for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B 
surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab) or human 
immunodeficiency virus antibodies (HIV Ab). 
7. History of seizures or convulsions occurring after age 5, including alcohol or drug 
withdrawal seizures. 
8. History of gastric surgery, cholecystectomy, vagotomy, bowel resection or any 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 8 of 39 
surgical procedure that might interfere with gastrointestinal motility, pH or 
absorption. 
9. History of any clinically significant illness, infection, or surgical procedure within 1 
month prior to study drug administration. 
10. History of stroke or myocardial infarction within the past 5 years. 
11. History of or current or suspected prostate or breast cancer.  
12. History of untreated and severe obstructive sleep apnea.  
13. 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. 
14. History of long QT syndrome (QTc > 450) or unexplained sudden death in a first 
degree relative (parent, sibling, or child). 
15. 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.   
16. 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.   
17. 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. 
18. Subjects who are not on stable dose of current medication. 
19. Donation or loss of 550 mL or more blood volume (including plasmapheresis) or 
receipt of a transfusion of any blood product within 3 months prior to the start of 
treatment. 
20. Inadequate venous access for collection of serial blood samples required for 
pharmacokinetic profiles. 
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 (when investigator 
criteria is used, exact reason should be specified). 
23. Subject who is not willing to use adequate contraception for the duration of the study.  
Investigational Product: Testosterone Undecanoate 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 (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).  
Administration Route: Oral. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 9 of 39 
Reference Therapy:  Not applicable. 
Study Duration:  Study duration will be up to 25 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. 
 Increase in hematocrit to > 54%, PSA > 4 ng/mL 
 Significant noncompliance with the protocol requirements. 
 Lost to follow-up. 
 
Criteria for Evaluation: 
The pharmacokinetics of T, dihydrotestosterone (DHT), TU, dihydrotestosterone undecanoate 
(DHTU) and estradiol (E2) will be assessed on Day 24.  
Safety and tolerability of LPCN 1021 will be reported over the duration of treatment for the 
following parameters: 
o Change from baseline in physical examinations and laboratory parameters (i.e., 
chemistries, hematology, hematocrit, lipids, PSA)   
o Incidence of AEs. 
Statistical Methods: Statistical analyses will be described in the Protocol and SAP. 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 10 of 39 
6.0 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6.1. 
Abbreviations 
AE  
Adverse event 
ALT (SGPT)  
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
AST (SGOT)  
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BID 
Twice daily 
BMI  
Body mass index 
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 
PD  
Pharmacodynamic 
PI 
Principal investigator 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 11 of 39 
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 
 
