Clinical trial NCT04134091
Conditions: Nonalcoholic Steatohepatitis (NASH)
Sponsor: Lipocine Inc.
Start date: 2019-08-27; Completion date: 2021-06-24
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo controlled, three arm study in adult men with biopsy confirmed NASH. The study is aimed at evaluating efficacy and tolerability of LPCN 1144 in adult men with NASH.

Detailed description:
This is a Phase 2, randomized, double-blind, placebo controlled, three arm study in adult men with biopsy confirmed NASH. The study is aimed at evaluating efficacy and tolerability of LPCN 1144 in adult men with NASH. The study will be conducted across multiple centers in the United States.

Approximately 75 subjects will be randomized in 1:1:1 ratio to receive one of the following treatments:

* Treatment A: Oral LPCN 1144 Formulation A
* Treatment B: Oral LPCN 1144 Formulation B
* Treatment C: Oral matching placebo

Subjects will undergo a screening period to determine study eligibility. As a part of screening, liver biopsies will be performed for subjects who have not had a liver biopsy within 6 months of Day 1, and fat fraction will be measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) in all subjects. Adult male subjects with histologic evidence of NASH will be enrolled into the study.

Eligible subjects will be randomized to one of the three treatment arms. The treatment phase will be for a duration of 36-weeks with assessments of liver biopsies, hepatic fat fraction, liver enzymes, lipid levels and other safety parameters. Safety and tolerability will be assessed throughout the study.

Arms: arm 1: LPCN 1144 Formulation A arm 2: LPCN 1144 Formulation B arm 3: Placebo
Interventions: intervention 1: LPCN 1144 Formulation A intervention 2: LPCN 1144 Formulation B intervention 3: Placebo
Intervention descriptions: intervention 1: Oral LPCN 1144 Formulation A capsule, total daily dose of 450 mg testosterone undecanoate administered as 225 mg testosterone undecanoate twice daily (BID). intervention 2: Oral LPCN 1144 + d-alpha tocopherol total daily dose of 450 mg testosterone undecanoate + 476 mg d-alpha tocopherol administered as 225 mg testosterone undecanoate + 238 mg d-alpha tocopherol BID intervention 3: Oral matching placebo capsule administered as BID

Protocol documents:
Prot_002.pdf: 
 
 
A Phase 2, Randomized Double-Blind, Placebo-
Controlled, Multi-Center Study to Assess the Efficacy, 
Safety and Tolerability of Oral LPCN 1144 in Subjects 
with Nonalcoholic Steatohepatitis (NASH) 
 
Protocol Number: LPCN 1144-18-002 
Phase: 2 
Coordinating Investigator: 
 
IND Number: 140203  
Sponsor: Lipocine Inc. 
 
 
Version Number:  3.0 
7 January 2020 
 
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. 


LPCN 1144 (Testosterone Undecanoate for NASH) 
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Protocol LPCN 1144-18-002 
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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ...........................................................................................6 
1 
SUMMARY OF CHANGES IN PROTOCOL VERSION 3.0 .........................................7 
2 
SUMMARY OF CHANGES IN PROTOCOL VERSION 2.0 .........................................8 
3 
PROTOCOL SYNOPSIS ..................................................................................................9 
 
Synopsis ...................................................................................................................9 
 
Scheme ...................................................................................................................14 
 
Schedule of Activities (SOA) ................................................................................14 
4 
STUDY POPULATION ..................................................................................................19 
 
Inclusion Criteria ...................................................................................................19 
 
Exclusion Criteria ..................................................................................................19 
 
Lifestyle Considerations ........................................................................................21 
 
Screen Failures .......................................................................................................21 
5 
INTRODUCTION ...........................................................................................................22 
 
Study Rationale ......................................................................................................22 
 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) ...............................................................................22 
 
Histology, Epidemiology and Disease Course.............................................22 
 
Current Treatment Options ..........................................................................23 
 
Clinical Trial Rationale ................................................................................23 
 
Rationale for Testosterone Treatment for NASH ........................................23 
 
Justification for Dose and Safety for Use in Proposed Population ........................25 
 
Receptor Pharmacology ...............................................................................25 
 
Non-Clinical Toxicology .............................................................................25 
 
Clinical Safety ..............................................................................................26 
 
Inclusion of D-alpha-Tocopherol Acetate in LPCN 1144 Formulation ................27 
6 
STUDY DESIGN.............................................................................................................27 
 
Overall Design .......................................................................................................27 
7 
STUDY INTERVENTION ..............................................................................................28 
 
Study Intervention(s) Administration ....................................................................28 
 
Study Intervention Description ....................................................................28 
 
Dosing and Administration ..........................................................................28 
 
Preparation/Handling/Storage/Accountability .......................................................28 
 
Acquisition and Accountability ...................................................................28 
 
Formulation, Appearance, Packaging, and Labeling ...................................29 
 
Product Storage and Stability.......................................................................29 
 
Measures to Minimize Bias: Randomization and Blinding ...................................29 
 
Description of Enrollment............................................................................29 


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Randomization and Blinding Procedures.....................................................29 
 
Maintenance of Trial Randomization Codes and Blinding ..........................29 
 
Procedures for Unblinding Treatment Assignment .....................................29 
8 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................................30 
 
Discontinuation of Study Intervention ...................................................................30 
 
Participant Discontinuation/Withdrawal from the Study .......................................30 
 
Monitoring and Stopping Criteria ..........................................................................31 
 
Blood Pressure Monitoring and Stopping Criteria.......................................31 
 
Creatinine Stopping Criteria ........................................................................31 
 
PSA Monitoring and Stopping Criteria........................................................31 
 
Hematocrit and Hemoglobin Monitoring and Stopping Criteria .................32 
 
Monitoring for Hepatotoxicity and Stopping Criteria for Hepatoxicity ......33 
 
Testosterone Monitoring and Stopping Criteria ..........................................33 
 
Common Terminology Criteria for Adverse Event Stopping Criteria.........33 
 
Lost to Follow-Up ..................................................................................................34 
9 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................34 
 
Visit Schedule Overview .......................................................................................34 
 
Screening Phase for Subject requiring testosterone/androgen washout ......35 
 
Screening Visits and Baseline Data Collection ...........................................35 
 
Randomization Visit (RZ; Day1) .................................................................37 
 
On Treatment and Follow – up Visits ..........................................................37 
 
Data and Safety Monitoring Board (DSMB) ..........................................................39 
 
Procedure Overview...............................................................................................39 
 
Subject Questionnaires.................................................................................39 
 
Liver MRI-PDFF .........................................................................................40 
 
Fibroscan (transient elastography) ...............................................................41 
 
Gait Speed ....................................................................................................41 
 
Hand Grip Strength Test ..............................................................................41 
 
Liver Biopsy.................................................................................................42 
 
Medical and Medication History .................................................................42 
 
Physical Examination...................................................................................43 
9.3.9 
Clinic BP and Pulse Rate (PR) Measurement Methodology: ......................43 
 
Clinical Laboratory Tests .............................................................................44 
 
Screens for Drugs of Abuse and Alcohol ....................................................44 
 
Prostate-Specific Antigen (PSA) and Digital Rectal Exam .........................44 
 
Testing for Adrenal Insufficiency ................................................................45 
 
Safety issues ...........................................................................................................45 


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Safety Concerns Related to the Therapeutic Agents....................................45 
 
Safety Issues Related to Liver Biopsy ..........................................................46 
 
Safety Issues Related to Specimen Repository ............................................46 
 
Adverse Events and Serious Adverse Events ........................................................46 
 
Definition of Adverse Events (AE)..............................................................47 
 
Definition of Serious Adverse Events (SAE) ..............................................47 
 
Classification of an Adverse Event ..............................................................48 
 
Time Period and Frequency for Event Assessment and Follow-Up ............48 
 
Adverse Event Reporting .............................................................................49 
 
Monitoring for Adverse Events ....................................................................49 
 
Reporting of Pregnancy ...............................................................................50 
10 STATISTICAL CONSIDERATIONS.............................................................................50 
 
Outcomes ...............................................................................................................50 
 
Sample Size Determination....................................................................................51 
 
Populations for Analyses .......................................................................................52 
 
Statistical Analyses ................................................................................................52 
 
General Approach ........................................................................................52 
 
Procedures for Missing Data ........................................................................52 
 
Efficacy Analyses ........................................................................................53 
 
Safety Analyses ............................................................................................53 
 
Cardiovascular Risk Evaluation ...................................................................54 
 
Other Assessments or Analysis ....................................................................54 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..54 
 
Regulatory, Ethical, and Study Oversight Considerations.....................................54 
 
Informed Consent Process ...........................................................................54 
 
Study Discontinuation and Closure .............................................................55 
 
Confidentiality and Privacy .........................................................................55 
 
Future Use of Stored Specimens and Data ..................................................56 
 
Key Roles and Study Governance ...............................................................56 
 
Safety Oversight...........................................................................................56 
 
Clinical Monitoring ......................................................................................56 
 
Quality Assurance and Quality Control .......................................................57 
 
Data Handling and Record Keeping ............................................................57 
 Protocol Deviations ......................................................................................58 
 Publication and Data Sharing Policy ...........................................................58 
 Conflict of Interest Policy ............................................................................58 
 
Abbreviations .........................................................................................................59 
12 APPENDICES .................................................................................................................61 


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APPENDIX A:  
INVESTIGATOR'S AGREEMENT ..................................................62 
APPENDIX B: DILI MONITORING ALGORITHM ............................................................64 
APPENDIX C:  CLOSE OBSERVATION FOR POTENTIAL DRUG INDUCED LIVER 
INJURY ...........................................................................................................................65 
APPENDIX D:  ALCOHOL QUESTIONNAIRE (AUDIT) ..................................................66 
APPENDIX E:  FUNCTIONAL ACTIVITY QUESTIONNAIRE (NHANES) .....................70 
APPENDIX F:  INTERNATIONAL-PROSTATE SYMPTOM SCORE (I-PSS) 
QUESTIONNAIRE .........................................................................................................78 
APPENDIX G:  HR-QOL (SF-36) QUESTIONNAIRE .........................................................80 
APPENDIX H:  PGI-S QUESTIONNAIRE............................................................................85 
APPENDIX I:  PGI-C QUESTIONNAIRE .............................................................................86 
APPENDIX J:  CHRONIC LIVER DISEASE QUESTIONNAIRE (CLDQ) ........................87 
APPENDIX K:  SEXUAL DESIRE AND DISTRESS QUESTIONNAIRE ..........................89 
APPENDIX L: SPONSOR SIGNATURES ............................................................................91 
13 REFERENCES ................................................................................................................92 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), applicable state, local and federal regulatory requirements, 
guidelines governing clinical study conduct and ethical principles that have their origin in the 
Declaration of Helsinki and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812)  
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
Responsibilities of the clinical investigator conducting the trial are specified in Appendix A. 
 
 
 


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1 
SUMMARY OF CHANGES IN PROTOCOL VERSION 3.0 
Version 3.0 of the LPCN 1144-18-002 study protocol was developed to make the following 
changes to the study: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
3.1 
4.1 
9.3.6.1  
10.1 
Inclusion Criterion #2: Biopsy eligibility 
criterion was changed. 
To include stage 1 fibrotic subjects with 
NAS ≥ 4 and advanced fibrosis subjects 
regardless of NAS ballooning score in the 
study. 
3.1 
3.3 
4.1 
9.1.2.2 
Inclusion Criterion #1, testosterone screening 
assessment: Subjects  without previously 
documented hypogonadal status will be eligible 
for the study if subject has a single AM 
testosterone level < 400 ng/dL 
Expand the criteria of subjects eligible for 
the trial to better reflect the NASH 
population. 
3.1, 4.2 
Cholecystectomy was removed from EC #18 
Expand the criteria of subjects eligible for 
the trial to better reflect the NASH 
population. 
3.1 
3.3 
4.1 
9.1.2.3 
9.3.2 
 MRI-PDFF, DXA imaging timing and data 
analysis was updated 
To allow a subject unable to undergo MRI-
PDFF or DXA imaging due health condition 
(e.g. claustrophobia, difficulty holding breath 
during the procedure etc.) to enter the study. 
3.1 
3.3 
4.1 
Lab value targets and procedure for approval to 
proceed to biopsy have been updated; Fibroscan 
target removed. 
Predictive value of Fibroscan is low in this 
obese population 
8.2 
Update procedures related to Participant 
Discontinuation/Withdrawal from the Study  
Clarify the procedures for subject who 
discontinue dosing and/or choose to 
discontinue the study  
8.3 
Close monitoring and stopping criteria have 
been updated  
To reflect the Endocrine Society Clinical 
Practice Guidelines; clarification 
3.1 
3.3 
4.2 
9.1.2.1-2 
Labs thought to be spurious can be repeated 
Clarification 
9.1.3 
Randomization visit section is being updated to 
collect testosterone and hormones prior to 
dosing 
To collect true t=0 (baseline) T levels   
9.1.4.2  
9.1.4.3 
Week 12 and Week 16 visits (of the specified 
sections) have been clarified and updated 
To clarify which lab should be drawn with 
the fasting labs 
9.3.3 
Prior to Fibroscan, subjects must not eat or 
drink for at least 3 hours prior to the procedure 
Fibroscan accuracy is decreased if subject 
has recently eaten/drank. 
9.3.10 
Table 1: Listing of the Clinical Laboratory Tests 
for all Subject is being updated to include more 
tests in hematology panel. This change will not 
increase the amount of blood drawn from the 
subject. 
To collect and analyze Complete Blood Count 
(CBC), PT and INR along with hemoglobin 
and hematocrit 
Not 
applicable 
Minor editorial changes for consistency. 
 


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2 
SUMMARY OF CHANGES IN PROTOCOL VERSION 2.0 
Affected 
Section 
Summary of Revisions Made 
Rationale 
2.1; 9.1 
Interim data analysis changed to primary endpoint, 
and primary endpoint analysis changed to secondary 
endpoint  
To properly power this study, calculations 
are based on previous experience 
regarding the effects of LPCN 1144 on 
MRI-PDFF hepatic fat fraction 
2.1; 5.1; 
8.1.3 
Subjects will be randomized in a 1:1:1 ratio 
For equal weightage between active and 
placebo groups 
2.3; 8.1 
Schedule of activities updated, including changes for 
DRE, serology, hormone markers, and cortisol. 
Clarification, consistency, patient safety 
monitoring,  and reducing the testing 
frequency  
2.1; 3.1 
Allowable timeframe for TZD/glitazones stable dose 
was decreased from 6 to 3 months. 
To evaluate the effect 
3.2 
Clarified the exclusion criteria for serum AST and 
ALT are 200 IU/L.  Further, both AST or ALT values 
should not exceed 200 IU/L and the second reading 
should not be >1.5x from the first screening value. 
 Per FDA’s recommendation 
3.2 
Clarified both total bilirubin screening values should 
not exceed the upper limit of normal, and the second 
screening value should not be >1.5x from the first 
screening value. 
Per FDA’s recommendation 
2.1; 3.2; 
8.1; 8.3.7 
Insulin, allergy shots, and vaccines are allowable 
injectable drugs; clarification on sliding scale insulin 
was added. 
 Clarification 
7.3 
Dose reduction, and stopping parameters for 
creatinine, blood pressure, and testosterone were 
added and clarified. 
Per FDA’s recommendation 
8.1.4 
Changes in baseline dose of blood pressure 
medications or introduction of new blood pressure 
medications will be captured at each visit. 
Per FDA’s recommendation 
8.2 
The role of the Data Safety Monitoring Board was 
more broadly defined. 
Allow the external charter to describe its 
role more specifically  
9.4.5 
Subgroup analyses of the blood pressure data for 
subjects with/without diabetes or diagnosis of 
hypertension were added. 
Per FDA’s recommendation 
11 
Various appendices and questionnaires added 
Clarification, data collection 
Not 
applicable 
Minor editorial changes for consistency. 
 
 
 
 


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3 
PROTOCOL SYNOPSIS 
 
Synopsis  
Title: 
A Phase 2, Randomized Double-Blind, Placebo-Controlled, Multi-Center Study to Assess 
the Efficacy, Safety and Tolerability of Oral LPCN 1144 in Subjects with Nonalcoholic 
Steatohepatitis (NASH) 
Study 
Description: 
The study is a Phase 2, multicenter, double-blinded, placebo-controlled study.  
Phase: 
2 
Sites 
The study site will be multi-center study.  Approximately 10 – 30 sites. 
Objectives: 
 
Primary Objective: To evaluate the change in hepatic fat fraction from Baseline to Week 12 
based on magnetic resonance imaging-proton density fat fraction (MRI-PDFF) 
measurements in LPCN 1144 treated subjects. 
 
Additional Analysis:   To evaluate whether 36 weeks of treatment with LPCN 1144 (Oral 
Testosterone (T)) lowers nonalcoholic steatohepatitis (NASH) activity as determined from 
hepatic histology in adult men with NASH. 
 
Secondary Objectives: To evaluate the change in hepatic fat fraction from baseline to Week 
36 based on MRI-PDFF measurements in LPCN 1144 treated subjects. 
 
To assess tolerability of oral LPCN 1144 in the study population. 
Eligibility  
Inclusion Criteria: 
1. Male between 18 and 80 years of age, inclusive 
2. Subjects with histologic evidence of NASH upon central read of a liver biopsy, 
defined by  
a. 
Stage 1 fibrosis (according to the NASH CRN staging system) with a 
NAFLD activity score (NAS) greater than or equal to 4 with at least 1 
point each in inflammation and ballooning, or 
b. Advanced fibrosis (Stage 2 or 3 according to the NASH CRN staging 
system) with at least 1 point for inflammation in the NAS  
i. A historical biopsy no more than 4 months before Screening may 
be considered for use with medical monitor approval if the 
following criteria are met: 
1. Stable weights between the time of the biopsy and 
Screening.  Stable weight is defined as no more than a 
5% change. 
2. Is either not taking or is on stable doses of 
TZDs/glitazones for 3 months before Day 1. 
ii. Subjects without a historical biopsy may undergo liver biopsy 
during Screening if at least one screening AST value is ≥ 22 U/L 
and at least one screening ALT value is ≥ 30 U/L.  Approval to 
proceed with biopsy when values of AST and/or ALT are below 
these levels will require review and approval by the medical 
monitor.   
3. Background therapy for other ongoing chronic conditions, and weight should be 
stable for at least 3 months before trial enrollment. Stable weight is defined as no 
more than a 5% change. 
4. Subjects must satisfy one of the following to meet these criteria: 
a. 
A previous historical diagnosis of hypogonadism  
i. If a subject is on androgen replacement therapy, then the subject 
must proceed with an appropriate washout (12 weeks following 
long acting intramuscular androgen injections; 4 weeks following 
topical or buccal androgens; 3 weeks following oral androgens) 


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prior to collection of baseline serum T sample. 
ii. If naïve to androgen replacement, there is no need for washout.  
b. If a subject does not have a previous hypogonadism diagnosis, a single 
screening of testosterone level < 400 ng/dL will be used as an eligibility 
criterion, and subject will be allowed to proceed to the next step of 
screening process. 
5. Naïve to vitamin E or has discontinued current treatment of vitamin E > 100 
IU/Day and completed adequate washout (at least four weeks) of prior vitamin E 
therapy (Including vitamin E contained in multivitamins). 
6. Judged to be in good general health as determined by the investigator at screening. 
 