 
6.2. 
Pharmacokinetic and Statistical Abbreviations 
AUC 
Area under the serum concentration-time curve 
AUCt 
Area under the serum concentration-time curve from time zero to time of last 
measurable concentration 
Cavg 
Average serum concentration 
Cmax 
Maximum observed serum concentration 
Cmax-tau 
The maximum serum concentration that occurs in the dosing interval 
Tmax 
Time to maximum observed serum concentration 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 12 of 39 
7.0 
TABLE OF CONTENTS 
1.0 
Title Page ...................................................................................................................1 
2.0 
Summary of Changes to Protocol in Version 02 ....................................................2 
3.0 
Synopsis......................................................................................................................5 
4.0 
List of Abbreviations and Definition of Terms ....................................................10 
4.1. 
Abbreviations .............................................................................................................................. 10 
4.2. 
Pharmacokinetic and Statistical Abbreviations ........................................................................... 11 
5.0 
Table of contents .....................................................................................................12 
6.0 
Introduction .............................................................................................................14 
7.0 
Study objectives.......................................................................................................16 
7.1. 
Primary Objective ....................................................................................................................... 16 
7.2. 
Secondary Objectives .................................................................................................................. 16 
7.3. 
Study Endpoints: ......................................................................................................................... 16 
7.3.1. 
Primary Endpoint: ............................................................................................................. 16 
7.3.2. 
Secondary Endpoint: ......................................................................................................... 16 
8.0 
Investigational plan.................................................................................................16 
8.1. 
Overall Study Design .................................................................................................................. 16 
8.2. 
Selection of Study Population ..................................................................................................... 17 
8.2.1. 
Inclusion Criteria .............................................................................................................. 17 
8.2.2. 
Exclusion Criteria ............................................................................................................. 18 
9.0 
Study Procedures ....................................................................................................19 
9.1. 
Screening Procedures .................................................................................................................. 19 
9.2. 
Randomization and Blinding ...................................................................................................... 20 
9.3. 
Treatment Phase .......................................................................................................................... 20 
9.4. 
Clinical Procedures ..................................................................................................................... 20 
9.4.2. 
Dosage Administration and Titration ................................................................................ 25 
9.5. 
Subject Discontinuation .............................................................................................................. 25 
9.5.1. 
Exit Evaluation ................................................................................................................. 26 
9.6. 
Study Discontinuation ................................................................................................................. 26 
9.7. 
Drug Product ............................................................................................................................... 26 
9.7.1. 
Packaging and Labeling .................................................................................................... 26 
9.7.2. 
Storage and Disposition of Study Drug ............................................................................ 26 
9.7.3. 
Treatment Compliance and Drug Accountability ............................................................. 26 
10.0 
Adverse Events ........................................................................................................27 
10.1. Definition of an Adverse Event .................................................................................................. 27 
10.2. Serious Adverse Events .............................................................................................................. 28 
10.3. Adverse Event Severity ............................................................................................................... 28 
10.4. Relationship to Study Drug ......................................................................................................... 29 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 13 of 39 
10.5. Adverse Event Collection Period ................................................................................................ 29 
10.6. Adverse Event Reporting ............................................................................................................ 29 
11.0 
Protocol Deviations .................................................................................................29 
12.0 
Statistical Analysis ..................................................................................................30 
12.1. Study Populations ....................................................................................................................... 30 
12.2. Pharmacokinetic Analyses .......................................................................................................... 30 
12.3. Primary Endpoint ........................................................................................................................ 31 
12.4. Secondary Endpoints .................................................................................................................. 31 
12.5. Safety Endpoints ......................................................................................................................... 32 
12.6. Statistical Analysis ...................................................................................................................... 32 
12.7. Determination of Sample Size .................................................................................................... 32 
13.0 
Ethics ........................................................................................................................33 
13.1. Institutional Review Board (IRB) ............................................................................................... 33 
13.2. Ethical Conduct of the Study ...................................................................................................... 33 
13.3. Subject Information and Consent ................................................................................................ 33 
14.0 
Source Documents and Case Report Form Completion .....................................33 
14.1. Source Documents ...................................................................................................................... 34 
14.2. Case Report Forms ...................................................................................................................... 34 
15.0 
Data Quality Assurance..........................................................................................35 
16.0 
Use of Information ..................................................................................................35 
17.0 
Completion of the Study .........................................................................................36 
Appendix A. 
Schedule of Events: ........................................................................................37 
Appendix B. 
Investigator's Agreement ..............................................................................38 
 
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 14 of 39 
8.0 
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.”i  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.ii  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 
                                                 
 
i  
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 
ii  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 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 15 of 39 
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.iii 
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.iv  
The LPCN 1021 clinical development program included eight Phase 1 studies and one Phase 3 
study.  In previous clinical studies (Study LPCN 1021-05-001 and Study LPCN 1021-09-001), 
various oral T undecanoate 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 clinical study, LPCN 1021-13-001, provides safety, efficacy, and pharmacokinetic 
data relating to the use of twice daily dosing of LPCN 1021 for T replacement therapy in men 
with primary and secondary hypogonadism.  Results indicate that eugonadal range levels can be 
achieved with a starting dose of 225 mg BID taken with a meal. 
Further discussion of the preclinical toxicology, metabolism, and pharmacology can be found in 
the Investigator's Brochure. 
                                                 
 
iii  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. 
iv 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 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 16 of 39 
9.0 
STUDY OBJECTIVES 
9.1. 
Primary Objective 
To validate the dosing regimen of LPCN 1021 to achieve therapeutic concentrations of T in 
Hypogonadal Men. 
9.2. 
Secondary Objectives  
To assess safety and tolerability of LPCN 1021.  
9.3. 
Study Endpoints:   
9.3.1. 
Primary Endpoint:   
To determine the proportion of LPCN 1021-treated subjects who achieve a 24-hour average 
serum total testosterone concentration [Cavg (0-24)] within the lab determined normal range on 
Day 24.  
9.3.2. 
Secondary Endpoint:  
To determine the proportion of T Cmax below 1500 ng/dL, T Cmax between 1800 and 2500 
ng/dL, and T Cmax > 2500 ng/dL in subjects treated with LPCN 1021 on Day 24.  
T Cmax is defined as the maximum serum T concentration that occurs in the dosing interval 
(tau=12 hour for LPCN 1021). On Day 24, all T Cmax values that occur following morning and 
evening doses will be used to compute the proportions.  
Additional Evaluation: 
To determine the proportion of T 24-hour Cmax below 1500 ng/dL, T Cmax between 1800 and 
2500 ng/dL, and T Cmax > 2500 ng/dL in subjects treated with LPCN 1021 on Day 24. The T 
24-hour Cmax is defined as the maximum serum T concentration that occurs in a 24-hour period. 
 
10.0 
INVESTIGATIONAL PLAN 
10.1. 
Overall Study Design 
This is a multicenter, open-label, one treatment study evaluating the efficacy of LPCN 1021 in 
adult hypogonadal male subjects.   Subjects may be naive to T treatment or may enroll after 
stopping current treatment and completing an adequate washout period. 
The study is comprised of four scheduled visits: Visit 1 and 2 are for screening; Visit 3 is 
scheduled on Day 1 of the study for the start of dosing, and Visit 4 is for confinement of subjects 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 17 of 39 
for intensive pharmacokinetic (PK) sampling. 
Visit 1 & 2: Subjects will undergo a screening period to complete the pre-study examinations 
and to confirm their hypogonadal status. Serum total 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.  
Visit 3: A total of 100 hypogonadal men meeting inclusion criteria and none of the exclusion 
criteria will be enrolled to the study and assigned to receive 225 mg of LPCN 1021 two times a 
day for about 24 days (window of 20 to 28 days).   
Visit 4: Starting on Day 23, subjects will undergo confinement lasting for about 38 hours. 
Subjects will enter the clinic in the afternoon of Day 23 (approximately 14 hours prior to 
anticipated dosing on Day 24 morning) and will remain confined until the 24-hour blood draw on 
Day 25 is completed. Subjects will be exited from the Study on Day 25.   
On Day 23, subjects will be provided with an evening meal and study drug is administered in the 
clinic (at approximately 12 hours prior to anticipated dosing on Day 24 morning). Following the 
administration of the morning dose with a meal (refer to Section 11.4.1.8) on Day 24, intensive 
PK sampling will be carried out. Blood samples at 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12 (prior to 
evening dose), 14, 15, 16, 17, 18, 20 and 24 hours relative to morning dose. A total of 15 blood 
samples are collected per subject with 12 mL of whole blood collected for each sample. A total 
of 180 mL of whole blood will be collected per subject for PK analysis. 
10.2. 
Selection of Study Population 
Subjects will undergo screening procedures approximately 30 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. 
10.2.1. 
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 
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 300 ng/dL based on 2 consecutive blood samples obtained between 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 18 of 39 
6 and 10 AM, on two separate days at approximately the same time of day (between 6 
and 10 AM), following an appropriate washout of current androgen replacement therapy. 
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 serum T samples to determine study eligibility. 
6. Judged to be in good general health as determined by the investigator at screening. 
 