Exclusion Criteria: 
1. Significant alcohol consumption more than 30 g/day on average, either currently (as 
determined by the AUDIT and Skinner alcohol questionnaire) or for a period of 
more than 3 consecutive months in the 5 years prior to screening. 
2. Inability to reliably quantify alcohol intake. 
3. Biochemical, clinical or histologic evidence of cirrhosis on liver biopsy (stage 4 
fibrosis). 
4. Evidence of other causes of chronic liver disease determined by medical history, 
including alcoholic liver disease, viral hepatitis, primary biliary cirrhosis, primary 
sclerosing cholangitis, autoimmune hepatitis, Wilson’s disease, hemochromatosis, 
alpha-1 antitrypsin deficiency, human immunodeficiency virus, etc. 
5. Suspected or proven liver cancer. 
6. Clinically significant abnormal laboratory value, in serum chemistry, hematology, 
or urinalysis including but not limited to: 
• 
Hematocrit > ULN 
• 
Hemoglobin > ULN 
• 
PSA > 4 ng/mL 
• 
Serum AST or ALT > 200 IU/L 
• 
Serum ALP > 2 x ULN 
• 
Serum creatinine of 2.0 mg/dL or greater 
• 
Total Bilirubin > ULN 
• 
International normalized ratio (INR) ≥ 1.3.  
• 
Prolactin > ULN 
Also: 
• 
Clinically significant abnormal prostate digital rectal examination (DRE) 
in the opinion of the PI 
• 
International Prostate Symptom Score > 19 points 
• 
History of stroke or myocardial infarction within the past 5 years 
• 
Screening systolic BP or diastolic BP above 140 mmHg or 90 mmHg, 
respectively 
If screening value is considered spurious by the investigator, the test may be 
repeated. 
7. Subjects with evidence of worsening liver function (ALP and GGT second 
Screening assessment value greater than the ULN and 1.5x greater than the first 
Screening assessment value.  Both AST or ALT screening values must not exceed 
200 IU/L and the second screening value must not be > 1.5x from the first 
screening value.  Both TB screening values must not exceed ULN and the second 
screening value must not be > 1.5x from the first screening value.  A second 
assessment will be performed no less than 14 days after the first assessment) based 
on the two initial laboratory values used to establish the screening / baseline values.  
If baseline value is suspected to be considered spurious, the test may be. 
8. Model for End-Stage Liver Disease (MELD) score greater than 12. 
9. Subjects with a documented history of Gilbert’s syndrome. 


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10. Evidence of portal hypertension (e.g., lower than normal platelet counts, 
esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly). 
11. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens, anabolic steroids, 
valproic acid, other known hepatotoxins) for more than 2 weeks in the 2 years prior 
to randomization. 
12. Subjects who are on a non – stable dose of lipid-lowering drugs, diabetic and / or 
hypertensive medication in the 3 months prior to biopsy or the 3 months prior to 
randomization and through the end of the study. 
13. Any over-the-counter medication or herbal remedy that is being taken with an 
intent to improve hyperlipidemia must be stable for at least 3 months prior to 
randomization and through the end of the study. 
14. Vitamin E supplementation of greater than 100 IU/day, unless completed adequate 
washout for at least 4 weeks prior to Day 1 or biopsy if one is required. 
15. Inability to safely obtain a liver biopsy. 
16. History of total parenteral nutrition in the year prior to screening. 
17. History of bariatric surgery or currently undergoing evaluation for bariatric 
surgery. 
18. History of gastric surgery, , vagotomy, bowel resection or any surgical procedure 
that might interfere with gastrointestinal motility, pH or absorption. 
19. History of biliary diversion. 
20. Known positivity for antibody to Human Immunodeficiency Virus (HIV). 
21. Known heart failure of New York Heart Association class 3, or 4. 
22. Active, serious medical disease with likely life-expectancy less than 5 years. 
23. History of current or suspected prostate or breast cancer. 
24. History of diagnosed, severe, untreated, obstructive sleep apnea. 
25. Active substance abuse, such as alcohol or inhaled or injection drugs, in the year 
prior to screening. Insulin, allergy shots, and vaccines are allowed. 
26. History of significant sensitivity or allergy to any androgens, including 
testosterone, or product excipients. 
27. History of seizures or convulsions, including alcohol or drug withdrawal seizures. 
Childhood febrile seizures are not exclusionary. 
28. Use of known strong 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. 
29. Subjects who are currently receiving any androgens (testosterone or other 
androgens or androgen supplements). 
30. Use of any investigational drug within 5 half-lives of the last dose or in the past 6 
months prior to Study Day –2 without medical monitor and/or Sponsor approval  
31. Receipt of any drug by injection within 30 days or 10 half-lives (whichever is 
longer) prior to study drug administration without Medical Monitor and/or Sponsor 
approval. Insulin, allergy shots, and vaccines are allowed. 
32. Subject who is not willing to use adequate contraception for the duration of the 
study. 
33. Any other condition, which in the opinion of the investigator would impede 
compliance or hinder completion of the study. 
34. Failure to give informed consent. 
Endpoints: 
Primary Outcome Measure: 
Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated 
subjects after 12 weeks of treatment.   
 
Key Secondary Outcome Measures: 
• 
Change in NASH activity evaluated via a standardized scoring of liver biopsies at 
baseline and after 36 weeks of treatment in LPCN 1144 treated subjects. 


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• 
Change in fibrosis evaluated via NASH CRN fibrosis score of liver biopsies at baseline 
and after 36 weeks of treatment in LPCN 1144 treated subjects. 
 
Other Secondary Outcome Measures: 
• 
Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 
1144 treated subjects after 12 weeks of treatment.   
• 
Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 
treated subjects after 36 weeks of treatment.   
• 
Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 
1144 treated subjects after 36 weeks of treatment.   
• 
NAFLD resolution of subjects who at baseline is at least 5% with a decrease to less than 
5% at end of study.  
• 
Resolution of NASH on overall histopathological reading.  Resolution of NASH is 
defined as NAS score of 0–1 for inflammation, 0 for ballooning, and any value for 
steatosis. 
• 
Change in individual NAS component scores (inflammation, ballooning, steatosis) in 
LPCN 1144 treated subjects after 36 weeks of treatment.  
• 
Resolution of NASH on overall histopathological reading and no worsening of liver 
fibrosis on NASH CRN fibrosis score. 
• 
Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score).  
• 
Change in anthropometric measurements (weight, body mass index (BMI), waist to hip 
ratio, waist circumference, triceps skin fold thickness, upper arm circumference,) in 
LPCN 1144 treated subjects. 
• 
Change in insulin resistance (assessed by Homeostasis Model Assessment (HOMA)) in 
LPCN 1144 treated subjects. 
• 
Changes in liver enzymes aspartate transaminase (AST), (alanine transaminase (ALT), 
alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), Total Bilirubin (TB) 
and Creatine Kinase (CK) in LPCN 1144 treated subjects compare to placebo. 
• 
Changes in non-invasive markers of fibrosis and steatosis including cytokines, leptin, 
fibrosis markers, and lipid profile in LPCN 1144 treated subjects compare to placebo. 
• 
Changes in lipid parameters (triglycerides, very low-density lipoprotein cholesterol 
(VLDL-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein 
cholesterol (LDL-C), and free fatty acids) in LPCN 1144 treated subjects compare to 
placebo. 
• 
Changes in Functional Activity (Appendix E), Health-Related Quality of Life (HR-
QOL) as measured by Short Form-36 (Appendix G), Patient Global Impression of 
Severity (PGI-S; Appendix H), Patient Global Impression of Change Scale (PGI-C; 
Appendix I) Chronic Liver Disease Questionnaire (CLDQ) (Appendix J), and Sexual 
desire and distress (Appendix K) questionnaire, in LPCN 1144 treated subjects. 
• 
Changes in safety laboratory parameters (clinical chemistry, hematology and 
urinalysis) in LPCN 1144 treated subjects compare to placebo. 
Scoring of Liver 
Biopsies for 
Enrollment and 
Data Analysis 
The tissue will be examined by light microscopy and scored based upon the NASH Clinical 
Research Network (CRN) Nonalcoholic Fatty Liver Disease (NAFLD)/NASH scoring 
system.  Baseline and follow-up liver biopsies will be scored by central review of the slides. 
The scores obtained centrally will be used for study eligibility and data analysis. 
Sample Size 
Approximately 75 subjects, 1:1:1 active to placebo. 
Description of 
Study 
Intervention: 
LPCN 1144 is an oral capsule formulation of testosterone undecanoate (TU) administered as 
225 mg TU two times a day for a total daily dose of 450 mg TU.  Two different 
formulations of LPCN 1144 will be evaluated, along with placebo. 
Treatment Arms 
Subjects will be randomized in a 1:1:1 ratio to the following study treatments:  
• 
Treatment A: Oral LPCN 1144 total daily dose of 450 mg TU administered as 
BID. 


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• 
Treatment B: Oral LPCN 1144 d-alpha tocopherol formulation, total daily dose 
of 450 mg TU administered as BID. 
• 
Treatment C: Oral placebo administered as BID. 
Study Duration: 
36 weeks of study treatment plus two weeks for follow up visit. 
Study Description 
Each participant will be in the study for a duration of 36 weeks, not including screening and 
follow up period.   
Screening Visits: Subjects will undergo a washout prior to screening period, if necessary. 
Screening periods to complete the pre-study examinations to evaluate study eligibility (See 
Schedule of Activities (SOA)). During Screening Visit, hepatic fat fraction will be measured 
by MRI-PDFF, and NASH will be confirmed by liver biopsy. 
 
At the Randomization Visit, subjects will be assigned to a treatment arm, and they will 
complete any outstanding study procedures. 
 
Visits at Weeks 4, 8, 12, 16, 20, 24, 30, 36 and 38 will be performed to evaluate safety 
clinical laboratory tests, adverse events, and overall subject health.  
 
Primary Analysis will be performed after the Week 12 visit to evaluate treatment effect.  
The change in hepatic fat fraction from Baseline (Screening Visit) to Week 12 will be 
measured by MRI-PDFF.   
 
At Week 36, End of Treatment (EOT) and exit procedures will be performed including the 
NASH activity, defined from change in standardized scoring of liver biopsies at baseline and 
after 36 weeks of treatment will be assessed. 
 
At Week 38, Follow-up procedure will include review of adverse events, PGI-S (Appendix 
H), PGI-C (Appendix I) questionnaires, Urinalysis and blood samples for clinical 
laboratory tests including testosterone assay, hormones and related markers (see SOA).  
Monitoring for 
Prostate, 
Cardiovascular, 
and Renal 
Stopping Criteria 
Subjects will be monitored for hematocrit, hemoglobin, creatinine, prostate specific antigen 
(PSA), and blood pressure with added close monitoring and discontinuation criteria noted in 
section 8.3. 
Monitoring for 
Hepatotoxicity 
and Stopping 
Criteria 
To minimize the risk of hepatotoxicity, aminotransferase levels will be monitored, with 
added close monitoring and discontinuation criteria noted section 8.3. 
Reduced Dose 
Subjects will be monitored for liver enzymes, hemoglobin, hematocrit, blood pressure, PSA 
and testosterone with close monitoring and discontinuation triggers; if levels exceed target 
criteria during close monitoring, subjects will be placed on a reduced dose (study drug one 
capsule once daily).  If subjects continue to exceed target, subject will proceed to exit 
procedures. 
 
 
 


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Scheme 
Trial Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of Activities (SOA) 
Randomize 
LPCN 1144 
Treatment A 
Placebo 
Treatment C 
Final Analysis, 
and Exit 
Evaluation 
Multiple Visits: 
8 Visits: 
Weeks: 4, 8, 12, 16, 20, 24, 30, 36 
Screening/Baseline: 4 -8 
Weeks 
 
Treatment: 36 Weeks 
Primary Analysis: 12 Weeks 
LPCN 1144 
Treatment B 
Week 38 
Follow – up Visit 


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Assessment / Procedure 
Optional 
Washout 
Screening 
Visits Day -
56 to -1 / 
Baseline 
 
On Treatment 
Follow-up 
Visit 
Testosterone/ 
Androgen / 
Vitamin E > 100 
IU/day Washout 
-12 to -3 weeks 
prior to 
Screening 
Screening 
assessments 
are 
completed 
over multiple 
visits 
Day 1 
Week 4 
(Day 
28±7) 
Week 8 
(Day 
56±7) 
Week 12 
(Day 
84±7) 
Week 16 
(Day 
112±7) 
Week 20 
(Day 
140±7) 
Week 24 
(Day 
168±7) 
Week 30 
(Day 
210±7) 
Week 36 
(Day 
252±7) 
EOT 
Week 38 
(Day 266±7) 
Informed consent 
X 1 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Review of concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Anthropomorphic 
measurements 2 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Review of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(D: detailed / A: 
abbreviated) 3 
 
D 
A 
A 
A 
D* 
A 
A 
A 
A 
D 
 
Imaging – Fibroscan 4 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
Review of historical biopsy 5 
 
X 
 
 
 
 
 
 
 
 
 
 
Imaging – MRI-PDFF 6 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Biopsy7 
 
X 
 
 
 
 
 
 
 
 
X 
 
Imaging – DXA 8 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Enrollment / Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Drug dispensing 17 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Drug accountability / 
adherence check 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol questionnaire 
AUDIT and Skinner 
 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol questionnaire 
AUDIT-C 
 
 
 
 
 
X 
 
 
 
 
 
 
Functional Activity 
 
X 
 
 
 
 
 
 
 
 
X 
 
I-PSS 
 
X 
 
 
 
X 
 
 
 
 
X 
 
HR-QOL (SF-36) 
 
X 
 
 
 
 
 
 
 
 
X 
 


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Assessment / Procedure 
Optional 
Washout 
Screening 
Visits Day -
56 to -1 / 
Baseline 
 
On Treatment 
Follow-up 
Visit 
Testosterone/ 
Androgen / 
Vitamin E > 100 
IU/day Washout 
-12 to -3 weeks 
prior to 
Screening 
Screening 
assessments 
are 
completed 
over multiple 
visits 
Day 1 
Week 4 
(Day 
28±7) 
Week 8 
(Day 
56±7) 
Week 12 
(Day 
84±7) 
Week 16 
(Day 
112±7) 
Week 20 
(Day 
140±7) 
Week 24 
(Day 
168±7) 
Week 30 
(Day 
210±7) 
Week 36 
(Day 
252±7) 
EOT 
Week 38 
(Day 266±7) 
PGI-S 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGI-C 
 
 
 
 
 
X 
 
 
 
 
X 
X 
CLDQ 
 
X 
 
 
 
 
 
 
 
 
X 
 
Sexual Desire and 
Distress 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory Tests 15 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 18 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
C-Reactive Protein, 
Fasting glucose and 
insulin 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Lipid profile 9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology panel 10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Metabolic and renal 
function panel 11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatic panel 12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers 13 
 
 
X 
 
 
 
 
 
 
 
X 
 
Testosterone assay 
(Total and calculated free 
T, SHBG) 
 
X 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hormones and related 
markers 
(DHT, LH, FSH, TSH, 
SHBG) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSA, prolactin 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cortisol and cortisol binding 
globulin (CBG)19 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug and alcohol screen 
 
X 
 
X 
 
X 
 
 
X 
 
 
 


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DHT = dihydrotestosterone; LH = Luteinizing Hormone; FSH = Follicle Stimulating Hormone; PSA = Prostate Specific Antigen; TSH = Thyroid Stimulating Hormone; SHBG = Sex Hormone Binding 
Globulin 
 
1. For subjects requiring washout 
2. Anthropomorphic measurements: include weight, body mass index (BMI), waist to hip ratio, waist circumference, triceps skin 
fold thickness, upper arm circumference. 
3. Detailed (D) physical defined in section 9.3.8. Abbreviated (A) physical defined section 9.3.8  *Week 12 will have a detailed 
physical examination without a DRE. 
4. Fibroscan will be done on all subjects but only required for eligibility on subject without a historical biopsy within 4 months 
from Screening. 
5. Review of Historical Biopsy: Historical biopsy must be done within 4 months of Screening and reviewed by a central reader.  
6. MRI-PDFF should be performed prior to randomization but not need to be performed prior to biopsy. 
7. Biopsy: Subjects without a biopsy within 4 months of Screening may have a biopsy during Screening if at least one screening 
AST value is ≥ 22 U/L and at least one screening ALT value is ≥ 30 U/L.  Approval to proceed with biopsy when values of 
AST and/or ALT are below these levels will require review and approval by the medical monitor.  
a. Subject must meet all other eligibility criteria including qualifying testosterone and retest of hepatic panel prior to 
performing biopsy. 
8. Subject should meet all inclusion criteria including eligible biopsy as assessed by the central reader and qualifying testosterone 
levels prior to performing DXA scan. 
9. Lipid profile: total cholesterol, triglyceride, fatty acids, VLDL-C, LDL-C, HDL-C. 
10. Hematology Panel:  complete blood count (CBC) including hemoglobin and hematocrit, prothrombin time (PT), international 
normalized ratio (INR). 
Assessment / Procedure 
Optional 
Washout 
Screening 
Visits Day -
56 to -1 / 
Baseline 
 
On Treatment 
Follow-up 
Visit 
Testosterone/ 
Androgen / 
Vitamin E > 100 
IU/day Washout 
-12 to -3 weeks 
prior to 
Screening 
Screening 
assessments 
are 
completed 
over multiple 
visits 
Day 1 
Week 4 
(Day 
28±7) 
Week 8 
(Day 
56±7) 
Week 12 
(Day 
84±7) 
Week 16 
(Day 
112±7) 
Week 20 
(Day 
140±7) 
Week 24 
(Day 
168±7) 
Week 30 
(Day 
210±7) 
Week 36 
(Day 
252±7) 
EOT 
Week 38 
(Day 266±7) 
Serum and plasma for 
banking 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Gait Speed and Hand Grip 16 
 
X 
 
 
 
 
 
 
 
 
X 
 
Study exit evaluation 
 
 
 
 
 
 
 
 
 
 
X 
 


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11. Metabolic and renal function panel: sodium, potassium, chloride, bicarbonate, calcium, phosphate, BUN, creatinine, uric acid, 
albumin, total protein, estimated glomerular filtration rate (GFR). 
12. Hepatic panel: total bilirubin (TB), direct bilirubin, ALT, AST, ALP, GGT, Bile acid and creatine kinase (CK).   
a. The Hepatic panel is assessed at two separate Screening assessments to determine if a subject’s liver enzymes are 
stable.  Last Screening assessment value will be used as baseline value. 
b. A second Screening assessment of ALT, AST, TB, and ALP will be performed no less than 14 days after the first 
Screening assessment. Values must meet criteria defined in Exclusion criteria 6. 
13. Biomarkers: Heat-Shock Protein 47 fibroblast marker (HSP47 fibroblast marker), Alpha-Smooth Muscle Actin (Alpha SMA), 
Enhanced Liver Fibrosis (ELF), Hyaluronic Acid (HA), N-terminal propeptide of type III collagen (PIIINP), Tissue inhibitor 
of metalloproteinase 1 (TIMP-1), Transforming Growth Factor-Beta (TGF-Beta), Tissue Necrosis Factor-alpha (TNF-alpha). 
14. Testosterone Screening Assessments: Only for subjects not previously diagnosed with hypogonadism 
a. Individuals without a diagnosis of hypogonadism are eligible for inclusion in the study with a single screening 
testosterone level < 400 ng/dL. 
b. Subject should have prior diagnosis of hypogonadism or confirmed inclusionary testosterone levels prior to completing 
MRI-PDFF, liver biopsy, and DXA.  
15. If baseline value is considered spurious, the test may be repeated. 
16. Gait speed and hand grip may be assessed for some subjects at select sites. 
17. Drug dispensing as necessary. 
18. Urinalysis consists of general routine tests – Color, appearance, specific gravity, pH, protein, blood, ketones, urobilinogen, 
glucose, bilirubin, leukocyte esterase, nitrite. 
19. Morning levels (7-9 AM) of Cortisol and CBG will only be performed at Screening, Week 12 and Week 36. There is no time 
restriction for all other cortisol and CBG labs. 
 