10.2.2. 
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 findings in the pre-study examinations including abnormal breast 
examination requiring follow-up.  
3. Abnormal prostate digital rectal examination (DRE) with palpable nodule(s). 
4. Subjects with symptoms of moderate to severe benign prostatic hyperplasia.  
5. Clinically significant abnormal laboratory value, in the opinion of the investigator, in 
serum chemistry, hematology, or urinalysis including but not limited to: 
a. Baseline 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 > 2 ng/mL 
g. Prolactin > 17.7 ng/mL 
6. Positive test result for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B 
surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab) or human 
immunodeficiency virus antibodies (HIV Ab).  
7. History of seizures or convulsions occurring after age 5, including alcohol or drug 
withdrawal seizures. 
8. History of gastric surgery, cholecystectomy, vagotomy, bowel resection or any surgical 
procedure that might interfere with gastrointestinal motility, pH or absorption. 
9. History of any clinically significant illness, infection, or surgical procedure within 1 
month prior to study drug administration. 
10. History of stroke or myocardial infarction within the past 5 years. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 19 of 39 
11. History of or current or suspected prostate or breast cancer. 
12. History of untreated and severe obstructive sleep apnea. 
13. 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. 
14. History of long QT syndrome (QTc >450) or unexplained sudden death in a first degree 
relative (parent, sibling, or child). 
15. 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.   
16. 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.   
17. 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. 
18. Subjects who are not on stable dose of current medication. 
19. Donation or loss of 550 mL or more blood volume (including plasmapheresis) or receipt 
of a transfusion of any blood product within 3 months prior to the start of treatment. 
20. Inadequate venous access for collection of serial blood samples required for 
pharmacokinetic profiles. 
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. 
23. Subject who is not willing to use adequate contraception for the duration of the study. 
11.0 
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). 
11.1. 
Screening Procedures 
Screening procedures will be performed within 30 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: demographic data, medical and medication histories, physical 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 20 of 39 
examination (including digital rectal examination, breast and testicular exams), vital signs, oral 
temperature and the first screening Testosterone sample. 
In the Second Screening Visit sampling for additional laboratory analysis will be carried out and 
will include second screening testosterone sample, electrocardiogram, hematology, coagulation 
(PT/INR and aPTT), biochemistry (including prolactin, PSA), HIV, hepatitis B and C tests, 
urinalysis and urine drug and alcohol screen.  In addition, baseline endocrinology assessments at 
Visit 2 include follicle simulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), sex 
hormone binding globulin (SHBG), and DHT.  Cosyntropin stimulation testing will be 
performed on a subset of approximately 50 subjects. 
11.2. 
Randomization and 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.   
11.3. 
Treatment Phase 
Treatment Phase of the study consists of approximately 25 days starting with Visit 3, and ending 
in Visit 4. 
Visit 3: Once subjects are enrolled into the study, they will come to the site where adequate 
quantities study drug will be dispensed. This will be the Day 1 of treatment. Subjects will be 
advised to take the study medication twice daily, at approximately 30 minutes following meal. 
Subjects will be scheduled to return to the clinic for the confinement visit (Visit 4, starting on 
Day 23). 
Visit 4 is a confinement visit with intensive PK blood sampling on Day 24. It starts on the day 
before and ends following 24th hour blood sample next day. This confinement visits lasts for 
about 38 hours. The permitted window for this visit to begin is Day 20 to Day 28. 
During the confinement visit, all meals and study drug administration (evening of Day 23, 
morning and evening on Day 24) will be carried out at the site. On Day 24, following study drug 
administration in the morning, intensive blood samples will be obtained for PK analysis. 
Subjects will be exited from the study confinement and study following 24th hour blood sampling 
and exit procedures. 
11.4. 
Clinical Procedures 
The following sections help define the requirements of medical / clinical information to be 
obtained as a part of the study. 
11.4.1.1. 
Medical and Medication History 
The subject’s medical history (key events) during the past 5 years will be obtained and recorded 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 21 of 39 
on the Medical History Electronic Case Report Form (eCRF). All subjects entering the study 
should have diagnosis of primary or secondary hypogonadism. 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. 
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 who have been under stable treatment with the same medication for at least 3 months 
for a stable chronic condition, with no change in dosage for at least 14 days before the first 
dosing, and no expected change throughout the study, and for which there is no interaction with 
the pharmacokinetics of the study drug or the bioanalytical methods, will be eligible for the. 
11.4.1.2. 
Electrocardiogram 
An electrocardiogram will be performed at the screening to identify, and subsequently exclude, 
subjects with long QT syndrome. 
11.4.1.3. 
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, breast, testicular exams and digital rectal 
exam (DRE) of prostate. Any changes during the study will be documented. Subject's height and 
weight will be used to calculate BMI.  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 22 of 39 
11.4.1.4. 
Vital Signs 
Body temperature, systolic and diastolic blood pressure and pulse rate will be measured at 
screening, confinement visit and at the end of the study. The vital sign measurements at 
screening will serve as the baseline measurements for clinical assessments. Vital signs must be 
measured after the subject has been sitting at rest for at least 5 minutes. 
11.4.1.5. 
Clinical Laboratory Tests 
11.4.1.5.1. 
Hematology, Chemistries, and Urinalysis 
Blood samples for the clinical laboratory tests will be performed screening and end of the study 
(refer Table 1 and Appendix A). Samples for serum chemistry tests will be collected in the 
morning prior to meals and study drug administration. The test results from screening will serve 
as the baseline for future clinical assessments.  
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.  
 
 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 23 of 39 
Table 1: Listing of Clinical Laboratory Tests 
Hematology 
Clinical Chemistry  
Urinalysis  
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count 
White blood cell (WBC) count  
Neutrophils bands (if detected)  
Lymphocytes  
Monocytes  
Basophils (if detected)  
Eosinophils (if detected)  
Absolute platelet count  
Mean corpuscular hemoglobin 
(MCH)  
Mean corpuscular volume (MCV)  
Mean corpuscular hemoglobin 
concentration (MCHC)  
Prothrombin time (PT)  
Activated partial thromboplastin 
time (aPTT)  
 
Blood urea nitrogen (BUN) 
Creatinine 
Total bilirubin 
Serum glutamic-pyruvic transaminase (SGPT/ALT) 
Serum glutamic-oxaloacetic transaminase (SGOT/AST) 
Alkaline phosphatase 
Sodium potassium 
Calcium  
Inorganic phosphorus  
Uric acid  
Cholesterol  
Total protein  
Triglycerides  
Albumin  
Chloride  
High density lipoprotein (HDL) cholesterol  
Low density lipoprotein (LDL) cholesterol  
Magnesium  
Gamma-glutamyl transpeptidase (GGTP)  
Specific gravity  
Ketones  
pH  
Protein  
Blood  
Glucose  
Urobilinogen  
Bilirubin  
 