 
 
 
 
 


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4 
STUDY POPULATION 
 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Male between 18 and 80 years of age, inclusive 
2. Subjects with histologic evidence of NASH upon central read of a liver biopsy, defined by  
a. Stage 1 fibrosis (according to the NASH CRN staging system) with a NAFLD activity 
score (NAS) greater than or equal to 4 with at least 1 point each in inflammation and 
ballooning, or 
b. Advanced fibrosis (Stage 2 or 3 according to the NASH CRN staging system) with at 
least 1 point for inflammation in the NAS.  
i. A historical biopsy no more than 4 months before Screening may be considered 
for use with medical monitor approval if the following criteria are met: 
1. Stable weights between the time of the biopsy and Screening.  Stable 
weight is defined as no more than a 5% change. 
2. Is either not taking or is on stable doses of TZDs/glitazones for 3 months 
before Day 1. 
ii. Subjects without a historical biopsy may undergo liver biopsy during Screening if 
at least one screening AST value is ≥ 22 U/L and at least one screening ALT 
value is ≥ 30 U/L.  Approval to proceed with biopsy when values of AST and/or 
ALT are below these levels will require review and approval by the medical 
monitor. 
3. Background therapy for other ongoing chronic conditions, and weight should be stable for at 
least 3 months before trial enrollment. Stable weight is defined as no more than a 5% change. 
4. Subjects must satisfy one of the following criteria: 
a. A previous historical diagnosis of hypogonadism  
i. If androgen replacement therapy, the subject must proceed with an appropriate 
washout (12 weeks following long acting intramuscular androgen injections; 4 
weeks following topical or buccal androgens; 3 weeks following oral androgens) 
prior to collection of baseline serum T sample. 
ii. If naïve to androgen replacement, there is no need for washout.  
b. If a subject does not have a previous hypogonadism diagnosis, a single screening of 
testosterone level < 400 ng/dL will be used as an eligibility criterion and subject will be 
allowed to proceed to the next step of screening process. 
5. Naïve to vitamin E or has discontinued current treatment of vitamin E > 100 IU/Day and 
completed adequate washout (at least four weeks) of prior vitamin E therapy 
6. Judged to be in good general health as determined by the investigator at screening. 
 
 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study 
unless agreed upon by the Principal Investigator (PI) and the Sponsor: 
 
1. Significant alcohol consumption more than 30 g/day on average, either currently (as determined 
by the AUDIT and Skinner alcohol questionnaire) or for a period of more than 3 consecutive 
months in the 5 years prior to screening 
2. Inability to reliably quantify alcohol intake. 
3. Biochemical, clinical or histologic evidence of cirrhosis on liver biopsy (stage 4 fibrosis). 


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4. Evidence of other causes of chronic liver disease determined by medical history, including 
alcoholic liver disease, viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, 
autoimmune hepatitis, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, 
human immunodeficiency virus, etc. 
5. Suspected or proven liver cancer. 
6. Clinically significant abnormal laboratory value, in serum chemistry, hematology, or urinalysis 
including but not limited to: 
• Hematocrit > ULN 
• Hemoglobin > ULN 
• PSA > 4 ng/mL 
• Serum AST or ALT > 200 IU/L 
• Serum ALP > 2 x ULN 
• Serum creatinine of 2.0 mg/dL or greater 
• Total Bilirubin > ULN 
• International normalized ratio (INR) ≥ 1.3.  
• Prolactin > ULN 
Also 
• Clinically significant abnormal prostate digital rectal examination (DRE) in the opinion 
of the PI 
• International Prostate Symptom Score > 19 points 
• History of stroke or myocardial infarction within the past 5 years 
• Screening systolic BP or diastolic BP above 140 mmHg or 90 mmHg, respectively 
If screening value is considered spurious, the test may be repeated. 
7. Subjects with evidence of worsening liver function (ALP and GGT second Screening assessment 
value greater than the ULN and 1.5x greater than the first Screening assessment value. The first 
and second screening values for AST or ALT must not exceed 200 IU/L.  The first and second 
screening for TB must not exceed the ULN.  The second screening for AST, ALT and TB must 
not be > 1.5x the first screening value.  A second assessment will be performed no less than 14 
days after the first assessment) based on the two initial laboratory values used to establish the 
screening / baseline values.  If baseline value is suspected to be considered spurious, the test may 
be repeated. 
8. Model for End-Stage Liver Disease (MELD) score greater 12. 
9. Subjects with a documented history of Gilbert’s syndrome. 
10. Evidence of portal hypertension (e.g., lower than normal platelet counts, esophageal varices, 
ascites, history of hepatic encephalopathy, splenomegaly). 
11. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens, anabolic steroids, valproic acid, other 
known hepatotoxins) for more than 2 weeks in the 2 years prior to randomization. 
12. Subjects who are on a non – stable dose of lipid-lowering drugs, diabetic and / or hypertensive 
medication in the 3 months prior to biopsy or the 3 months prior to randomization and through 
the end of the study. 
13. Any over-the-counter medication or herbal remedy that is being taken with an intent to improve 
hyperlipidemia must be stable for at least 3 months prior to randomization and through the end 
of the study. 
14. Vitamin E supplementation of greater than 100 IU/day, unless completed adequate washout for 
at least 4 weeks prior to Day 1 or biopsy if one is required. 
15. Inability to safely obtain a liver biopsy. 
16. History of total parenteral nutrition in the year prior to screening. 


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17. History of bariatric surgery or currently undergoing evaluation for bariatric surgery. 
18. History of gastric surgery, , vagotomy, bowel resection or any surgical procedure that might 
interfere with gastrointestinal motility, pH or absorption. 
19. History of biliary diversion. 
20. Known positivity for antibody to Human Immunodeficiency Virus (HIV). 
21. Known heart failure of New York Heart Association class 3, or 4. 
22. Active, serious medical disease with likely life-expectancy less than 5 years. 
23. History of current or suspected prostate or breast cancer. 
24. History of diagnosed, severe, untreated, obstructive sleep apnea. 
25. Active substance abuse, such as alcohol or inhaled or injection drugs, in the year prior to 
screening. Insulin, allergy shots, and vaccines are allowed. 
26. History of significant sensitivity or allergy to any androgens, including testosterone, or product 
excipients. 
27. History of seizures or convulsions, including alcohol or drug withdrawal seizures. 
28. Use of known strong 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. 
29. Subjects who are currently receiving any androgens (testosterone or other androgens or androgen 
supplements). 
30. Use of any investigational drug within 5 half-lives of the last dose or in the past 6 months prior 
to Study Day –2 without medical monitor and/or Sponsor approval  
31. Receipt of any drug by injection within 30 days or 10 half-lives (whichever is longer) prior to 
study drug administration without MM and/or Sponsor approval. Insulin, allergy shots, and 
vaccines are allowed. 
32. Subject who is not willing to use adequate contraception for the duration of the study. 
33. Any other condition, which in the opinion of the investigator would impede compliance or 
hinder completion of the study. 
34. Failure to give informed consent. 
 
 
Lifestyle Considerations 
Some NASH subjects are treated with vitamin E or glitazone.  Because enrollment of such subjects in 
clinical trials may confound treatment effects, subjects must either discontinue glitazone or be on stable 
doses for 3 months before enrollment.  As one of the treatment arms is vitamin E formulation, subjects 
treated with vitamin E must washout prior to randomization (at least four weeks). 
Subjects should maintain their normal level of physical activity, diet, and lifestyle throughout the entire 
study (i.e., will not begin a new exercise program or participate in any unusually strenuous physical 
exertion). 
Subjects will be allowed to continue on prescription antihyperlipidemic agents. Subjects will be 
interviewed in a detailed fashion at screening, randomization, and at every clinic visit to document the 
absence or stable doses of such use. If using a statin or fibrate medication, the subject must have been on 
a stable dose in the 3 months prior to liver biopsy and must have been on a stable dose in the 3 months 
prior to randomization. 
 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 


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screen failure information will be collected to ensure transparent reporting of screen failure participants 
and to respond to queries from regulatory authorities. Minimal information includes data for any 
procedure conducted until the point of screen failure (excluding questionnaires unless the questionnaire 
data leads to the screen failure), including but not limited to demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of some of 
the clinical lab values may be allowed to re-screen, subject to Medical Monitor/Sponsor approval. 
Rescreened participants will be assigned a new participant number. 
5 
 INTRODUCTION 
 
Study Rationale  
 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH) 
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the 
United States (US) and its prevalence and clinical importance is increasing worldwide.i,ii Recent studies 
estimate that between 30 and 40% of the population in the US, 80-100 million Americans, is affected by 
NAFLD.iii,iv,v The number of people at risk for NAFLD is even greater given the increasing prevalence 
of obesity, diabetes and metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is a frequently 
progressive subset of NAFLD that can be complicated by cardiovascular disease, cirrhosis and 
hepatocellular carcinoma (HCC).vi,vii  There are no FDA approved drugs for NASH. 
 
Histology, Epidemiology and Disease Course 
Non-alcoholic fatty liver disease is characterized by hepatic steatosis, without a history of excessive 
alcohol use, in the absence of other known liver disease.i NAFLD can be broadly classified into two 
subtypes; nonalcoholic fatty liver (NAFL), which is generally considered to be benign with negligible 
risk of progression to advanced fibrosis and liver-related mortality, and NASH, which is generally 
considered to be progressive with substantial risk of progression to advanced fibrosis, and liver-related 
mortality.viii NAFL and NASH have traditionally been considered two separate clinical entities, rather 
than two points on a disease continuum.ix Recent studies evaluating sequential liver biopsies are 
challenging this notion.x,xi,xii  Based upon evidence derived from systematic review and meta-analysis of 
paired liver biopsy studies, both patients with NAFL and NASH may develop progressive liver fibrosis. 
The annual fibrosis progression rate (FPR) in patients with NAFL versus NASH, with baseline stage 0 
fibrosis, was 0.07 stages versus 0.14 stages, respectively, corresponding to an average progression by 1 
stage over 14.3 versus 7.1 years, respectively.xiii Patients with NAFL and mild lobular inflammation, 
without ballooning or fibrosis (and thus not qualifying as NASH), had increased risk of disease 
progression compared to those without inflammation. xiii Another retrospective study evaluated serial 
liver biopsies in 108 patients and found no significant difference in the proportion of fibrosis 
progression between patients with NAFL and NASH at index biopsy (37% vs. 43%, p = 0.65).xi  
Similarly, a recent study analyzing paired liver biopsies over time showed that even patients with bland 
steatosis can progress to NASH, especially in the setting of metabolic risk factors.xiv 
In the western world, NAFLD is most commonly associated with obesity, metabolic syndrome and 
diabetes.xv As with other metabolic conditions, NAFLD appears to have a strong genetic component. 
Both family history of diabetes and Hispanic ethnicity have been identified as risk factors. xv Metabolic 
syndrome, diabetes and advanced age have all been shown to increase the risk of liver disease 
progression in NAFLD patients.xvi,xvii  


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It is estimated that NASH occurs in 20% of patients with NAFLD (3–12% of the US population).xviii,xix  
Approximately 30–40% of patients with NASH will develop fibrosis.xx,xxi,xxii,xiii  Although fibrosis 
regresses in some patients,xxiii,viii,xxiv others progress to advanced fibrosis or cirrhosis. viii,
xxvii
xxviii
xxv  In fact, 
NASH is the third leading cause of cirrhosis in the US, and the third most common indication for liver 
transplant.xxvi,
  In addition to cirrhosis, and the complications that accompany it, NASH places 
patients at risk for hepatocellular carcinoma (HCC).
  
 
Current Treatment Options 
There are no approved treatment options for NAFLD or NASH. Numerous clinical trials are underway 
with multiple products in development for the treatment of NAFLD, NASH, NASH fibrosis and NASH 
cirrhosis.  
 
Clinical Trial Rationale 
Numerous literature reports support a role for T therapy in management and / or treatment of NASH and 
liver cirrhosis. The current study is planned as a preliminary proof of concept study evaluating efficacy 
and tolerability of oral LPCN 1144 in the NASH subject population. 
 Scientific Rationale for Study Design 
Currently, there is no proven pharmacotherapy available for the treatment of NASH. In the current 
study, the Sponsor intends to test if T benefits subjects with NASH. The efficacy of LPCN 1144 will be 
compared to placebo. As there is no proven pharmacologic therapy for NASH, using a placebo for 
comparative purposes is justified. 
Given the study is a Phase 2 proof of concept study, the outcome measures will be evaluated for 
comparison purpose and where applicable a superiority test will be conducted.  
LPCN 1144, also referred to as “Oral T”, is an oral capsule product containing an ester prodrug of T, 
TU.  Testosterone undecanoate is an esterified T derivative that is orally bioavailable, unlike T which 
undergoes extensive first pass metabolism.  After oral administration, TU is absorbed into systemic 
circulation primarily via the lymphatic system following incorporation into chylomicrons.1 Once within 
systemic circulation TU is de-esterified by plasma esterases to T and becomes available to systemic 
target tissues.  Additionally, dihydrotestosterone undecanoate (DHTU), formed from TU and 
transported into systemic circulation via lymphatic absorption, also becomes de-esterified in plasma to 
dihydrotestosterone (DHT). Based on a receptor binding study, TU and DHTU had negligible binding 
and therefore, TU and DHTU can be thought of as “inactive transport forms” that provide systemically 
active T and DHT.  
 
Rationale for Testosterone Treatment for NASH 
LPCN 1144 has a number of potential mechanisms of action that could prove to be beneficial to subjects 
with NASH and NASH cirrhosis: 
• Androgens aid in the maintenance of liver homeostasis.2 
 
 
1 Shackleford DM, Faassen WA, Houwing N, Lass H, Edwards GA, Porter CJ, Charman WN. Contribution of lymphatically 
transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol 
formulations in conscious lymph duct-cannulated dogs. J Pharmacol Exp Ther. 2003 Sep;306(3):925-33. Epub 2003 Jun 13. 
2  Shen M, Shi H. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis.  International Journal of 
Endocrinology, vol. 2015, Article ID 294278, 12 pages, 2015.  


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• Androgens are known to provide benefits in terms of: 
o Anti-inflammatory properties. 
o Immune-modulating properties.3 
• Androgens aid in liver regeneration.4 
• Glucose homeostasis: increase insulin receptor, reduce insulin resistance/increase insulin 
sensitivity;5 favorable impact on glucose metabolism. 
A growing body of evidence from nonclinical and clinical studies reported in the literature support that 
T should be evaluated a potential treatment for NASH and NASH cirrhosis:   
 
Nonclinical studies reported in the literature  
• Two nonclinical studies have investigated the effects of T on the pathogenesis of hepatic 
steatosis in intact and castrated rats fed a high-fat diet. 
o A study by Nikolaeno et al. showed that T deficiency may contribute to the severity of 
hepatic steatosis, and that T may play a protective role in hepatic steatosis and 
nonalcoholic fatty liver disease development without insulin resistance 
o A study by Jia et al. showed that T suppressed endoplasmic reticulum (ER) stress, 
inhibited the formation of macrovesicular lipid droplets, promoted lipid export, and 
ameliorated steatohepatitis induced by high fat diet and castration in male rats. 
• A survival study by Vic et al. found that rats treated with testosterone enanthate prior to a 90% 
hepatectomy had a striking difference in post-procedure survival compared to an untreated 
control, with 100% of the untreated control dying before Hour 40, while 80 % of the testosterone 
enanthate treated rats. survived beyond Hour 40, and of the 80% alive at Hour 40, 50% survived 
for a normal life span.  Additionally, liver weight was significantly higher in the testosterone 
enanthate treated group, as early as 24 hours post-hepatectomy. 
 
Proof of Concept Liver Fat Evaluation using MRI-PDFF 
 
Study LPCN 1021-18-001, included an assessment of liver fat via Magnetic Resonance Imaging-Proton 
Density Fat Fraction (MRI-PDFF) on a cohort of Oral T treated hypogonadal male subjects at baseline 
(MRI-1), at interim (MRI-2: 2 months), and at end of study (MRI-3: 4 months).  The cohort included 36 
hypogonadal males, with 34 evaluable subjects who had at least one post-baseline MRI-PDFF visit.  Of 
these subjects, 62% had non-alcoholic fatty liver disease (NAFLD), defined as baseline liver fat of at 
least 5%. The study showed a 5% and 20% decrease in mean percent liver fat from baseline to MRI-2 
and to MRI-3 respectively in all subjects, 14% and 33% decrease in mean percent liver fat in subjects 
with MRI-PDFF measurement of >5% at baseline, and 38% and 40% decrease in mean percent liver fat 
in subjects with MRI-PDFF measurements of >10% at baseline.   
  
Clinical studies in the literature 
• A retrospective observational cross-sectional study by Kim et al. found that patients with serum 
T levels in the lowest quintile had an odds ratio (OR) (95% confidence interval (CI)) of 5.12 
(2.43–10.77) for NAFLD (P value, 0.0004). 
 
 
3 Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones H, The Effect of Testosterone Replacement on Endogenous 
Inflammatory Cytokines and Lipid Profiles in Hypogonadal Men. JCEM, Vol. 89 (7), July, 2004, p 3313 – 3318. 
4 Vic P, Saint-Aubert, Astre C, Bories P, Bonardet A, Descomps B, Humeau C, Joyeux H. Complete Liver Regeneration in 
One-Stage 90% Hepatectomized Rats Treated with Testosterone. Hepatology; 1982; Vol. 2, No. 2, p. 247. 
5 Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ: Association of bioavailable, free, and total testosterone with insulin 
resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care 2004, 27:861–868. 


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• A study by Yurci et al. evaluating the efﬁcacy and safety of T replacement on muscle strength, 
bone mineral density (BMD), body composition and gynecomastia in hypogonadal men with 
liver cirrhosis found that T replacement improves muscle strength, ameliorates gynecomastia, 
alters body fat distribution and causes upper body adiposity in hypogonadal men with cirrhosis. 
• A 12-month, double-blinded, placebo-controlled trial by Sinclair et al. evaluating of 
intramuscular TU in 101 men with established cirrhosis and low serum T showed that T therapy 
in men with cirrhosis and low serum T safely increases muscle mass, bone mass and 
hemoglobin, and reduces fat mass and HbA1c. 
 
 
Justification for Dose and Safety for Use in Proposed Population 
LPCN 1144 is an easy to administer oral capsule product containing TU with a proprietary formulation 
comprised of lipids. The product is designed to enable absorption of TU via 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.  
In summary, LPCN 1144 in as inactive agent that converts to active testosterone. Based on a 90 day 
toxicology study in dogs, the non-androgenic no observed adverse effect level (NOAEL) was identified 
as 240 mg/kg/day, translating to a dose of about 7,776 mg in an average adult male. This level is 
approximately 17 times proposed daily human dose in the current study and therefore provides adequate 
support for a proof of concept study being proposed.  
The comorbid conditions that are normally seen in the NAFLD/NASH population are consistent with 
the comorbid conditions of hypogonadism. Clinical evidence summarized in the Investigator Brochure 
suggest beneficial trends in liver-related biomarkers at a daily dose of 450 mg TU as evaluated by the 
Sponsor.  This is further supported by beneficial roles of T administration in liver cirrhotic and 
transplant patients as discussed in literature. 
Based on the summary above and discussion provided below, the proposed daily dose of 450 mg LPCN 
1144 administered in two equal divided doses of 225 mg administered can be considered as a safe 
starting dose in NASH subjects. 
 
Receptor Pharmacology  
Testosterone undecanoate is a bio-reversible ester prodrug of testosterone. An androgen receptor 
binding study was conducted to investigate the pharmacological activity of TU relative to T in the in 
vitro human androgen receptor (AR) binding assay. This study showed that binding of TU is negligible 
compared to T (TU inhibitory concentration 50% (IC50) binding affinity was in the order of 1.0E-04 
lower compared to testosterone) and can be considered to be inactive transport entities for delivery of 
testosterone.  
 
Non-Clinical Toxicology  
Numerous non-clinical studies were conducted in rats, and dogs.  Repeat dose toxicity and toxicology 
studies were conducted at various doses with the longest studies being 26 weeks in rats and the 
previously reference 90-day toxicology study in dogs, with results described below in greater detail. 
In dogs, doses of up to 1000 mg/kg were evaluated (equivalent human dose of 35,100 mg, 
approximately 78X human daily dose). The NOAEL for non-reproductive effects was 240 mg/kg/day 
corresponding to 7,776 mg human dose (approximately 17 times proposed human dose). Hepatocellular 


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effects were minimal with focal hepatocellular degeneration/necrosis and one of dog had minimal 
periportal acute/subacute inflammation and minimal bile duct hyperplasia with correlating elevations in 
ALT, AST and ALP at the 1000 mg/kg dose, corresponding to 78X the proposed human daily dose.  
Bile duct hyperplasia was also seen in 1 animal at 240 mg/kg/day but was not considered to be adverse 
since the severity was minimal.   
Based on the 90 days dog toxicology study, doses of 450 mg TU/day in human for a duration of 36 
weeks is well justified as a starting dose.  
 
 
Clinical Safety 
5.2.3.1 
Prior Human Experience- Ex-US 
In the UK, TU is approved as an intramuscular injection (Nebido: 1000 mg TU every 10 to 14 weeks) 
and oral (Restandol: 40 mg TU capsule 3 to 4 times daily) dosage forms.  A post marketing cohort study 
was conducted using the UK-based General Practice Research Database (GPRD) to explore the risk of 
idiopathic liver disease in association with use of T products. The study provides data on ~8400 patients 
accounting for ~ 15600 patient years of T use over 19 years, of which oral T use accounted for ~ 1800 
patients over 19 years (~1945 person years).  Based on the findings of liver disease or liver adenoma (or 
liver adenocarcinoma) occurrence in T users, the upper 95 % CI for event rate in users of TU was 
0.0537 per 10,000 person-days (0 cases in 686,791 person-days). Based on the findings of rates of 
various adverse outcomes among users of oral T was comparable or lower to other routes that are 
commercially used in the US. 
5.2.3.2 
Prior Experience with LPCN 1144: US Clinical Studies 
Sponsor conducted numerous clinical studies with LPCN 1144 (Oral T), a total of 597 individuals were 
dosed with LPCN 1144 including 525 hypogonadal men across eight clinical studies, 6 healthy adult 
men in one clinical study, and 66 postmenopausal women across four clinical studies, at doses ranging 
75 mg TU to 300 mg TU, with up to 52 weeks exposure.   
LPCN 1144 was generally well tolerated, and the safety findings were consistent with those observed 
with other TRT products.  Gastrointestinal adverse events were of low frequency.  Most adverse events 
that occurred were mild or moderate in severity.  No severe cardiac or hepatic disorders occurred during 
any clinical studies and no deaths were reported.  
In the 52-week clinical study, 210 subjects received LPCN 1144 treatment at a dose with 300 mg to 600 
mg TU daily, and 105 received T gel.  In the LPCN 1144 arm, a total of 16 treatment-emergent serious 
adverse events (SAEs) were reported for 12 LPCN 1144-treated subjects (5.7%) in the clinical study. 
The SAEs were varied in nature and none were considered by the investigator to be related to study 
drug. 
Overall, key laboratory parameters and other biomarkers were mostly within reference ranges and/or 
were consistent with levels observed for other approved T replacement products. Increased hematocrit is 
a known androgenic effect of T administration and mean increases observed were minor.   
Liver and renal function tests did not reveal any safety concerns with respect to LPCN 1144, and an 
evaluation of ALT and bilirubin showed no Hy’s law cases in the LPCN 1144 clinical database.  
Therefore, drug induced liver injury is not expected with LPCN 1144. 


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There were no excess in hypertension-associated adverse events with LPCN 1144 (1.6% and 0.8%, 
respectively) as compared to the T gel active control (4.8% and 1.9%, respectively).   
In summary, the overall safety results demonstrate that LPCN 1144 has an acceptable safety profile. 
5.2.3.3 
Prior Experience with Testosterone in Men with NASH and Liver Cirrhosis 
There is a large body of evidence supporting the role of T in NAFLD / NASH / liver cirrhosis. Prior 
clinical studies as discussed have evaluated role of administering T in both hypogonadal and eugonadal 
men with liver cirrhosis, and / or liver injury, as discussed in section 4.2.  
 
Inclusion of D-alpha-Tocopherol Acetate in LPCN 1144 Formulation 
Vitamin E (d-alpha tocopherol acetate) is included in one of the LPCN 1144 formulations.  In previous 
nonalcoholic steatohepatitis (NASH) trials, d-alpha tocopherol has been evaluated as a potential 
treatment.  Sanyal et al. showed that d-alpha tocopherol therapy (800 mg IU per day), as compared with 
placebo, was associated with a significantly higher rate of improvement in NASH (43% vs. 19%, 
p=0.001).xxix Therefore, d-alpha-tocopherol acetate (at a dose of 800 mg IU day) was included in one of 
the LPCN 1144 formulations in proof of concept LPCN 1144-18-002 Study to evaluate if a higher rate of 
improvement in NASH is observed when LPCN 1144 (Oral T) is used in combination with d-alpha 
tocopherol.  The amount of d-alpha tocopherol included in the LPCN 1144 formulation is the same 
amount evaluated by Sanyal et al.  At 800 IU daily dose, d-alpha tocopherol has shown no significant 
toxicity in adults.xxx,xxxi 
6 
STUDY DESIGN  
 
Overall Design 
This is a proof of concept, Phase 2, randomized, double-blind, placebo controlled, three arm study in 
adult men with biopsy confirmed NASH.  The study will be conducted across multiple centers in the 
United States. 
Approximately 75 subjects will be randomized in 1:1:1 ratio to receive one of the following treatments:  
• 
Treatment A: Oral LPCN 1144 total daily dose of 450 mg TU administered as BID  
• 
Treatment B: Oral LPCN 1144 d-alpha tocopherol formulation, total daily dose of 450 mg 
TU administered as BID  
• 
Treatment C: Oral matching placebo administered as BID  
 
Subjects will undergo a screening period to determine study eligibility. As a part of screening, liver 
biopsies will be performed for subjects who have not had a liver biopsy within 4 months of Screening 
Visit 1.  Adult male subjects with histologic evidence of NASH will be enrolled into the study.  Baseline 
fat fraction will be measured by MRI-PDFF in all eligible subjects. 
Eligible subjects will be randomized to one of the three treatment arms.  The treatment phase will be for 
a duration of 36-weeks (without including screening and follow up periods) with assessments of liver 
biopsies, hepatic fat fraction, liver enzymes, lipid levels and other safety parameters. Safety and 
tolerability will be assessed throughout the study.  A follow-up visit will be performed to assess adverse 
events, complete patient reported questionnaires including PGI-C (Appendix I), a urinalysis and to 
obtain blood samples for clinical laboratory tests including, lipid panel, hematology panel, metabolic 
and renal function panel, hepatic panel, Testosterone, and hormones and related markers. 


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7 
STUDY INTERVENTION 
 
Study Intervention(s) Administration 
 
Study Intervention Description 
The following study treatments will be administered:  
• 
Treatment A: Oral LPCN 1144 capsule, total daily dose of 450 mg TU administered as BID  
• 
Treatment B: Oral LPCN 1144 capsule, d-alpha tocopherol formulation, total daily dose of 
450 mg TU administered as BID 
• 
Treatment C: Oral placebo capsule administered as BID  
 
Subjects may be switched to a reduced dose (LPCN 1144 or placebo) of once daily administration (one 
capsule, once daily) based on criteria described in section 8.3.  
 
Dosing and Administration 
All subjects will be instructed to take Treatment A (225 mg TU per dose), B (225 mg TU per dose), or C 
(placebo) twice daily, approximately 12 hours apart, approximately 30 minutes after morning and 
evening meals, with water. If a dose is missed, the subjects should take it as soon as they remember 
(within 4 hours of missed dose). If second dose is not taken within 16 hours of the first dose of the day, 
the subject should skip that dose and resume dosing at 24 hours past the last dose.  If a subject is 
switched to a reduced dose, the subject should take the dose in the morning, approximately 30 minutes 
after the morning meal, with water. 
 
Preparation/Handling/Storage/Accountability 
 
Acquisition and Accountability 
LPCN 1144 will be provided in high-density polyethylene (HDPE) bottles. Adequate supplies of study 
drug will be provided to the study center. 
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.  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 a Sponsor appointed 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 the 


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Sponsor (or a designee), according to instructions from the Sponsor and according to local regulations. 
Labels must remain attached to the containers. 
 
Formulation, Appearance, Packaging, and Labeling 
Both LPCN 1144 active treatment arms will be provided as gelatin capsule products that contain 225 mg 
TU per capsule.  The placebo capsules will be matching gelatin capsules. 
Each bottle will be labeled appropriately and at minimum will contain, quantity, manufactured by, retest 
date and a caution that the product is an investigational drug.  The containers will not contain the 
treatment name as the study is blinded.  Instead a unique individual bottle identification number will be 
provided. 
 
Product Storage and Stability 
The study drug must be stored at room temperature 15°C to 25°C (59°F to 77°F). LPCN 1144 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 the Sponsor. 
 
Measures to Minimize Bias: Randomization and Blinding 
 
Description of Enrollment  
All subjects meeting the inclusion criteria and not meeting any of the exclusion criteria will be enrolled 
into the study.  
 
Randomization and Blinding Procedures  
Subjects meeting the enrollment criteria will be randomly assigned to one of the three treatment arms. 
The randomization will be carried out by central assignment. The study is a blinded study; therefore, all 
the randomization codes will be centrally maintained and no data from the randomization will be 
available to Sponsor, contract research organization (CRO) operations team, medical monitors, monitors 
or any site staff. The treatment assigned to the study subject will not be available to anyone except pre-
identified study personnel.  
 
Maintenance of Trial Randomization Codes and Blinding 
All randomization codes will be centrally assigned and stored. Each subject will receive a unique 
treatment ID that does not directly associate with the treatment assigned.  
 
Procedures for Unblinding Treatment Assignment  
The study is a double blinded study and treatments will remain masked throughout the study until all 
data collection has been completed.  
Every effort will be made to maintain the blinding throughout the study except in emergency situations. 
The assignment code for the treatment will not be broken without the knowledge of the PI. 


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The following conditions describe when unblinding may be allowed: 
• 
Severe allergic reaction: Study medication is stopped indefinitely. The subject, primary care 
provider (PCP), and the investigator will be unblinded. 
• 
Pregnancy in partner during the study: Study medication will be stopped indefinitely, and the 
coded medication will be unblinded. The subject, PCP, and investigator will be notified of 
the assigned treatment and the associated risks in the partner. 
In unforeseen situations where the clinical center PI considers unblinding is in the best interest of the 
participant’s health and well-being, unblinding may be done after notifying the Sponsor and/or medical 
monitor. The DSMB will review all instances of unblinding that occur. 
8 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
Discontinuation of Study Intervention 
Discontinuation from LPCN 1144 does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed (see section 8.3 for 
stopping criteria). Any new clinically relevant finding will be reported as an adverse event (AE). 
The data to be collected at the time of study intervention discontinuation will include the following: 
• Biomarker and clinical safety markers samples. 
• Adverse events.  
• Investigational product return. 
 
 
Participant Discontinuation/Withdrawal from the Study 
All 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 (specific events are discussed in section 8.3).  Additionally, if 
a subject experience any of the following serious adverse events associated with T use during the 
trial, then study drug should be discontinued:  
a. Venous thromboembolism  
b. Myocardial infarction  
c. Stroke 
d. Edema with or without congestive heart failure, as a complication in subjects with 
cardiac, renal and hepatic disease 
e. New onset of any malignancy.  Exceptions may be approved by PI, such as basal cell 
carcinoma of the skin. 
f. If a subject develops new onset or worsening of sleep apnea. 
• Significant noncompliance with the protocol requirements. 
• Lost to follow-up. 
 
Any subject who requires permanent discontinuation of the study drug will be followed at the scheduled 
procedures according to the protocol until at least the end of the study. If a subject is discontinued from 
the study with an ongoing AE or an unresolved laboratory result that is in the opinion of the investigator 


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is significantly outside of the reference range, the investigator will attempt to provide follow-up until a 
satisfactory clinical resolution of the AE or laboratory result is achieved. 
If a subject chooses to discontinue the study, Week 36 procedures should be completed if the subject is 
willing. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not 
receive the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
 
Monitoring and Stopping Criteria  
Baseline for Safety assessments is the Day 1 pre-dose values or last screening value. 
 
Blood Pressure Monitoring and Stopping Criteria 
Subjects will be monitored for Blood Pressure exceeding 140/90 mmHg throughout the study.  Standard 
clinical care should be provided to treat blood pressure. 
Close Monitoring 
While under standard clinical care, if blood pressure cannot be adequately controlled, the subject must 
be discontinued from study medication until stabilization and a level of <140/90 mmHg is achieved 
prior to resumption of the study medication. 
Stopping Criteria 
While under standard clinical care, if blood pressure exceeds 160/100 mmHg, an immediate repeat 
assessment should be performed, to confirm elevation of blood pressure.  If confirmed, the subject must 
stop study medication and should be urgently treated.  Creatinine Stopping Criteria 
 
Creatinine Stopping Criteria 
Subjects will be monitored for Creatinine throughout the study.  Stopping criteria for Creatinine are 
provided below: 
Stopping Criteria 
For Creatinine, an increase in Creatinine > 2 mg/dL will be used as stopping criteria. Creatinine > 2 
mg/dL will initiate a discussion with the medical monitor and initiation of clinical workup. PSA 
Monitoring and Stopping Criteria 
 
PSA Monitoring and Stopping Criteria 
Subjects will be monitored for PSA throughout the study.  Close monitoring and stopping criteria for 
PSA are provided below: 
Close Monitoring 


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Subjects with a change from baseline > 1.4 ng/ml will trigger close monitoring procedures.  The subject 
should have the PSA measured again within one week.  If the PSA value is still > 1.4 ng/ml from 
baseline, then subject will be switched to a reduced dose (LPCN 1144 or placebo) of once daily 
administration (one capsule, once daily). 
Stopping Criteria 
For PSA, an increase in PSA > 4 ng/mL will be used as stopping criteria. Subjects with PSA > 4 ng/mL 
should have the PSA measured again within one week.  If the PSA > 4 ng/mL value is repeated, the 
subject will have study drug discontinued, and will proceed to exit procedures.  
 
Hematocrit and Hemoglobin Monitoring and Stopping Criteria  
Plasma Volume Depletion  
Subjects who develop elevated hematocrit of 52% during the study must be evaluated to ascertain if the 
elevation is due to plasma volume depletion.  If the subject has experienced recent symptoms of postural 
dizziness, fatigue, confusion, muscle cramps, chest pain, abdominal pain, postural hypotension, or 
tachycardia or has recently experienced hemorrhage, vomiting, diarrhea, or diuresis, then schedule 
weekly hematocrit and hemoglobin tests, with a reassessment of subject symptoms until levels return to 
target. 
Subjects will be monitored for hematocrit and hemoglobin throughout the study.  Close monitoring and 
stopping criteria for hematocrit and hemoglobin are provided below: 
Close Monitoring and Stopping: Hematocrit 
The ULN for hematocrit is 52% according to our reference laboratory. Subjects with hematocrit > 52% 
(ULN) during the study will trigger the following close monitoring procedures.   
 
• Hematocrit > 52% (ULN): Confirm that subject is hydrated and retest the hematocrit as soon as 
possible, ideally within 48 hours. 
• Hematocrit > 52% (ULN) on two consecutive assays: dose reduction (once daily dosing) will be 
initiated 
o Weekly monitoring of hematocrit for subjects on once-daily dosing 
o Phlebotomy may be initiated at investigator discretion 
• Hematocrit continues to increase while on once daily dosing: study drug discontinued 
• Hematocrit does not return to normal range within 4-8 weeks of once daily dosing: study drug 
discontinued 
• Hematocrit returns to normal range within 4-8 weeks of initiation of once-daily dosing: remain 
on once daily dosing 
• Hematocrit > 48% (ULN -4%) and symptoms of polycythemia: study drug discontinued and 
subject followed until the end of study. 
 
Close Monitoring and Stopping: Hemoglobin 
The ULN for hemoglobin is 18 g/dL according to our reference laboratory. Subjects with hemoglobin > 
18.0 g/dL (ULN) during the study will trigger the following close monitoring procedures.   
 


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• Hemoglobin > 18 g/dL (ULN):  confirm that subject is hydrated and retest as soon as possible, 
ideally within 48 hours  
• Hemoglobin > 18 g/dL (ULN) on two consecutive assays: dose reduction (once daily dosing) 
will be initiated 
o Weekly monitoring of hemoglobin for subjects on once-daily dosing 
o Phlebotomy may be initiated at investigator discretion 
• Hemoglobin continues to increase while on once daily dosing: study drug discontinued 
• Hemoglobin does not return to normal range within 4-8 weeks of once daily dosing: study drug 
discontinued 
• Hemoglobin returns to normal range within 4-8 weeks of initiation of once-daily dosing: remain 
on once daily dosing 
 
 
Monitoring for Hepatotoxicity and Stopping Criteria for Hepatoxicity 
Each subject’s baseline values of ALT, AST, ALP, and TB (by at least two samples obtained at least 2 
weeks apart) will be established during screening. After the baseline values are established during 
screening, the DILI algorithm provided in Appendix B and Appendix C will be used for monitoring 
liver safety AEs and drug-induced liver injury (DILI). 
 
Testosterone Monitoring and Stopping Criteria 
Testosterone will be measured periodically during the study to ensure subjects do not experience 
elevated T levels.  An independent safety physician, not a part of the study team, will be assigned to 
monitor testosterone levels and implement appropriate protocol directed procedures throughout the 
study.  
Close monitoring and stopping criteria for T are provided below: 
Stopping Criteria for T 
If a subject experiences a T measurement in excess of 1500 ng/dL while on treatment, a repeat of the T 
assay should be scheduled within 48 hours.xxxii  If T concentrations in excess of 1500 ng/dL are repeated 
in the subject, the subject will be placed on a reduced dose (LPCN 1144 or placebo) of once daily 
administration (one capsule, once daily).    
If T concentrations in excess of 1500 ng/dL are repeated in a subject at a once daily dose, study drug 
must be discontinued, but the subject should be followed in the clinical trial.  If the T concentration 
remains above 1500 ng/dL at exit, proceed with weekly T assays until T concentrations have returned to 
below 1500 ng/dL. 
 
Common Terminology Criteria for Adverse Event Stopping Criteria 
The trial will be stopped based on the following stopping criteria: 
a. If one subject experience a Grade V CTCAE (Common Terminology Criteria for 
Adverse Event) related to study drug,  
b. or two subjects experience the same Grade IV CTCAE related to study drug,  
c. or three subjects experienced the same Grade III CTCAE related to study drug. 


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d. If four subjects experience the same Grade II CTCAE, enrollment of new subjects into 
the trial will be paused. The DSMB will assess the causality of these adverse events; if 
adverse events are deemed to be unrelated, determined by the DSMB, then enrollment 
may resume. 
The following CTCAE criteria will be used for evaluating and discontinuing subjects in the trial: 
a. If a subject experience a Grade IV CTCAE or meets criteria listed in Appendix A, 
discontinue the study drug.  
b. The DSMB will perform a causality assessment. The study drug may be restarted if the 
DSMB concludes that the AE or laboratory abnormalities were not related to study drug, 
the AE has resolved, laboratory abnormalities have returned to baseline, and the subject 
is amenable to close clinical follow-up.  
c. If, after re-challenge, a subject has a second serious AE or recurrent elevations of total 
bilirubin, ALT, or AST as defined in Appendix A, study drug must be discontinued 
permanently.   
 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for the scheduled visits and 
is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
9 
STUDY ASSESSMENTS AND PROCEDURES 
 
Visit Schedule Overview 
There are four phases of study: 
• Screening Phase for Subject requiring testosterone/androgen washout up to 12 weeks 
  
(12 weeks following intramuscular androgen injections; 4 weeks following topical or buccal 
androgens; 3 weeks following oral androgens).  
• Screening Phase for eligibility assessments (maximum 8 weeks prior to randomization) 
• Randomization Phase (one visit) 
• Treatment Phase (eight visits) 
• Follow-up (one visit) 
The visits are described in the following sections.  Note that given that all the procedures noted for a 
visit may not be available at a given clinic, visit procedures may take place over several days, at 
different sites. 