A laboratory test value that requires a subject to be discontinued from the study or requires a 
subject to receive treatment will be recorded as an AE.  
11.4.1.5.2. 
Screening for Hepatitis 
HAV-IgM, HBsAg and HCV Ab tests will be performed at screening. The hepatitis test panel 
will be performed by a certified laboratory. Some states might require facilities that perform this 
testing to report the name of anyone who tests positive for hepatitis B or hepatitis C antibodies. 
11.4.1.5.3. 
Screening for HIV 
Subjects will have blood tested by a certified laboratory for the presence of HIV antibodies at 
screening. Only those subjects negative for the presence of antibodies will be allowed to enroll in 
the study. The results of the HIV antibodies testing will be retained by the study site under 
confidential restriction. However, some states might require facilities that perform this testing to 
report the names of anyone who tests positive for HIV antibodies. 
11.4.1.5.4. 
Urine Screens for Drugs of Abuse and Alcohol 
A urine screen for drugs of abuse and alcohol will be performed at screening and exit. The panel 
for drugs of abuse will minimally include cannabinoids, opiates, barbiturates, amphetamines, 
cocaine, and benzodiazepines. Analyses will be performed by a certified laboratory. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 24 of 39 
11.4.1.5.5. 
Endocrinology Assessments 
The sex hormone binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing 
hormone (LH) and prolactin will be performed at screening and exit.  
11.4.1.5.6. 
Cosyntropin Stimulation Test 
On 50 subjects, a Cosyntropin stimulation test will be performed at screening Visit 2.  Subjects 
who have the Cosyntropin stimulation test at screening who are subsequently enrolled and 
complete the study will have the test repeated at exit (Visit 4).   
Cosyntropin stimulation testing will be conducted after obtaining a control blood sample for 
cortisol measurement. Refer to product label of Cosyntropin for exact dosage and administration 
instructions. 
11.4.1.5.7. 
Prostate-Specific Antigen (PSA) 
Samples for PSA (prior to DRE if applicable) will be collected at screening and end of the study.  
11.4.1.5.8. 
Serum Testosterone and Related Hormones 
At screening, serum total T must be below 300 ng/dL based on 2 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. The analytical method used to 
assess screening testosterone will be the same method as used for pharmacokinetic analysis. In 
addition, a blood sample for determination of baseline serum hormones (E2, and DHT) will be 
collected at screening. Refer to the Schedule of Events (Appendix A) for sample collection days 
and times. 
11.4.1.6. 
Blood Samples for Pharmacokinetic Analyses 
On the day of confinement, the timing of blood collections will take priority over all other 
scheduled study activities except for dosing. Intensive pharmacokinetic sampling will be done as 
follows. A total of 12 mL whole blood will be collected for the PK analysis. 
 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12 (prior to evening dose), 14, 15, 16, 17, 18, 20 and 24 
hours relative to morning dose. 
A total of 15 blood samples, 180 mL of blood will be collected per subject.  The time that each 
blood sample is collected will be recorded to the minute. Blood sample collection should be 
performed within ± 10 minutes of the scheduled time points (with the exception of the 0-hour 
time point).  Details on the handling and processing of samples are provided in the laboratory 
manual. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 25 of 39 
11.4.1.7. 
Confinement: 
There is one confinement visit for each subject on Day 24 (20 to 28 days). Subjects will be 
admitted to the clinic approximately 14 hours prior to the morning dose and remain confined for 
approximately 38 hours. The evening meal and dose of subject on the day before (Day 23) will 
be administered at the clinic.  Serial blood samples will be drawn for approximately 24 hours 
after the AM dose. Subjects will be released from the clinic 24 hours after the AM dose blood 
draw. Strenuous activity during confinement will not be permitted.  
11.4.1.8. 
Meals and Dietary Requirements 
Throughout the study, subjects will be advised to maintain a standard diet which 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.  
11.4.2. 
Dosage Administration and Titration 
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.    
11.5. 
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. 
 Increase in hematocrit to > 54%, PSA > 4 ng/mL 
 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. 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 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 26 of 39 
resolution of the laboratory result or AE is achieved. 
 
11.5.1. 
Exit Evaluation 
Exit evaluation is the same as Day 25 procedures (24 hours from morning dose of Day 24) for 
subjects who complete the study. For subjects who withdraw from the study or discontinued 
early exit evaluation should be conducted.   
11.6. 
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. 
11.7. 
Drug Product 
LPCN 1021 is gelatin capsule product that will be provided as 112.5 mg TU per capsule.  
11.7.1. 
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.  
11.7.2. 
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. 
11.7.3. 
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 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 27 of 39 
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 
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. 
12.0 
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. 
12.1. 
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, 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 28 of 39 
and/or if the investigator considers them to be AEs. 
12.2. 
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.  
12.3. 
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 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 29 of 39 
and may be incapacitating or life-threatening. 
12.4. 
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. 
12.5. 
Adverse Event Collection Period 
All AEs in the subject and pregnancies that occur in subject’s partner reported from the time of 
study drug administration until 30 days after last dose of study drug will be collected, whether 
solicited or spontaneously reported by the subject. In addition, SAEs will be collected from the 
time the subject provided written informed consent. 
12.6. 
Adverse Event Reporting 
In the event of an SAE in the subject or pregnancy in subject partner, 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 
13.0 
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 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 30 of 39 
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. 
14.0 
STATISTICAL ANALYSIS 
The primary and secondary endpoints and associated analyses are described in this section. 
Details of the analyses to be performed will be given in a statistical analysis plan 
14.1. 
Study Populations 
Statistical analyses will be performed on the full analysis set (FAS), pharmacokinetic set (PK 
set), and safety set.  
Safety Set (SS): The safety set includes all subjects who were randomized and received a dose 
of study drug.  
Full Analysis Set (FAS): The FAS consists of all subjects enrolled into the study with at least 
one post baseline efficacy variable data point (Cmax or Cavg).  
Pharmacokinetic Set (PK set): The PK set consists of subjects in FAS who complete the study 
without major protocol deviations. 
 
14.2. 
Pharmacokinetic Analyses 
The following pharmacokinetic parameters will be calculated by standard non-compartmental 
methods for T, DHT, TU, and DHTU:  
 AUC0-24: area under the concentration-time curve from time zero to the 24 hours. 
 Cavg0-24: average concentration from 0 to 24 hours obtained by dividing AUC0-24 /24. 
 Cmax: maximum concentration following administration of LPCN 1021 prior to next 
dose. 
 24-hour Cmax: maximum concentration occurring in a 24-hour interval 
Pharmacokinetic parameters will be calculated based on serum concentrations as appropriate.  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 31 of 39 
Additional analysis includes estimating the duration for which a subject’s serum T concentration 
levels exceed 1500 ng/dL, 1800 ng/dL and 2500 ng/dL. A comprehensive listing of the serum 
hormone concentrations measured during the study confinement periods will be presented. 
Individual and treatment overall, will be presented. 
 
14.3. 
Primary Endpoint 
The primary endpoint will be the percentage of LPCN 1021-treated subjects who achieve a 
24-hour average serum T concentration within the lab determined normal range upon completion 
of 24 days of treatment. The target minimum acceptable percentage is 75%. A 95%, 2-sided, 
binomial confidence interval surrounding the point estimate must have a lower bound of  65%.  
Statistical analyses of the primary endpoint will be described in the SAP. 
14.4. 
Secondary Endpoints 
The secondary endpoints will be based on the proportion of T Cmax below 1500 ng/dL, T Cmax 
between 1800 and 2500 ng/dL, and T Cmax > 2500 ng/dL in subjects treated with LPCN 1021 
for 24 days.  
T Cmax is defined as the maximum serum T concentration that occurs in the dosing interval 
(tau=12 hour for LPCN 1021). On Day 24, all Cmax values that occur following morning and 
evening doses will be used to compute the proportions.  
Testosterone Cmax must be 1)  1500 ng/dL in ≥ 85% of all subjects, 2) between 1800 and 2500 
ng/dL in ≤ 5% of subjects, and 3) > 2500 ng/dL in no subjects treated.  
Statistical analyses of the secondary endpoints will be described in the SAP. 
Additional Evaluation: 
To determine the proportion of T 24-hour Cmax below 1500 ng/dL, T Cmax between 1800 and 
2500 ng/dL, and T Cmax > 2500 ng/dL in subjects treated with LPCN 1021 on Day 24. The T 
24-hour Cmax is defined as the maximum serum T concentration that occurs in a 24-hour period. 
Testosterone 24-hour Cmax must be 1)  1500 ng/dL in ≥ 85% of all subjects, 2) between 1800 
and 2500 ng/dL in ≤ 5% of subjects, and 3) > 2500 ng/dL in no subjects treated.  
Statistical analyses of additional evaluations will be described in the SAP. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 32 of 39 
14.5. 
Safety Endpoints 
Key safety endpoints are AEs, physical examination, clinical laboratory tests and vital signs. 
 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 
discontinuation, and target treatment-emergent AEs (e.g., elevated PSA, elevated hematocrit, 
elevated LDL) will be summarized. Listings will be provided for all AEs, SAEs, AEs resulting in 
discontinuation, and target AEs. 
 