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Screening Phase for Subject requiring testosterone/androgen washout 
Subjects who are on medications that require washout for eligibility prior to screening will complete the 
following procedures: 
• Obtain informed consent. 
• Baseline medical history and chart review to determine basic eligibility based on history. 
• Review current and past medication history to determine eligibility or require discontinuation. 
 
 
Screening Visits and Baseline Data Collection 
Investigators will review subject charts for their eligibility and complete standard of care tests and 
procedures for NASH and invite to undergo screening. All screening related activities will be conducted 
after subject reads and signs study specific informed consent.  
Screening and baseline data collection procedures will include questionnaires, physical examination, 
determination of the subject’s hypogonadal status based on T levels below the normal range, 
measurement of serum glucose, routine liver tests, and urine analysis. Prior therapy for NASH, lipid 
lowering, diabetes, hypertension medication will be reviewed, and subjects will be asked to stop any 
specific or contraindicated / prohibited treatments, if medically acceptable.  Subjects taking diabetic, 
lipid lowering, hypertensive medication will be reviewed and only enrolled if they are on stable 
medication for at least 3 months prior to screening and encouraged to maintain stable medication after 
randomization. Sliding scale insulin is allowable, so long as the parameters of the scale do not change. 
Subjects who are currently taking an androgen (wash out period described earlier) or vitamin E > 100 
IU/day (at least 4 weeks washout period prior to randomization during screening) will be washed out.  
Subject charts will be reviewed for historical information.  
All subjects screening outcomes will be captured in the source documents; further all subjects should 
either be screen pass to continue, or a screen fail.  
 
9.1.2.1 
Screening period will consist of multiple visits with confirmation of subject eligibility 
through progression. 
Subjects who appear to qualify based on physician chart review and invited to participate will complete 
the following procedures as provided in Schedule of Activities (SOA): 
Initial assessments: 
• Obtain Informed Consent (unless main Informed Consent was given at Washout). 
• Baseline medical history and chart review to determine basic eligibility based on history. 
• Obtain demographic information, anthropomorphic measurements. 
• Review current and past medication history to determine eligibility or require 
discontinuation. 
• Collect adverse events information (solicited or spontaneously reported). Subjects should be 
specifically queried if they have experienced any untoward signs or symptoms that would 
reflect cardiovascular or hypertensive adverse events, such as changes to medication due to 
elevations in blood pressure. 
• Conduct a detailed physical examination. 


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• Assess if any Fibroscan data collected within 30 days of screening 
If subject appears to qualify based on initial assessments:  
• Perform Urinalysis 
• Perform drug and alcohol screen. 
• Fibroscan if needed for subjects but only evaluated for eligibility on subjects without a 
qualifying historical biopsy within 4 months of Screening. 
• Obtain data on historical liver biopsy if available within 4 months from Screening and 
submit to the central reader for review. 
• Collect blood samples for clinical laboratory tests including Serology, Hematology panel 
including HbA1c, Metabolic panel and renal function, Hepatic panel, Testosterone Assay for 
subjects without history of previous diagnosis of hypogonadism, Hormones and related 
markers, cortisol and CBG (see SOA).   
 
9.1.2.2 
Second Screening Assessment 
• Collect blood samples for repeat of clinical laboratory tests (see SOA) to establish baseline ALT, 
AST, ALP, TB in second Screening. Second assessment must occur not less than 14 days after 
first Screening assessment.  If baseline value is suspected to be spurious, the test may be 
repeated. 
 
9.1.2.3 
Screening Visit if no prior liver biopsy within the last 4 months 
• MRI-PDFF scans should be completed for eligible subjects prior to randomization. 
• If a subject is unable to undergo MRI-PDFF or DXA imaging due to health condition (e.g. 
claustrophobia, difficulty holding breath during the procedure, etc.), the missing MRI-PDFF will 
be treated as missing data, and the subject will be allowed to proceed to randomization or 
continue therapy upon investigator and medical monitor approval. 
• Collect adverse events information (solicited or spontaneously reported). Subjects must be 
specifically queried if they have experienced any untoward signs or symptoms that would reflect 
cardiovascular or hypertensive adverse events, such as changes to medication due to elevations 
in blood pressure. 
• Subject reported questionnaires will be completed and includes Alcohol (Appendix D), 
Functional Activity (Appendix E), I-PSS (Appendix F), HR-QOL (Appendix G), PGI-S 
(Appendix H), Chronic Liver Disease Questionnaire (CLDQ)(Appendix J) and Sexual Desire 
and Distress (Appendix K) questionnaires.  Details are provided in section 7.3.1. 
• Liver biopsy. 
• Continued eligibility with respect to medications taken or new medical history developed or 
reported. 
 
9.1.2.4 
Imaging Screening Visit  
• Imaging study: dual-energy absorptiometry (DXA) scan for whole body lean mass, appendicular 
lean mass, fat mass, and bone mineral density (femoral and lumbar).  
• If not completed in an earlier visit, complete subject reported questionnaires (see SOA) (See 
Appendix D-K).  Details are provided in section 7.3.1. 
• Continued eligibility with respect to medications taken or new medical history developed or 
reported 
• Perform gait speed and hand grip assessments, as applicable 


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Randomization Visit (RZ; Day1) 
• Subjects who meet all the inclusion criteria and do not meet any exclusion criteria will be 
allowed to participate in the study. 
• Screening medical history and chart review to determine basic eligibility based on history. 
• Review current and past medication history to determine eligibility or require discontinuation. 
• Collect adverse events information (solicited or spontaneously reported). Subjects must be 
specifically queried if they have experienced any untoward signs or symptoms that would reflect 
cardiovascular or hypertensive adverse events, such as changes to medication due to elevations 
in blood pressure. 
• The Randomization Visit marks the Day 1 of treatment and subsequent time duration of 
treatment will be based on the randomization day. 
• Subject’s eligibility will be randomly assigned to receive Treatment A (LPCN 1144 formulation) 
B (LPCN 1144 formulation with Vitamin E) or C (placebo) at 1:1:1 randomization.  
• The random treatment assignment will consist of assigning medication bottle numbers; these 
numbers will be unique and will be specific to the particular subject and visit it was generated 
for. Once the assignment has been generated, the subject will be issued the assigned study drugs 
(in person) and instructed about starting the drugs and monitoring for adverse effects. 
• Conduct an abbreviated physical examination. 
• If not completed at Screening visit, complete subject reported questionnaires (see SOA).  Details 
are provided in section 7.3.1. 
• Collect blood samples prior to meal and study drug administration for all clinical laboratory tests 
including testosterone, hormones, C-reactive protein, fasting glucose and insulin, lipid panel, 
hematology panel, hepatic panel, biomarkers, and related markers (see SOA) for baseline 
assessment prior to meal and study drug administration. 
• Perform baseline urinalysis. 
• An additional blood sample will be collected for serum and plasma banking.  Remind subjects to 
call or return to the clinic before next visit if they develop any of the signs/symptoms listed in 
the hepatoxicity assessment/stopping criteria section 8.3. 
 
 
On Treatment and Follow – up Visits  
The following visit durations are referenced from the day of randomization. Subjects will return to the 
clinic for On Treatment visits at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 30, 
Week 36 and Week 38. 
9.1.4.1 
Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 30, Week 36 Visits  
• Review current and past medication history to determine eligibility or require discontinuation. 
• Collect adverse events information (solicited or spontaneously reported). Subjects must be 
specifically queried if they have experienced any untoward signs or symptoms that would reflect 
cardiovascular or hypertensive adverse events, such as changes to medication due to elevations 
in blood pressure. 
• Collect dispensed investigation product (IP) bottle and perform accountability / adherence 
checks. 
• Dispense IP at Week 4, Week 12, Week 20, and Week 30 
o Re-dispense all returned IP. 
• Conduct physical examination (see SOA). 


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• Complete subject reported questionnaires (see SOA).  Details are provided in section 7.3.1. 
• Perform Urinalysis 
• Obtain blood sample for clinical laboratory tests (see SOA).  Hematology panel, HbA1c will not 
be collected at every visit. 
• To ensure target T levels are achieved, subjects will have their T, hormones and related markers 
measured 3 to 5 hours post-dose; instruction for the evaluation of T levels is provided in section 
8.3.6. 
• Drug and alcohol screen (during Week 4, Week 12, and Week 24). 
• An additional blood sample will be collected for serum and plasma banking drawn at Week 12 
and Week 36. 
• Remind subjects to call or return to the clinic before next visit if they develop any of the 
signs/symptoms listed in the hepatoxicity assessment/stopping criteria section 8.3. 
 
9.1.4.2 
Week 12 Visit (Additional Analysis)  
• Perform anthropomorphic measurements, including weight, body mass index (BMI), waist to hip 
ratio, waist circumference, triceps skin fold thickness, upper arm circumference, 
• Conduct a Detailed physical examination, except for DRE. 
• Fibroscan imaging. 
• MRI-PDFF imaging. 
• Alcohol questionnaire AUDIT-C (Appendix D), I-PSS (Appendix F), and PGI-C (Appendix I). 
• Blood draws for all required labs except testosterone and hormones will be taken prior to meal 
and study drug administration. Include HbA1c in Hematology panel. 
• Subject eats breakfast. 
• 30 minutes post meal the subject will dose. 
• 3-5 hours after dosing, testosterone and hormone samples are drawn. 
 
 
PRIMARY ANALYSIS 
The DSMB reviews the planned primary analysis of the MRI-PDFF outcome measure and will be 
communicated to Sponsor unblinded at the treatment group level but, without unblinding up to the 
individual patient level. This review will occur when 100% of the MRI-PDFF measurements are 
complete. 
 
The DSMB also reviews the overall progress of the trial in terms of recruitment and data quality and 
makes a formal recommendation to Sponsor at the end of each scheduled meeting as to whether the trial 
should continue unmodified, continue with protocol modifications, or be stopped. 
 
9.1.4.3 
Week 36 Visit End of treatment (Additional Analysis) 
• Perform anthropomorphic measurements. 
• Collect dispensed IP bottle and perform accountability / adherence checks. 
• Blood draws for all required labs except testosterone and hormones will be taken prior to meal 
and study drug administration.  
• Include HbA1c in Hematology panel 
• An additional blood sample will be collected for serum and plasma banking. 
• Subject eats breakfast 


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• 30 minutes post meal the subject will dose. 
• 3-5 hours after dosing, testosterone and hormone samples are drawn 
• Conduct a detailed physical examination. 
• Patient reported questionnaires will be completed including Functional Activity (Appendix E), 
I-PSS (Appendix F), HR-QOL (Appendix G), PGI-S (Appendix H), PGI-C (Appendix I), 
Chronic Liver Disease Questionnaire (CLDQ)(Appendix J) and Sexual Desire and Distress 
questionnaires (Appendix K). 
• Perform Gait Speed and Hand Grip assessments. 
• Imaging study: DXA scan. 
• Fibroscan imaging 
• Perform Biopsy. 
• Study exit evaluation. 
 
9.1.4.4 
Follow up visit 
• Collect adverse events information (solicited or spontaneously reported).  Subjects must be 
specifically queried if they have experienced any untoward signs or symptoms that would reflect 
cardiovascular or hypertensive adverse events, such as changes to medication due to elevations 
in blood pressure. 
• Patient reported questionnaire will be completed including PGI-C (Appendix I). 
• Perform Urinalysis 
• Collect blood samples for clinical laboratory tests including, lipid profile, hematology panel, 
metabolic and renal function panel, hepatic panel, Testosterone assay, and hormones and related 
markers (see SOA). 
 
 
 
 Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB), appointed by Sponsor, is responsible for 
monitoring the accumulated interim data as the trial progresses to ensure subject safety and to review 
efficacy. The DSMB is a multidisciplinary group with a written charge provided by Sponsor. The 
DSMB will include three or more members, at least one of whom is a hepatologist.  After the trial 
commences, the DSMB will establish a charter and meet to review data, evaluate emerging safety 
information, or other issues.  
 
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled meetings. 
Serious adverse events will be reviewed by the DSMB as they occur with the option of a teleconference 
discussion if any DSMB member so requests. 
 
 
Procedure Overview 
 
Subject Questionnaires 
Standardized questionnaires will be administered to subjects participating in the trial at baseline (prior to 
randomization) and during follow-up at specified intervals. The purpose of the questionnaires is to 
obtain important information regarding alcohol intake to assess eligibility, functional activity, health-
related quality of life, and Chronic Liver Disease Questionnaire (CLDQ) 


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Alcohol questionnaires: Subjects enrolled in the treatment protocol will complete AUDIT (Appendix 
D) and Skinner (Appendix D) (lifetime drinking history) questionnaires during screening, and AUDIT-
C (Appendix D) questionnaire at interim follow-up visits. The purpose of these questionnaires is to 
ascertain that there is no significant alcohol consumption at enrollment. 
Functional Activity: The NHANES III Activity Questionnaire will be administered during screening 
and after 36 weeks of treatment. The scores can be converted to METS; then the activity of NASH 
subjects can be compared to U.S. population, and the activity of NASH subjects can be compared to 
other liver disease subjects. (Appendix E) 
I-PSS:  A questionnaire used for men who are having problems that are likely to be related to an 
enlarged prostate. (Appendix F) 
Health-Related Quality of Life (HR-QOL): The SF-36 questionnaire will be administered during 
screening and after 36 weeks of treatment. (Appendix G) 
Patient Global Impression of Severity (PGI-S) Scale: The Patient Global Impression of Severity 
(PGI-S) is a global index that may be used to rate the severity of a specific condition (a single-state 
scale).  It is a simple, direct, easy to use scale that is intuitively understandable to clinicians. (Appendix 
H) 
Patient Global Impression of Change (PGI-C) Scale: This scale evaluates all aspects of subjects' 
health and assesses if there has been an improvement or decline in clinical status. (Appendix I) 
Chronic Liver Disease Questionnaire (CLDQ): A questionnaire on liver symptoms developed by the 
NASH CRN will be administered at screening and after 36 weeks of treatment. (Appendix J) 
Sexual Desire and Distress Questionnaire: A questionnaire used to assess level of a subject’s distress 
due to low sexual desire. (Appendix K) 
Alcohol questionnaires (AUDIT and Skinner; Appendix D) and I-PSS questionnaire (Appendix F) are 
primarily used for eligibility assessment, therefore they need to be completed during the Screening visits 
(prior to biopsy). 
 
Liver MRI-PDFF 
Sites will schedule subjects to have their hepatic fat fraction measured via MRI-PDFF at a local MRI 
facility. A local MRI facility capable of performing the MRI-PDFF test will be pre-identified by 
Sponsor/CRO within the geographic location of the site. Alternatively, if the site has a preferred MRI 
facility, the site can use their preferred facility following confirmation by the Sponsor/CRO.  The MRI-
PDFF details are as follows: 
• MRI-PDFF scan will be conducted at baseline, Week 12, and Week 36. All subjects capable of 
undergoing MRI will be scheduled to undergo an MRI scan of the liver. In case if a subject is 
unable to undergo MRI-PDFF imaging due to health condition (e.g. claustrophobia, difficulty 
holding breath during the procedure, etc.), the missing MRI-PDFF will be treated as missing 
data, and the subject will be allowed to proceed to randomization or continue the therapy upon 
investigator and medical monitor approval. 
• Individual subjects should have MRI-PDFF scans performed on the same MRI machine 
throughout screening and the study. 
• A central reader will assess the MRI-PDFF scans to determine the liver fat fraction.  
• All imaging sites will be provided with the LPCN 1144-18-002 Manual to help with the imaging. 
• Further, all imaging sites are qualified to ensure the scan obtained is centrally readable and 
meets the criteria for a valid imaging.  


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• MRI-PDFF should be performed prior to randomization but not need to be performed prior to 
biopsy, if one is required. 
 
 
Fibroscan (transient elastography) 
For all screening and on-treatment Fibroscans, subjects must not eat food and must avoid drinking large 
volumes of water (> 400 mL, 13.5 oz) for at least 3 hours prior to the procedure. xxxvi, xxxvii 
Sites will measure subject liver fibrosis and (if available) Controlled Attenuation Parameter (CAP) using 
Fibroscan devices.  The Fibroscan device works by measuring shear wave velocity. A 50-MHz wave is 
passed into the liver from a small transducer on the end of an ultrasound probe. The probe also has a 
transducer that can measure the velocity of the shear wave (in meters per second) as this wave passes 
through the liver. The shear wave velocity can then be converted into liver stiffness, which is expressed 
in kilopascals.  
 
Gait Speed  
Gait speed may be assessed for some subjects at select sites. Standing start, usual pace, over ground gait 
speed was assessed.  Time to complete the 10-meter walk will be measured using a stopwatch, and the 
tester will start the time when the participant step over the starting line and will stop when the 
participant completely crosses the end line. 
 
Hand Grip Strength Test 
Hand Grip Strength test may be assessed for some subjects at select sites. 
Supplies 
• Hydraulic Hand Dynamometer 
 
Definition and Purpose 
Handgrip strength is a simple and commonly used test of a person’s general strength level. 
 
Measurement 
1. Have subject sit comfortably with the shoulder adducted and neutrally rotated, with the elbow 
towards/against the body and flexed at 90 degrees, and the forearm and wrist in a neutral 
position. 
2. Place the hand dynamometer in the participant’s hand, and gently support the base to prevent 
accidental dropping and damage to the instrument. 
3. Let the participant arrange the instrument so that it fits comfortably in the hand.  Adjust the 
handle, if necessary, for a comfortable grip.  Make sure that the handle clip is located at the 
lower (furthest) post from the gauge.  If the handle is not in the correct position, results will be 
inaccurate. 
4. Reset the indication needle by rotating it to zero. 
5. Request that the subject squeeze with maximum strength.  The needle will automatically record 
the highest force exerted.  Grip force should be applied smoothly, without rapid wrenching or 
jerking motion.  Minimal wrist extension (30 degrees or less) is permissible as maximum grip is 
achieved.  Wrist extension greater than 30 degrees shall  be noted with results. 
6. Test each hand twice and record the handgrip strength measurement (in pounds) for each 
measurement.  Reset the indicator needle before each and every effort. 
 


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Liver Biopsy 
9 . 3 . 6 . 1  Baseline liver biopsy:  
Subjects who have not had a liver biopsy within 4 months of Screening or whose previous liver biopsy is 
not available for review or whose previous liver biopsy is of inadequate quality must have a liver biopsy 
prior to randomization. The biopsy should be done once the subject has been found to be eligible with 
respect to all other criteria. Biopsy slides should be of adequate size, preferably 1.5 cm or more and of 
adequate quality for interpretation. The subject must have not been using anti-NASH drugs in the 3 
months prior to baseline biopsy, and the subject must have histologic evidence of definite or possible 
NASH and F1-F3  fibrosis as described in section 3.1 of this protocol. 
In the case of a biopsy done previously as standard of care, the NASH CRN study physician should 
check if tissue blocks and/or additional slides can be obtained from the original biopsy. If the liver 
biopsy is completed as part of screening for this trial, the liver tissue will be prepared for light 
microscopy and stains will include hematoxylin and eosin, Masson’s trichrome and iron stain; 
additionally, a piece of liver tissue will be snap frozen and stored at -70 degrees C and set aside for 
banking. 
In the event that a subject has two liver biopsies with 4 months of Screening, and both are of sufficient 
quality, the higher biopsy scoring will be used for baseline.  
9.3.6.2 
Follow-up Liver Biopsy:  
A follow-up liver biopsy will be obtained at the Week 36 Visit. Guidelines for obtaining the biopsy 
specimen are provided in the LPCN 1144-18-002 Liver Biopsy Procedure and NAFLD/NASH 
Histology Scoring System Manual; a 16-gauge needle is preferred, and the specimen should be at least 
1.5 cm in length. The slides should be of adequate size (preferably 1.5 cm or more) and adequate quality 
for interpretation. The follow-up liver biopsy should be taken from the same lobe of the liver as the 
baseline/historical biopsy. The liver tissue will be prepared for light microscopy and stains will include 
hematoxylin and eosin, Masson’s trichrome and iron stain; additionally, a piece of liver tissue will be 
snap frozen and stored at -70 degrees C and set aside for banking. 
9.3.6.3 
Overview of Scoring of Liver Biopsies 
The tissue will be examined by light microscopy and scored based upon the NAS and NASH CRN 
fibrosis score. The scoring system is detailed in the LPCN 1144-18-002 Liver Biopsy Procedure 
Manual. 
The component scores will be used to determine eligibility as well as primary histologic outcome 
measure defined elsewhere in this protocol. Baseline and follow-up liver biopsies will be scored by 
central review of the slides. The scores obtained centrally will be used for inclusion criteria, and data 
analysis. 
 