14.6. 
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 [%]), min., max., and median) of the serum concentrations versus time will be 
presented for the pharmacokinetic parameters. 
A complete description of the statistical analyses to be performed will be presented in a 
Statistical Analysis Plan (SAP) as a separate document.  
14.7. 
Determination of Sample Size 
Sample size for the study was based on the primary endpoint, the incidence and binomial 
confidence interval for the percentage of subjects achieving serum T concentrations within the 
normal range. In a previous safety and efficacy study (Study LCPN 1021-13-001), 86% of 
subjects administered LPCN 1021 225 mg BID would have achieved the primary efficacy 
endpoint (e.g., ≥ 75% of subjects have normal T concentrations) based on a post-hoc analysis of 
Week 3 data.  Assuming similar efficacy in the current study, a sample size of 11 subjects would 
meet the 95 % CI lower bound of  65%.  Based on the recommedations of the Food and Drug 
Administration (FDA), a sample size of 100 subjects was selected.  


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 33 of 39 
15.0 
ETHICS 
15.1. 
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. 
15.2. 
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. 
15.3. 
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. 
16.0 
SOURCE 
DOCUMENTS 
AND 
CASE 
REPORT 
FORM 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 34 of 39 
COMPLETION 
16.1. 
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. 
16.2. 
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 (e.g., Rave, Medidata). 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 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 35 of 39 
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 
printouts from that media. 
17.0 
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. 
 
18.0 
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. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 36 of 39 
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 
records under adequate security and restricted access, and will not be retrieved by 
Lipocine/CRO. 
19.0 
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 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 37 of 39 
Appendix A. 
SCHEDULE OF EVENTS:  
Visit 
Visit 1 Visit 2 Visit 3 
Visit 4 (Confinement Visit) 
Exit1 
Day 
 
 
Day 1 
Day 24 (Window: 20 to 28 days); Time relative to time of dosing on Day 24 morning 
25 
Time 
 
 
 
-14 hrs -12 hrs 
0 
2 
3 
4 
5 
6 
8 
12 
14 
15 
16 
17 
18 
20 
24 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight, BMI3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample collection10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening T Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry including PSA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum hormones (E2, DHT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen, Serology5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cosyntropin9, LH, FSH, SHBG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Reporting 
 
 
 
 
Concomitant medication reporting7 
 
 
 
 
Meal administration & record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement begin2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug returned 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Study exit can be conducted at 24-hour time-point (up to 2 hours later) on Day 24 or when subject discontinues the study. 
2. 
Confinement begins in the afternoon on the day before intensive PK  
3. 
Height and BMI at screening only. 
4. 
Medical history for the past 5 years at screening, anything changed basis at subsequent visits. 
5. 
Serology includes HIV, Hepatitis A, B and C. 
6. 
Sample at T=0 and 12 will be taken prior to dose administration (up to about 45 minutes’ prior)  
7. 
Full medication history at screening and anything changed basis at subsequent visits. 
8. 
Study drug to be administered approximately 30 minutes after administration of meals 
9. 
On 50 subjects , a Cosyntropin stimulation test will be performed at screening Visit 2.  Subjects who have the Cosyntropin stimulation test at screening who are subsequently enrolled and 
complete the study will have the test repeated at exit (Visit 4). 
10. Listing of clinical laboratory tests provided in Table 1. 


Oral Testosterone Undecanoate 
TU, LPCN 1021 
Protocol No. LPCN 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 38 of 39 
Appendix B. 
INVESTIGATOR'S AGREEMENT 
Study Title: 
Validation of dosing regimen of oral Testosterone Undecanoate (TU, 
LPCN 1021) in hypogonadal men 
Study Number: 
LPCN 1021-16-002 
Final Date: 
January 24th 2017 
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 1021-16-002 
 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, UT-84108 
 
Date: January 24th 2017 
Confidential  
Page 39 of 39 
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)