Medical and Medication History 
The subject’s medical history (key events) during the past 5 years will be obtained and recorded on the 
Medical History Electronic Case Report Form (eCRF). Any new information / changes shall 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 shall also be recorded on the Medical History 


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eCRF. 
All subjects must be instructed to use adequate contraception for the duration of the study, acceptable 
methods of birth control for subjects and their partners 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 must be naive to androgen replacement and vitamin E or has 
discontinued current therapy and completed an adequate washout. Recommended adequate washout is 
up to 12 weeks following long acting intramuscular androgen injections; 4 weeks following topical or 
buccal androgens; 3 weeks following oral androgens; 4 weeks following oral vitamin E > 100 IU/day, 
or, in the judgement of the Medical Monitor, the subject has had an adequate washout window to be 
eligible. 
Subjects with a chronic condition requiring medication must: 
• Be under stable treatment, with the same medication and dosage for at least 3 months prior to 
first dosing.  
• Have no expected change to medication planned throughout the study. Sliding scale insulin 
dosing is acceptable.  
• The subject’s medication should have no interaction with the pharmacokinetics of the study 
drug or the bioanalytical methods. 
 
Physical Examination 
Physical examinations will be performed at visits throughout the study noted in the SOA. A detailed 
physical includes measurement of height, weight, waist, and hips; vital signs  (temperature (single 
measurement), respiratory rate (single measurement), a prostate digital rectal examination (DRE), and 
clinic BP (triplicate measurement) and pulse rate (triplicate measurement); triceps skin fold thickness, 
mid upper arm circumference; examination for scleral icterus and pedal edema and auscultation of the 
heart and lungs; general physical findings (hepatosplenomegaly, peripheral manifestations of liver 
disease, ascites, wasting, fetor). An abbreviated physical includes measurement of height, weight, waist, 
and hips; vital signs (temperature (single measurement), respiratory rate (single measurement), and 
clinic BP (triplicate measurement) and pulse rate (triplicate measurement); examination for scleral 
icterus and pedal edema and auscultation of heart and lungs. Any changes during the study will be 
documented. Subject's height and weight will be used to calculate BMI.  
9.3.9 
Clinic BP and Pulse Rate (PR) Measurement Methodology: 
Clinic BP and PR will be measured at visits throughout the study as part of physical examination.  An 
appropriately sized cuff for the size of the subject’s arm circumference must be utilized to minimize 
inaccurate readings.  No smoking or exercise for at least 30 minutes before a blood pressure 


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measurement.  Subjects must sit in a chair with a back support and the arm supported at heart level with 
feet flat on the floor. If necessary, the subject should void prior to the measurement.  Blood pressure and 
PR will be measured in triplicate over a minimum of approximately 10 minutes after the subject has 
rested in a sitting position for at least 10 minutes. The three measurements will each be recorded in the 
CRF and a mean value for that visit will be calculated. 
 
Clinical Laboratory Tests 
For all subjects, blood and urine samples will be taken as directed in the SOA. Sites will collect samples 
for serum chemistry tests in the morning prior to meals.  Specific stopping criteria for hematocrit, 
hemoglobin, prostate specific antigen, testosterone, and liver enzymes are provided in section 8.3.  In 
addition, subjects will be monitored for other clinical laboratory tests provided in the SOA; if a subject 
develops clinically significant laboratory abnormality/ies for any other laboratory test during the study, 
closely monitor the subject and perform the laboratory test(s) weekly, until the laboratory 
abnormality/ies are normalized. 
Table 1:  Listing of Clinical Laboratory Tests for all Subjects  
 
Hematology/Coagulation 
Clinical Chemistry  
Hormones  
Hematocrit  
Hemoglobin  
Hemoglobin A1c    
  (HBA1C) 
Complete Blood Count  
  (CBC) 
Prothrombin time (PT) 
International normalized ratio 
  (INR) 
Albumin 
Alkaline phosphatase (ALP) 
Bile acid 
Bilirubin 
Blood urea nitrogen (BUN) 
Cortisol and Cortisol Binding Globulin  
C-reactive protein 
Creatinine kinase 
Gamma-glutamyltransferase (GGT) 
Glucose 
Prolactin 
Prostate Specific Antigen (PSA) 
Serum glutamic-pyruvic transaminase 
(SGPT/ALT)  
Serum glutamic-oxaloacetic transaminase 
(SGOT/AST)  
 
DHT 
FSH 
Insulin 
LH 
Prolactin  
Prostate specific antigen  
SHBG 
Testosterone 
TSH 
 
Lipids 
Free fatty acid 
HDL cholesterol 
LDL cholesterol 
Total cholesterol 
Triglycerides 
VLDL cholesterol 
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. 
 
Screens for Drugs of Abuse and Alcohol 
Sites will collect urine samples to screen for drugs of abuse and alcohol at screening. The panel for 
drugs of abuse will minimally include opiates, barbiturates, amphetamines, cocaine, and 
benzodiazepines. Analyses will be performed by a certified laboratory. 
 
Prostate-Specific Antigen (PSA) and Digital Rectal Exam 
Sites will collect samples for PSA at screening.  A digital rectal exam (DRE) is also part of screening 
procedures.  The PSA samples must be collected prior to the DRE. 


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Testing for Adrenal Insufficiency 
If, at any time during the study, a subject experiences signs and symptoms of adrenal insufficiency (AI) 
(i.e. unexplained extreme fatigue, abdominal pain, nausea, vomiting, unexplained hypoglycemia, 
hyponatremia with hyperkalemia), or, if the cortisol is < 18 mcg/dL at baseline or end of study, the 
subject will have a cosyntropin stim test as follows: 
The current standard for diagnosing adrenal insufficiency is cosyntropin stimulation testing using the 
standard high-dose of cosyntropin (250 mcg). An adequate response is defined by a peak cortisol level 
of at least 18 mcg/dL (497 nmol/L) after 30 or 60 minutes of cosyntropin administration.  
Subjects must be educated about the signs or symptoms of adrenal insufficiency (such as -- fatigue, 
muscle weakness, low appetite, weight loss, and belly pain); and cortisol will be drawn at any time 
during the study if AI is suspected, followed by a cosyntropin stim test as needed. If a subject develops 
AI or has an abnormal stimulation testing at the end of the study, they will be followed until 
normalization of the results or return to baseline.  
 
Safety issues 
Safety issues can be divided into (a) safety concerns relating to the therapeutic interventions, (b) safety 
concerns related to liver biopsy, and (c) issues related to the central specimen repository. 
 
Safety Concerns Related to the Therapeutic Agents 
The following paragraphs discuss the important potential adverse effects and the proposed safeguards to 
minimize the risks involved. 
9.4.1.1 
Safety Issues Related to LPCN 1144 
 LPCN 1144 was extensively studied in non-clinical and clinical studies. In clinical studies a twice daily 
dose 225 mg of TU (450 mg total daily dose) was exposed in multiple studies for up to one-year 
duration.  In clinical studies, the most frequently occurring adverse events in LPCN 1144 treated 
subjects were headache (4.0% of subjects), upper respiratory tract infection (3.0% of subjects), weight 
increased (2.3% of subjects), and nasopharyngitis (1.7% of subjects). 
LPCN 1144 must not be used in any of the following subjects:  
• 
Men with carcinoma of the breast or known or suspected carcinoma of the prostate. 
• 
Women who are, or who may become pregnant, or who are breastfeeding. LPCN 1144 may 
cause fetal harm when administered to a pregnant woman. LPCN 1144 may cause serious 
adverse reactions in nursing infants. If a pregnant woman is exposed to testosterone, she 
must be apprised of the potential hazard to the fetus. 
 
LPCN 1144 capsules shall not be used in subjects with known hypersensitivity to any of its ingredients. 
9.4.1.2 
Safety Issues Related to Placebo 
The ingredients in the placebo capsules are commonly used compendial excipients.  Subjects with 
known hypersensitivity to any of the ingredients shall not be included in the trial.  Participants will be 
seen frequently during the study period for assessment of symptoms, clinical laboratory tests, and reporting 
of adverse events. 


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9.4.1.3 
Safety Issues Related to Vitamin E (d-alpha tocopherol) 
Vitamin E at 800 IU daily dose has no significant toxicity in adults.xxxiii xxxiv
,
 Although use of 
antioxidants may improve insulin resistance and thereby may reduce the incidence of new-onset 
diabetes, it is safe to assume that the magnitude of risk of new-onset diabetes mellitus in subjects 
randomized to vitamin E is the same as placebo.  
9.4.1.4 
Management of Adverse Effects Attributed to Study Medication 
During the trial, if a participant develops side effects thought to be due to the study medication and 
requires cessation of study medication, the medication will be stopped for 4 weeks. If the side effects 
disappear, an attempt will be made to reintroduce the study medication after 4 weeks. If the symptoms 
reappear, study medication will be once again stopped, and the subject will no longer receive the study 
medication, but will be followed in the study according to the protocol, in keeping with the “intention-to-
treat” paradigm. 
 
Safety Issues Related to Liver Biopsy 
Subjects will have up to two liver biopsies for research purposes during their participation in this 
protocol. About 20% of people who have a liver biopsy have some degree of pain over the liver that 
may last a few minutes up to several hours. This occasionally requires pain medication and usually 
disappears completely within a day or two. A rare complication of liver biopsy is severe bleeding such 
that a blood transfusion or even radiological/surgical interventions are required to stop the bleeding (less 
than 1 in 1,000). Very rarely (less than 1 in 10,000 reported cases) death has occurred from bleeding 
after a biopsy. We intend to minimize the risks associated with liver biopsy (a) by requiring that each of 
the physicians who will obtain liver biopsies in the NASH CRN be very experienced in safely obtaining 
the liver biopsy specimens, (b) by not enrolling subjects with cirrhosis or subjects with coagulopathy, 
and assuring that subjects do no develop coagulopathy during the course of the trial, (c) by adhering to 
the good clinical practice in performing the liver biopsy, (d) by assuring that an attending hepatologist or 
radiologist directly supervises if a physician trainee is performing the procedure, and (e) by considering a 
trans jugular liver biopsy in morbidly obese subjects in whom a percutaneous, mid-axillary approach may 
not be feasible. 
 
Safety Issues Related to Specimen Repository 
It is anticipated that serum, plasma, DNA, and liver tissue from the participants will be stored for future 
studies related to NASH and possibly other liver/metabolic diseases. These samples will be stored in a 
central repository.  
 
Adverse Events and Serious 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. 


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Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)).  
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 will be reported as a 
new AE. Laboratory abnormalities and changes in vital signs are considered to be AEs only if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, and/or if the 
investigator considers them to be AEs. 
 
Definition of Serious Adverse Events (SAE)  
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 


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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.  
 
Classification of an Adverse Event 
9.5.3.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading CTCAE system, the following 
guidelines will be used to describe severity.  
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
9.5.3.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician 
who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a 
clinical trial, the study product must always be suspect.  
• Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
9.5.3.3 
Expectedness  
The investigator will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
Time Period and Frequency for Event Assessment and Follow-Up 
All AEs in the subject and pregnancies that occur in subject’s partner reported from the time of 
informed consent until completion of the last visit after the last dose of study drug will be collected, 
whether solicited or spontaneously reported by the subject. 


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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
Site staff will record all reportable events with start dates occurring any time after informed consent is 
obtained until the last follow up visit. If the site becomes aware of a related SAE at any time after 
completion of the study, it must be reported.  Events will be followed for outcome information until 
resolution or stabilization. 
 
Adverse Event Reporting 
To report an SAE, complete the SAE eCRF in the EDC system for the study. When the form is 
completed, Medpace Clinical Safety personnel will be notified electronically and will retrieve the form. 
If the event meets serious criteria and it is not possible to access the EDC system, send an email to 
Medpace Clinical Safety at medpace-safetynotification@medpace.com or call the Medpace SAE hotline 
(phone number listed below), and fax/email the completed paper back-up SAE form to Medpace 
(contact information listed below) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 
Incoming reports are reviewed during normal business hours.  
Safety Contact Information:  
Medpace Clinical Safety Medpace SAE hotline – USA: Telephone: +1-800-730-5779, dial 3 or +1-513-
579-9911, dial 3 Facsimile: +1-866-336-5320 or +1-513-579-0444 e-mail: medpace-
safetynotification@medpace.com 
 
Monitoring for Adverse Events 
Summary data on adverse events will be monitored by the DSMB as needed. These summaries will 
include analyses comparing rates of adverse events by treatment group, by clinic, or in other subgroups 
requested by the DSMB. Where applicable, signs and symptoms associated with the adverse event will 
be graded as to severity by the clinical site staff as mild, moderate, or severe using the Common 
Terminology Criteria for Adverse Events. 
After each meeting, the DSMB will issue a written summary of its review of the study data, including 
adverse events, for transmission to the IRBs at each of the study centers. Analyses or listings of adverse 


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events will not be provided to the IRBs; however, adverse events involving unanticipated problems 
involving risks to participants, or breaches of protocol which might entail risk to participants must be 
reported to local IRBs as soon as possible after they are discovered. Each participating center is 
responsible for ensuring that all local IRB requirements for reporting adverse events are met. 
 
Reporting of Pregnancy  
The study only enrolls male participants who will be required to use adequate contraception throughout 
the duration of the study.  
However, if the subject’s partner becomes pregnant while the subject is in the study, it must be reported 
to the site as soon as possible. 
The study site staff will fill a Pregnancy in Partner form and the Sponsor will be notified within 24 
hours. 
 
10 STATISTICAL CONSIDERATIONS  
A formal Statistical Analysis Plan (SAP) will be completed and incorporated prior to database lock and 
unblinding of the study data. The SAP will govern the statistical analysis for the study. The following 
sections only outlines key statistical points. 
 Outcomes 
Primary Outcome Measure: 
Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated subjects after 
12 weeks of treatment. 
 
Key Secondary Outcome Measures: 
Change in NASH activity or change in fibrosis.  Changes in NASH activity will be evaluated via a 
standardized scoring of liver biopsies at baseline and after 36 weeks of treatment in LPCN 1144 treated 
subjects, while changes in fibrosis will be evaluated via NASH CRN fibrosis score of liver biopsies at 
baseline and after 36 weeks of treatment. 
Change in NASH activity is derived from changes from baseline to the end of treatment in NAS. The 
NAS ranges from 0 to 8 (highest activity) and is calculated as the sum of three components of the 
standardized histologic feature scoring system for liver biopsies: 
NAS   =  
Steatosis score (0-3) + 
Lobular inflammation score (0-3) +  
Hepatocyte ballooning score (0-2) 
 
The analysis of the Key Secondary Outcome Measure will include both improvement in NAS and 
fibrosis, and numerical change in NAS and fibrosis.  The analysis for improvement of NAS will only 
include subjects with a baseline hepatocyte ballooning score of 1 or 2. The definition of improvement of 
NAS after treatment as the key secondary outcome measure requires the following three conditions: 
• No worsening of the NASH CRN scoring system. 
• Improvement by at least 1 point in the hepatocyte ballooning feature score. 


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• Either:     
1. Improvement in NAS by 2 or more points spread across at least two of the NAS components, 
OR 
2. Post-treatment NAS is 3 points or less. 
Similarly, improvement in fibrosis will be defined as improvement in liver fibrosis greater than or equal 
to one stage using the NASH CRN fibrosis score with no worsening of ballooning, inflammation, or 
steatosis.  
 
Other Secondary Outcome Measures: 
• Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated 
subjects after 12 weeks of treatment.   
• Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated subjects 
after 36 weeks of treatment.   
• Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated 
subjects after 36 weeks of treatment.   
• NAFDL resolution of subjects who at baseline is at least 5% of hepatic fat fraction with a decrease 
to less than 5% at end of study.  
• Resolution of NASH on overall histopathological reading.  Resolution of NASH is defined as NAS 
score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis. 
• Change in individual NAS component scores (inflammation, ballooning, steatosis) in LPCN 1144 
treated subjects after 36 weeks of treatment.  
• Resolution of NASH on overall histopathological reading and no worsening of liver fibrosis on 
NASH CRN fibrosis score. 
• Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score).  
• Change in anthropometric measurements (weight, body mass index (BMI), waist to hip ratio, waist 
circumference, triceps skin fold thickness, upper arm circumference,) in LPCN 1144 treated 
subjects. 
• Change in insulin resistance (assessed by HOMA) in LPCN 1144 treated subjects. 
• Changes in liver enzymes (AST, ALT, ALP, GGT, TB and CK) in LPCN 1144 treated subjects. 
• Changes in non-invasive markers of fibrosis and steatosis including cytokines, leptin, fibrosis 
markers, and lipid profile in LPCN 1144 treated subjects. 
• Changes in lipid parameters (triglycerides, VLDL-C, HDL-C, LDL-C, and free fatty acids) in LPCN 
1144 treated subjects. 
• Changes in Functional Activity (Appendix E), HR-QOL as measured by Short Form-36 (Appendix 
G), PGI-S (Appendix H), PGI-C (Appendix I), and Chronic Liver Disease Questionnaire (CLDQ) 
(Appendix J) and Sexual desire and distress (Appendix K) questionnaires in LPCN 1144 treated 
subjects. 
• Changes in laboratory parameters (clinical chemistry, hematology and urinalysis) in LPCN 1144 
treated subjects. 
 
 Sample Size Determination 
This is a proof of concept Phase 2 study aimed at evaluating the LPCN 1144 as potential therapeutic 
agent in the treatment and / or management of NASH. The sample size for the study was not based on 
any statistical considerations but based on similar Phase 2 studies in this therapeutic area.  


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 Populations for Analyses 
The study populations that will be used in various analysis are defined as: 
• Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants) 
• Modified Intention-to-Treat (mITT) Analysis Dataset (e.g., participants who took at least one 
dose of study intervention and/or have some particular amount of on-treatment data) 
• Safety Analysis Dataset: defines the subset of participants for whom safety analyses will be 
conducted (e.g., participants who took at least one dose of study intervention) 
• Per-Protocol (PP) Analysis Dataset: defines a subset of the participants in the full analysis (ITT) 
set who complied with the protocol sufficiently to ensure that these data would be likely to 
represent the effects of study intervention according to the underlying scientific model (e.g., 
participants who took at least 80% of study intervention for 80% of the days within the 
maintenance period). 
 
 Statistical Analyses 
 
General Approach 
A p-value of 0.05 will be considered significant.  No adjustments for the additional analysis or multiple 
comparisons will be applied; however, any significant findings must be interpreted taking into account 
the strength of the finding and its biologic plausibility. 
Continuous data will be summarized using count, mean, median, standard deviation (SD), minimum, 
and maximum.  For continuous data specified to be analyzed using parametric procedures, non-
parametric procedures will be used if the parametric procedure is felt to be inappropriate. 
Potential treatment-by-site interactions in terms of the baseline data and the primary efficacy and safety 
endpoints will be investigated by visual inspection of the data by site. Visual evidence of extreme 
imbalance by site will be handled in subsequent models by including site as a term in the model.  
Summary tables, listings, and figures, and statistical analyses will be done using SAS version 9.1 or 
higher or R, version 2.0 or higher. 
Unless otherwise noted, efficacy analyses will be conducted for the ITT. Safety analyses will be 
conducted for the Safety population only. 
When an analysis calls for statistical modeling of the outcome variable using potential confounders as 
well as the treatment effect, the analysis will begin with the full model. If a potential confounder is not 
statistically significant in the full model, it will be dropped, and the analysis repeated using a reduced 
model. 
 
Procedures for Missing Data 
Missing data will be reported as such. Raw data will be subjected to a statistical screen for outliers using 
commonly accepted procedures.  


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Efficacy Analyses 
10.4.3.1 
Primary Efficacy Analyses 
The primary outcome measure will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group as a factor and baseline hepatic fat fraction (%) based on MRI-PDFF measurements as a 
covariate. The LPCN 1144 dose groups will be compared to each other and compared to placebo 
independently using linear contrasts. 
The analysis of the primary outcome measure will be performed using the ITT population. The mITT 
and PP populations will be used as sensitivity analyses.   
10.4.3.2 
Key Secondary Efficacy Analyses 
Change from baseline in key secondary outcome measures will be analyzed both as a binary outcome 
(improved vs. not improved) and also in terms of the numerical change in the outcomes.  For the key 
secondary outcomes, improvement will be assessed based on the criteria provided in section 10.1. 
Comparative analyses for the key secondary outcome measure will be analyzed both as a binary outcome 
(improved vs. not improved) and also in terms of the numerical change in the outcome. Binary outcomes 
will be compared using Fisher’s exact test. Numerical changes will be analyzed by descriptively 
comparing the between-treatment group differences in mean and median changes; P-values will be 
derived from Wilcoxon rank sum tests for comparison of the distribution of changes in each group. If 
concerns about confounding arise, logistic regression models for improvement outcomes and linear 
regression models for numerical change outcomes will be used to correct for the confounding. Analyses 
for outcome measures will generally involve three separate analyses, one for each treatment group 
comparison.  
10.4.3.3 
Other Secondary Efficacy Analyses 
Other secondary efficacy outcome measures will be conducted in the similar methods of the primary and 
secondary efficacy analyses. The details of other secondary efficacy analyses will be provided in the 
SAP. 
10.4.3.4 
Subgroup Analyses 
The analyses of the primary outcome measure will be performed for the following subgroups: 
1. Subjects with baseline liver fat ≥ 5% 
2. Subjects with baseline liver fat ≥ 8% 
3. Subjects with baseline liver fat ≥ 10% 
 
The details of the subgroup analyses will be provided in the SAP. 
 
Safety Analyses 
An AE that starts during a unique treatment or that already exists before the start of that unique 
treatment but worsens during the treatment will be considered as treatment emergent for that unique 
treatment. 


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AEs will be reported on a per-subject basis, i.e., counting subjects rather than events.  This means that if 
a subject suffers the same AE repeatedly during the applicable study period, the event will be counted 
only once for that period.  Repeated events per subject will be summarized according to the following 
rule; if a subject suffered the same AE more than once, the event will be assigned the worst severity, the 
closest relationship to the study drug, and the earliest onset date.  Only treatment-emergent events will 
be reported.  For each unique treatment, treatment-emergent AEs will be summarized per primary 
System Organ Class (SOC) and per Preferred Term (PT) using the MedDRA classification system.  All 
AEs, serious AEs and deaths, Serious AEs that are considered treatment-related, and AEs leading to 
premature discontinuation from the study will also be provided in data listings. 
 
Cardiovascular Risk Evaluation 
Each subject will be evaluated for cardiovascular risk using the following algorithms. 
• Framingham Coronary Heart Disease Risk Score. 
• Framingham Risk Score for cardiovascular disease 
• Reynolds Risk Score.  
 
A subgroup analysis will be performed showing the central tendency towards increased blood pressure 
in subjects who have a diagnosis of diabetes mellitus at baseline, in subjects who do not have a 
diagnosis with hypertension and are normotensive at baseline, and in subjects who have a diagnosis of 
hypertension at baseline and are controlled with medical management. 
 
 
Other Assessments or Analysis 
Demographics and other baseline characteristics will be summarized by analysis set.  Medical history will 
be summarized.  Major protocol deviations will be listed.  Abnormal physical examination assessments 
will be summarized for the Safety population. Medication use will be summarized for the Safety 
population.  Prior (prior to the start of treatment) medication use and concomitant (after the start of 
treatment) medication use will be summarized separately.  If the end date of a prior medication occurs 
after treatment starts, then the medication will be reported in both the prior and concomitant listings.  
Concomitant medication use will be summarized per treatment group.  These listings will present the 
number and percentage of subjects for each medication. 
 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 Regulatory, Ethical, and Study Oversight Considerations 
 
Informed Consent Process 
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. 


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Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the investigator, IRB and regulatory authorities.  If 
the study is prematurely terminated or suspended, the PI will promptly inform study participants, the 
Institutional Review Board (IRB), and Sponsor and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
• Administrative reasons by the Sponsor 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the Sponsor, IRB and/or Food and Drug Administration (FDA). 
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. 
 
Confidentiality and Privacy  
All information concerning LPCN 1144 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 1144. 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. 


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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. 
 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored at the central facility as indicated in the 
administrative study structure page. After the study is completed, the de-identified, archived data will be 
transmitted to and stored at the central facility. 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored.  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to bio 
sample storage may not be possible after the study is completed.  
When the study is completed, access to study data and/or samples will not be available to investigators 
or subjects. 
 
Key Roles and Study Governance 
Lipocine is the Sponsor of this study. On the initial approval date of this protocol, the administrative 
structure and the external organizations supporting the study are as follows: 
Sponsor: 
Lipocine Inc 
 
675 Arapeen Drive, Suite 202 
 
Salt Lake City, Utah 84108   USA 
 
 
Telephone: (801) 994-7383 
 
Study Director: 
  
 
Vice President Product Development 
 
Lipocine Inc 
 
 
 
 
 
 
 
Safety Oversight 
Safety oversight will be under the direction of the Sponsor and CRO medical monitor of the study.  
 
 
Clinical Monitoring 
A separate clinical monitoring plan (CMP) will be developed and used to govern the monitoring and 
quality control / conduct of the study.  
 


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Quality Assurance and Quality Control 
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 may 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. 
All imaging evaluations will be conducted by certified central reader. The source documents / site 
documents shall capture the information of the personnel and facilities including qualifications. 
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. 
 
 
Data Handling and Record Keeping  
11.1.9.1 
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. 
 
11.1.9.2 
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 


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personnel in the EDC system. All data entered into the eCRF will be supported by source 
documentation.  
The investigator or an authorized member of the investigator's staff will make any necessary corrections 
to the eCRF. All change information, including the date and person performing the corrections, will be 
available via the audit trail, which is part of the EDC system. For any correction, a reason for the 
alteration will be provided. The eCRFs will be reviewed periodically for completeness, legibility, and 
acceptability by CRO personnel (or their representatives). The CRO (or their representatives) will also 
be allowed access to all source documents pertinent to the study in order to verify eCRF entries. The 
investigator will review the eCRFs for completeness and accuracy and provide his or her electronic 
signature and date to eCRFs as evidence thereof. 
The CRO will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access. Such access will be removed from investigator sites at 
the end of the site's participation in the study. Data from the EDC system will be archived on 
appropriate data media (e.g., CD-ROM) and provided to the investigator at that time as a durable record 
of the site's eCRF data. It will be possible for the investigator to make paper printouts from that media. 
 Protocol Deviations  
The investigator shall not implement any deviation from the protocol without prior review and written 
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): 
Primary Contact 
  
 
 
Alternate Contact 
 
 
 
 
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. 
 Publication and Data Sharing Policy 
The data obtained is confidential property of the Sponsor, Lipocine Inc.  The Publication policy with 
sites will be covered under the respective clinical trial agreements. In general, no part of the trial or data 
can be published by sites, investigator or staff without explicit written approval of the Sponsor. 
 Conflict of Interest Policy 
All participating investigators will be required to provide a financial disclosure and conflict of interest 
statement. 
 


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 Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
CFR 
Code of Federal Regulations 
CK 
Creatine Kinase 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DILI 
Drug-Induced Liver Injury 
DRE 
Digital Rectal Examination 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
GLP 
Good Laboratory Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
mITT 
Modified-Intent-To-Treat 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NAFL 
Non-Alcoholic Fatty Liver 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Non-Alcoholic Steatohepatitis 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PP 
Per-Protocol 


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QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TB 
Total Bilirubin 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


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12 APPENDICES 
APPENDIX A:  Investigator’s Agreement 
APPENDIX B:  DILI monitoring algorithm 
APPENDIX C:  Close Observation for Potential Drug Induced Liver Injury 
APPENDIX D:  Alcohol Questionnaire (AUDIT, AUDIT-C and Skinner) 
APPENDIX E:  Functional Activity Questionnaire 
APPENDIX F:  I-PSS Questionnaire 
APPENDIX G:  HR-QOL (SF-36) Questionnaire 
APPENDIX H:  PGI-S Questionnaire 
APPENDIX I:  PGI-C Questionnaire 
APPENDIX J:  Chronic Liver Disease Questionnaire (CLDQ) 
APPENDIX K:  Sexual Desire and Distress Questionnaire 
APPENDIX L: Sponsor Signatures 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A:  INVESTIGATOR'S AGREEMENT 
Study Title: 
A Phase 2, Randomized Double-Blind, Placebo-Controlled, Multi-Center 
Study to Assess the Efficacy, Safety and Tolerability of Oral LPCN 1144 
in Subjects with Nonalcoholic Steatohepatitis (NASH) 
Study Number: 
LPCN 1144-18-002 
Final Date: 
7 January 2020 
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. 
 
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.  


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1. I have received and reviewed the Investigator's Brochure for LPCN 1144. 
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) 
 
 
 
 
 


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APPENDIX B: DILI MONITORING ALGORITHM 
Treatment-Emergent 
ALT 
Treatment-
Emergent 
TB 
Liver Symptoms 
Action 
Normal baseline: 
ALT > 5x ULN 
 
Elevated baseline: 
ALT > 3x baseline 
or > 300 U/L 
(whichever occurs first) 
Normal 
None 
Repeat ALT, AST, 
ALP, TBL, in 2–5 
days  
 
Reduce dose (LPCN 1144 or placebo) to 
once daily administration (one capsule, 
once daily). 
 
Follow-up for symptoms. 
Normal baseline: 
ALT > 8x ULN 
 
Elevated baseline: 
ALT > 5x baseline 
or > 400 U/L 
(whichever occurs first) 
Normal 
None 
Interrupt study drug. 
Initiate close observation (see Appendix 
C below and FDA guidance*) and workup 
for competing etiologies. 
 
Study drug can be restarted only if an 
alternative etiology is identified, and liver 
enzymes return to baseline.  Restart at 
reduced dose (LPCN 1144 or placebo) 
once daily administration (one capsule, 
once daily). 
 
Normal baseline: 
ALT > 5x ULN 
 
Elevated baseline: 
ALT > 3x baseline 
or > 300 U/L 
(whichever occurs first) 
TB > 2x ULN 
None 
Interrupt study drug. 
Initiate close observation and workup for 
competing etiologies. 
 
Study drug can be restarted only if an 
alternative etiology is identified, and liver 
enzymes return to baseline.  Restart at 
reduced dose (LPCN 1144 or placebo) 
once daily administration (one capsule, 
once daily). 
Normal baseline: 
ALT > 5x ULN 
 
Elevated baseline: 
ALT > 3x baseline  
or > 300 U/L  
(whichever occurs first) 
Normal or elevated 
Symptoms of 
clinical hepatitis - 
severe fatigue, 
nausea, vomiting, 
right upper quadrant 
pain 
Interrupt study drug. 
Initiate close observation and workup for 
competing etiologies. 
 
Study drug can be restarted only if an 
alternative etiology is identified and liver 
enzymes return to baseline.  Restart at 
reduced dose (LPCN 1144 or placebo) 
once daily administration (one capsule, 
once daily). 
Source: Adapted from Chalasani, Naga and Regev, Arie et al. Drug-Induced Liver Injury in Subjects 
with Preexisting Chronic Liver Disease in Drug Development: How to Identify and Manage? 
Gastroenterology, Volume 151, Issue 6, 1046 – 1051 
*https://www.fda.gov/downloads/Drugs/Guidance/UCM174090.pdf    
 
 


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APPENDIX C:  CLOSE OBSERVATION FOR POTENTIAL DRUG INDUCED 
LIVER INJURY 
Within 72 hours, perform a complete history, physical, and liver biochemistries, including: 
New or worsening signs and symptoms of clinical hepatitis such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia.  
Concomitant medications, including acetaminophen, dietary supplements, herbal remedies, over-the-
counter medications, recreational drug use, and special diets: 
• Alcohol consumption 
• Exposure to environmental chemical agents 
• Past medical history 
• Complete review of systems 
• Obtain liver biochemistries including ALT, AST, alkaline phosphatase, total bilirubin, and INR.   
Evaluate subjects two or three times a week for signs and symptoms of clinical hepatitis and liver 
biochemistries until biochemistries stabilize. 
If biochemistries stabilize and the subject is asymptomatic, monitor liver biochemistries once a week 
until they return to baseline.  
Subjects who liver far from study sites can be evaluated locally for history, physical exam, and 
laboratories, if the results are communicated promptly to the site investigator. 
 
 


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APPENDIX D:  ALCOHOL QUESTIONNAIRE (AUDIT) 
 
 
 
The Alcohol Use Disorders Identification TestI:nterview Version 
Read questions as written. Record answers carefull.yBegin the AUDIT by saying 
“ Now I am going to ask you some questions about your use of alcoholic beverages 
during this past year.” Explain what is meant by “ alcoholic beverages” by using 
local examples of beer, wine, vodka, etc. Code answers in terms of “ standard 
drinks” . Place the correct answer number in the box at the right. 
1. How often do you have a drink containing alco- 
hol? 
(0) Never [Skip to Qs 9-10] 
(1) Monthly or less 
(2) 2 to 4 times a month 
(3) 2 to 3 times a week 
(4) 4 or more times a week 
2. How many drinks containing alcohol do you have 
on a typical day when you are drinking? 
(0) 1 or 2 
(1) 3 or 4 
(2) 5 or  6 
(3) 7, 8, or 9 
(4) 10 or more 
3. How often do you have six or more drinks on one 
occasion? 
(0) Never 
(1) Less than monthly 
(2) Monthly 
(3) Weekly 
(4) Daily or almost daily 
Skip to Questions 9 and 10 if Total Score 
for Questions 2 and 3 = 0 
4. How often during the last year have you found 
that you were not able to stop drinking once you 
had started? 
(0) Never 
(1) Less than monthly 
(2) Monthly 
(3) Weekly 
(4) Daily or almost daily 
5. How often during the last year have you failed to 
do what was normally expected  from you 
because of drinking? 
(0) Never 
(1) Less than monthly 
(2) Monthly 
(3) Weekly 
(4) Daily or almost daily 
6. How often during the last year have you needed 
a first drink in the morning to get yourself going 
after a heavy drinking session? 
(0) Never 
(1) Less than monthly 
(2) Monthly 
(3) Weekly 
(4) Daily or almost daily 
 
7. How often during the last year have you had a 
feeling of guilt or remorse after drinking? 
(0) Never 
(1) Less than monthly 
(2) Monthly 
(3) Weekly 
(4) Daily or almost daily 
 
8. How often during the last year have you been 
unable to remember what happened the night 
before because you had been drinking? 
(0) Never 
(1) Less than monthly 
(2) Monthly 
(3) Weekly 
(4) Daily or almost daily 
 
 
9. Have you or someone else been injured as a 
result of your drinking? 
(0) 
No 
(2) 
Yes, but not in the last year 
(4) 
Yes, during the last year 
 
 
 
10. Has a relative or friend or a doctor or another 
health worker been concerned about your drink- 
ing or suggested you cut down? 
(0) No 
(2) Yes, but not in the last year 
(4) Yes, during the last year 
Record total of specific items here 
If total is greater than recommended cut-off, consult User’s Manual. 


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APPENDIX D:  Alcohol Questionnaire (AUDIT) 
 
 


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APPENDIX D:  Alcohol Questionnaire – AUDIT-C 
 
 
 
Patient Name Date of Visit _ 
 
1. How often do you have a drink containing alcohol? 
 a. Never 
 b. Monthly or less 
 c. 2-4 times a month  
 d. 2-3 times a week 
 e. 4 or more times a week 
 
2. How many standard drinks containing alcohol do you have on a typical day? 
 
a. 1 or 2 
 
b. 3 or 4 
 
c. 5 or 6 
 
d. 7 to 9 
 
e. 10 or more 
3. How often do you have six or more drinks on one occasion? 
a. Never 
b. Less than monthly 
c. Monthly 
 
d. Weekly 
e. Daily or almost daily 
 
 
 
 
 
 
 
 
 


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APPENDIX D:  Alcohol Questionnaire - Skinner 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E:  FUNCTIONAL ACTIVITY QUESTIONNAIRE (NHANES)  
 
NHANES 2017 
PAQ.605  
Next I am going to ask you about the time {you spend/SP spends} doing different types of physical activity in a 
typical week. 
 
Think first about the time {you spend/he spends/she spends} doing work. Think of work as the things that 
{you have/he has/she has} to do such as paid or unpaid work, household chores, and yard work.  
 
Does {your/SP’s} work involve vigorous-intensity activity that causes large increases in breathing or heart 
rate like carrying or lifting heavy loads, digging or construction work for at least 10 minutes continuously? 
 
 
 
PAQ.610  
In a typical week, on how many days {do you/does SP} do vigorous-intensity activities as part of {your/his/her} 
work? 
 
PROBE IF NEEDED: Vigorous-intensity activity causes large increases in breathing or heart rate and is done 
for at least 10 minutes continuously. 
 
INTERVIEWER: REMEMBER, WE ARE ONLY ASKING ABOUT WORK AND CHORES IN THIS QUESTION. 
HARD EDIT: 1-7. 
ERROR MESSAGE: THE NUMBER OF DAYS SHOULD BE BETWEEN 1 AND 7. 
|      |      | 
ENTER NUMBER OF DAYS 
REFUSED ..................................................... 77 (PAQ.620) 
DON'T KNOW ............................................... 99 (PAQ.620) 
 
PAQ.615  
How much time {do you/does SP} spend doing vigorous-intensity activities at work on a typical day? 
Q/U 
 
PROBE IF NEEDED: Think about a typical day when {you do/he does/she does} vigorous-intensity activities 
during {your/his/her} work. 
 
PROBE IF NEEDED: Vigorous-intensity activity causes large increases in breathing or heart rate and is 
done for at least 10 minutes continuously. 
INTERVIEWER: REMEMBER, WE ARE ONLY ASKING ABOUT WORK AND CHORES. 
SOFT EDIT: >4 HOURS. 
ERROR MESSAGE: INTERVIEWER, YOU HAVE RECORDED THAT THE SP SPENDS MORE THAN 4 
HOURS DOING VIGOROUS-INTENSITY ACTIVITIES AT WORK ON A TYPICAL DAY. PLEASE CONFIRM 
WITH SP THAT OVER 4 HOURS IS CORRECT. 
 
HARD EDIT: >24 HOURS. 
HARD EDIT: <10 MINUTES. 
ERROR MESSAGE: THE TIME SHOULD BE 10 MINUTES OR MORE, BUT LESS THAN 24 HOURS. 
 
|      |      |     | 
ENTER NUMBER OF MINUTES OR HOURS 
 
YES ............................................................... 
1 
NO ................................................................. 
2 (PAQ.620) 
REFUSED ..................................................... 
7 (PAQ.620) 
DON'T KNOW ............................................... 
9 (PAQ.620) 


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REFUSED ................................................. 7777 (PAQ.620) 
 
 
APPENDIX E:  con’t. 
DON'T KNOW ........................................... 9999 (PAQ.620)  
ENTER UNIT 
MINUTES ...................................................... 1 
HOURS ......................................................... 2 
PAQ.620  
Does {your/SP’s} work involve moderate-intensity activity that causes small increases in breathing or heart 
rate such as brisk walking or carrying light loads for at least 10 minutes continuously? 
 
YES ............................................................... 
1 
NO ................................................................. 
2 (PAQ.635) 
REFUSED ..................................................... 
7 (PAQ.635) 
DON'T KNOW ............................................... 
9 (PAQ.635) 
 
 
PAQ.625  
In a typical week, on how many days {do you/does SP} do moderate-intensity activities as part of 
{your/his/her} work? 
 
PROBE IF NEEDED: Moderate-intensity activity causes small increases in breathing or heart rate and is 
done for at least 10 minutes continuously. 
INTERVIEWER: REMEMBER, WE ARE ONLY ASKING ABOUT WORK AND CHORES. 
HARD EDIT: 1-7. 
ERROR MESSAGE: THE NUMBER OF DAYS SHOULD BE BETWEEN 1 AND 7. 
 
|      |      | 
ENTER NUMBER OF DAYS 
 
REFUSED ..................................................... 77 (PAQ.635) 
DON'T KNOW ............................................... 99 (PAQ.635) 
 
PAQ.630  
How much time {do you/does SP} spend doing moderate-intensity activities at work on a typical day? 
Q/U 
 
PROBE IF NEEDED: Think about a typical day when {you do/he does/she does} moderate-intensity 
activities during {your/his/her} work. 
 
PROBE IF NEEDED: Moderate-intensity activity causes small increases in breathing or heart rate and is 
done for at least 10 minutes continuously. 
INTERVIEWER: REMEMBER, WE ARE ONLY ASKING ABOUT WORK AND CHORES. 
SOFT EDIT: >4 HOURS. 
ERROR MESSAGE: INTERVIEWER, YOU HAVE RECORDED THAT THE SP SPENDS MORE THAN 4 
HOURS DOING MODERATE-INTENSITY ACTIVITIES AT WORK ON A TYPICAL DAY. PLEASE 
CONFIRM WITH SP THAT OVER 4 HOURS IS CORRECT. 
 
HARD EDIT: >24 HOURS. 
HARD EDIT: <10 MINUTES. 
ERROR MESSAGE: THE TIME SHOULD BE 10 MINUTES OR MORE, BUT LESS THAN 24 HOURS. 


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APPENDIX E:  con’t. 
 
|      |      |     | 
ENTER NUMBER OF MINUTES OR HOURS 
 
REFUSED ................................................. 7777 (PAQ.635) 
DON'T KNOW ........................................... 9999 (PAQ.635) 
 
|      | 
ENTER UNIT 
MINUTES ...................................................... 1 
HOURS ......................................................... 2 
 
 
PAQ.635  
The next questions exclude the physical activities at work that you have already mentioned. Now I would like 
to ask you about the usual way {you travel/SP travels} to and from places. For example to work, for shopping, 
to school. 
 
In a typical week {do you/does SP} walk or use a bicycle for at least 10 minutes continuously to get to and 
from places? 
 
YES ............................................................... 
1 
NO ................................................................. 
2 (PAQ.650) 
REFUSED ..................................................... 
7 (PAQ.650) 
DON'T KNOW ............................................... 
9 (PAQ.650) 
 
PAQ.640  
In a typical week, on how many days {do you/does SP} walk or bicycle for at least 10 minutes continuously 
to get to and from places? 
 
HARD EDIT: 1-7. 
ERROR MESSAGE: THE NUMBER OF DAYS SHOULD BE BETWEEN 1 AND 7. 
 
|      |      | 
ENTER NUMBER OF DAYS 
 
REFUSED .................................................. 77(PAQ.650) 
DON'T KNOW ............................................ 99(PAQ.650) 
 
PAQ.645  
How much time {do you/does SP} spend walking or bicycling for travel on a typical day? 
Q/U 
 
PROBE IF NEEDED: Think about a typical day when {you walk or bicycle/SP walks or bicycles} for travel. 
 
SOFT EDIT: >4 HOURS. 
ERROR MESSAGE: INTERVIEWER, YOU HAVE RECORDED THAT THE SP SPENDS MORE THAN 4 
HOURS WALKING OR BICYCLING TO GET TO AND FROM PLACES ON A TYPICAL DAY. PLEASE 
CONFIRM WITH SP THAT OVER 4 HOURS IS CORRECT. 
 
HARD EDIT: >24 HOURS. 
HARD EDIT: <10 MINUTES. 
ERROR MESSAGE: THE TIME SHOULD BE 10 MINUTES OR MORE, BUT LESS THAN 24 HOURS. 
 
|      |      |     | 
ENTER NUMBER OF MINUTES OR HOURS 
 


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REFUSED ................................................. 7777 (PAQ.650) 
DON'T KNOW ........................................... 9999 (PAQ.650) 
 
|      | 
ENTER UNIT 
MINUTES ...................................................... 1 
HOURS ......................................................... 2 
 
 
 
PAQ.650  
The next questions exclude the work and transportation activities that you have already mentioned. Now I 
would like to ask you about sports, fitness and recreational activities. 
 
In a typical week {do you/does SP} do any vigorous-intensity sports, fitness, or recreational activities that 
cause large increases in breathing or  heart rate like running or  basketball for  at least  10 minutes 
continuously? 
 
YES ............................................................... 
1 
NO ................................................................. 
2 (PAQ.665) 
REFUSED ..................................................... 
7 (PAQ.665) 
DON'T KNOW ............................................... 
9 (PAQ.665) 
 
PAQ.655  
In a typical week, on how many days {do you/does SP} do vigorous-intensity sports, fitness or recreational 
activities? 
 
PROBE IF NEEDED: Vigorous-intensity activity causes large increases in breathing or heart rate and is done 
for at least 10 minutes continuously. 
 
HARD EDIT: 1-7. 
ERROR MESSAGE: THE NUMBER OF DAYS SHOULD BE BETWEEN 1 AND 7. 
 
|      |      | 
ENTER NUMBER OF DAYS 
 
REFUSED ..................................................... 77 (PAQ.665) 
DON'T KNOW ............................................... 99 (PAQ.665) 
 
 
PAQ.660  
How much time {do you/does SP} spend doing vigorous–intensity sports, fitness or recreational activities on a 
typical day? 
 
PROBE IF NEEDED: Think about a typical day when {you do/SP does} vigorous-intensity sports, fitness or 
recreational activities. 
 
SOFT EDIT: >4 HOURS. 
ERROR MESSAGE: INTERVIEWER, YOU HAVE RECORDED THAT THE SP SPENDS MORE THAN 4 
HOURS DOING VIGOROUS-INTENSITY RECREATIONAL ACTIVITIES ON A TYPICAL DAY. PLEASE 
CONFIRM WITH SP THAT OVER 4 HOURS IS CORRECT. 
 
Q/U 
 
 


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APPENDIX E:  con’t. 
 
 
HARD EDIT: >24 HOURS. 
HARD EDIT: <10 MINUTES. 
ERROR MESSAGE: THE TIME SHOULD BE 10 MINUTES OR MORE, BUT LESS THAN 24 HOURS. 
 
| | | | 
ENTER NUMBER OF MINUTES OR HOURS 
 
REFUSED ................................................. 7777 (PAQ.665) 
DON'T KNOW ........................................... 9999 (PAQ.665) 
 
| | 
ENTER UNIT 
MINUTES ...................................................... 1 
HOURS ......................................................... 2 
 
 
PAQ.665  
In a typical week {do you/does SP} do any moderate-intensity sports, fitness, or recreational activities that 
cause a small increase in breathing or heart rate such as brisk walking, bicycling, swimming, or golf for at 
least 10 minutes continuously? 
 
YES ............................................................... 
1 
NO ................................................................. 
2 (PAQ.680) 
REFUSED ..................................................... 
7 (PAQ.680) 
DON'T KNOW ............................................... 
9 (PAQ.680) 
 
PAQ.670  
In a typical week, on how many days {do you/does SP} do moderate-intensity sports, fitness or recreational 
activities? 
 
PROBE IF NEEDED: Moderate-intensity sports, fitness or recreational activities cause small increases in 
breathing or heart rate and is done for at least 10 minutes continuously. 
 
HARD EDIT: 1-7. 
ERROR MESSAGE: THE NUMBER OF DAYS SHOULD BE BETWEEN 1 AND 7. 
 
| | | 
ENTER NUMBER OF DAYS 
REFUSED ..................................................... 77 (PAQ.680) 
DON'T KNOW ............................................... 99 (PAQ.680) 
 
Page 6 of 268 
 
PAQ.675 
Q/U 
 
How much time {do you/does SP} spend doing moderate-intensity sports, fitness or recreational activities on a 
typical day? 
 
PROBE IF NEEDED: Think about a typical day when {you do/SP does} moderate-intensity sports, fitness or 
recreational activities. 
 
 


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APPENDIX E:  con’t. 
 
PROBE IF NEEDED: Moderate-intensity sports, fitness or recreational activities cause small increases in 
breathing or heart rate and is done for at least 10 minutes continuously. 
 
SOFT EDIT: >4 HOURS. 
ERROR MESSAGE: INTERVIEWER, YOU HAVE RECORDED THAT THE SP SPENDS MORE THAN 4 
HOURS DOING MODERATE-INTENSITY RECREATIONAL ACTIVITIES ON A TYPICAL DAY. PLEASE 
CONFIRM WITH SP THAT OVER 4 HOURS IS CORRECT. 
 
HARD EDIT: >24 HOURS. 
HARD EDIT: <10 MINUTES. 
ERROR MESSAGE: THE TIME SHOULD BE 10 MINUTES OR MORE, BUT LESS THAN 24 HOURS. 
 
| | | | 
ENTER NUMBER OF MINUTES OR HOURS 
 
REFUSED ................................................. 7777 (PAQ.680) 
DON'T KNOW ........................................... 9999 (PAQ.680) 
 
| | 
ENTER UNIT 
MINUTES ...................................................... 1 
HOURS ......................................................... 2 
 
PAQ.680 
Q/U 
 
The following question is about sitting at work, at home, getting to and from places, or with friends, including 
time spent sitting at a desk, traveling in a car or bus, reading, playing cards, watching television, or using a 
computer. Do not include time spent sleeping. 
 
How much time {do you/does SP} usually spend sitting on a typical day? 
 
| | | | 
ENTER NUMBER OF MINUTES OR HOURS 
 
REFUSED ................................................. 7777 (BOX 2) 
DON'T KNOW ........................................... 9999 (BOX 2) 
 
| | 
ENTER UNIT 
 
MINUTES ...................................................... 1 
HOURS ......................................................... 2 
 
SOFT EDIT: 18 HOURS OR MORE. 
ERROR MESSAGE: PLEASE VERIFY TIMES OF 18 HOURS OR MORE. 
 
HARD EDIT: 24 HOURS OR MORE. 
ERROR MESSAGE: THE TIME SHOULD BE LESS THAN 24 HOURS. 
 
 
 
 


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APPENDIX E:  con’t. 
 
 
 
 
PAQ.706  
Now I'd like to ask you some questions about {your/SP's} activities. 
 
During the past 7 days, on how many days {were you/was SP} physically active for a total of at least 60 
minutes per day?  Add up all the time {you/he/she} spent in any kind of physical activity that increased 
{your/his/her} heart rate and made {you/him/her} breathe hard some of the time. 
 
0 days............................................................ 0 
1 day.............................................................. 1 
2 days............................................................ 2 
3 days............................................................ 3 
4 days............................................................ 4 
5 days............................................................ 5 
6 days............................................................ 6 
7 days............................................................ 7 
REFUSED ..................................................... 77 
DON’T KNOW ............................................... 99 
PAQ.710  
Now I will ask you first about TV watching and then about computer use. 
Over the past 30 days, on average how many hours per day did {you/SP} sit and watch TV or videos? 
Would you say . . . 
less than 1 hour, ............................................ 0 
1 hour, ........................................................... 1 
2 hours, ......................................................... 2 
3 hours, ......................................................... 3 
4 hours, ......................................................... 4 
5 hours or more, or ........................................ 5 
{You do/SP does} not watch TV or videos..... 8 
REFUSED ..................................................... 77 
DON'T KNOW ............................................... 99 
PAQ.715  
Over the past 30 days, on average how many hours per day did {you/SP} use a computer or play computer 
games outside of school? Include time spent on things such as Xbox, PlayStation, an iPod, an iPad or other 
 
BOX 
2 
CHECK ITEM PAQ.720: 
IF SP AGE 18+, GO TO NEXT SECTION. 


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APPENDIX E:  con’t. 
 
tablet, a smart phone, YouTube, Facebook or other social networking tools, and the internet. Would you 
say 
. . . 
less than 1 hour, ............................................ 0 
1 hour, ........................................................... 1 
2 hours, ......................................................... 2 
3 hours, ......................................................... 3 
4 hours, ......................................................... 4 
5 hours or more, or ........................................ 5 
{You do/SP does} not use a computer 
  outside of work or school ............................   8 
REFUSED ..................................................... 77 
DON'T KNOW ............................................... 99 
HELP SCREEN: 
If the SP watches T.V. or video at the same time as working on the computer, count this time as 
watching T.V. 
or video. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F:  INTERNATIONAL-PROSTATE SYMPTOM SCORE (I-
PSS) QUESTIONNAIRE 
 
 
 
 
INTERNATIONAL-PROSTATE SYMPTOM SCORE (I-PSS) 
 
Not at all 
Less Than 
1 Time in 5 
Less Than 
Half the 
Time 
 
About Half 
the Time 
More Than 
Half the 
Time 
 
Almost 
Always 
1 
Over the past month, how often 
have you had a sensation of not 
emptying your bladder completely 
after you finished urinating? 
0 
1 
2 
 
3 
 
4 
 
5 
2 
Over the past month, how often 
have you had to urinate again less 
than two hours after you finished 
urinating? 
0 
1 
2 
 
3 
 
4 
 
5 
3 
Over the past month, how often 
have you found you stopped and 
started again several times when 
you urinated? 
0 
1 
2 
 
3 
 
4 
 
5 
4 
Over the past month, how often 
have you found it difficult to 
postpone urination? 
0 
1 
2 
 
3 
 
4 
 
5 
5 
Over the past month, how often 
have you had a weak urinary 
stream? 
0 
1 
2 
 
3 
 
4 
 
5 
6 
Over the past month, how often 
have you had to push or strain to 
begin urination? 
0 
1 
2 
 
3 
 
4 
 
5 
 
None 
1 time 
2 times 
 
3 times 
 
4 times 
5 or more 
times 
7 
Over the past month, how many 
times did you most typically get up 
to urinate from the time you went 
to bed at night until the time you 
got up in the morning? 
0 
1 
2 
 
 
3 
 
 
4 
 
 
5 
Total I-PSS Score S = 


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APPENDIX F. International-Prostate Symptom Score (I-PSS) (CONTINUED) 
 
QUALITY OF LIFE DUE TO URINARY SYMPTOMS 
Delighted Pleased 
Mostly 
Satisfied 
Mixed 
About 
Equally 
Satisfied 
and 
Dissatisfied 
Mostly 
Dissatisfied Unhappy Terrible 
1 
If you were to spend 
the rest of your life 
with your urinary 
condition just the way 
it is now, how would 
you feel about that? 
0 
1 
2 
3 
4 
5 
6 
 
Quality of life assessment index L = 
 
International – Prostate Symptom Score© (I-PSS©) Michael J. Barry, 1992. All rights reserved. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX G:  HR-QOL (SF-36) QUESTIONNAIRE 
 
 


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APPENDIX G:  con’t. 
 


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APPENDIX G:  con’t. 
 


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APPENDIX G:  con’t. 
 


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APPENDIX G:  con’t. 
 


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APPENDIX H:  PGI-S QUESTIONNAIRE 
 
PGI Scales PGI-S (Severity) Scale  
Please choose the response below that best describes the severity of your 
symptoms over the past 4 weeks.  
1. None.  
2. Mild.  
3. Moderate.  
4. Severe.  
5. Very severe.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I:  PGI-C QUESTIONNAIRE 
 
PGI-C (Change) Scale  
Please choose the response below that best describes the overall change in your 
symptoms since you started using the study treatment.  
1. Very much better.  
2. Moderately better.  
3. A little better.  
4. No change. 
5. A little worse.  
6. Moderately worse.  
7. Very much worse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX J:  CHRONIC LIVER DISEASE QUESTIONNAIRE (CLDQ)  
THE CHRONIC LIVER DISEASE QUESTIONNAIRE 
(CLDQ)—QUALITY OF LIFE INDEX FOR PATIENTS WITH CHRONIC LIVER DISEASE 
This questionnaire is designed to find out how you have been feeling during the last two weeks. 
You will be asked about your symptoms related to your liver disease, how you have been 
affected in doing activities, and how your mood has been. Please complete all of the questions 
and select only one response for each question. 
RESPONSE OPTIONS 
1 All of the time 
2 Most of the time 
3 A good bit of the time 
4 Some of the time 
5 A little of the time 
6 Hardly any of the time 
7 None of the time 
QUESTIONS 
1. How much of the time during the last two weeks have you been troubled by a feeling of 
abdominal bloating? 
2. How much of the time have you been tired or fatigued during the last two weeks? 
3. How much of the time during the last two weeks have you experienced bodily pain? 
4. How often during the last two weeks have you felt sleepy during the day? 
5. How much of the time during the last two weeks have you experienced abdominal pain? 
6. How much of the time during the last two weeks has shortness of breath been a problem for 
you in your daily activities? 
7. How much of the time during the last two weeks have you not been able to eat as much as you 
would like?  
8. How much of the time in the last two weeks have you been bothered by having decreased 
strength? 


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9. How often during the last two weeks have you had trouble lifting or carrying heavy objects? 
10. How often during the last two weeks have you felt anxious? 
11. How often during the last two weeks have you felt a decreased level of energy? 
12. How much of the time during the last two weeks have you felt unhappy? 
13. How often during the last two weeks have you felt drowsy? 
14. How much of the time during the last two weeks have you been bothered by a limitation of 
your diet? 
15. How often during the last two weeks have you been irritable? 
16. How much of the time during the last two weeks have you had difficulty sleeping at night? 
17. How much of the time during the last two weeks have you been troubled by a feeling of 
abdominal discomfort? 
18. How much of the time during the last two weeks have you been worried about the impact 
your liver disease has on your family? 
19. How much of the time during the last two weeks have you had mood swings? 
20. How much of the time during the last two weeks have you been unable to fall asleep at night? 
21. How often during the last two weeks have you had muscle cramps? 
22. How much of the time during the last two weeks have you been worried that your symptoms 
will develop into major problems? 
23. How much of the time during the last two weeks have you had a dry mouth? 
24. How much of the time during the last two weeks have you felt depressed? 
25. How much of the time during the last two weeks have you been worried about your condition 
getting worse? 
26. How much of the time during the last two weeks have you had problems concentrating? 
27. How much of the time have you been troubled by itching during the last two weeks? 
28. How much of the time during the last two weeks have you been worried about never feeling 
any better? 
29. How much of the time during the last two weeks have you been concerned about the 
availability of a liver if you need a liver transplant? 


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APPENDIX K:  SEXUAL DESIRE AND DISTRESS QUESTIONNAIRE 
 
PROVIDE A 7-PAGE PRINTOUT OF THE FOLLOWING QUESTION FOR SUBJECTS 
TO COMPLETE DURING SCREENING, AND PRIOR TO WEEKS 4, 8, 12, 16, 20, 24, 
30, AND 36. 
Sexual Desire Question: Daily Rating 
Instructions: Please read the item below carefully and circle the number that best describes how 
you feel.  Circle only one number.   
 
How would you rate your level (degree) of sexual desire today? 
0 
1 
2 
3 
4 
5 
None at all 
Very low 
Low 
Moderate 
High 
Very high 
 
 


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PROVIDE A SINGLE PAGE PRINTOUT OF THE FOLLOWING QUESTION FOR 
SUBJECTS TO COMPLETE DURING SCREENING, AND PRIOR TO WEEKS 4, 8, 12, 
16, 20, 24, 30, AND 36.  
Sexual Distress Question: Weekly Rating 
Instructions: Please read the item below carefully and circle the number that best describes how 
you feel.  Circle only one number. Rate how much the problem listed below has bothered you 
over the past 7 days, including today.  
 
How often did you feel: Bothered by low sexual desire? 
Past 7 Days 
0 
1 
2 
3 
4 
Never 
Rarely 
Occasionally 
Frequently 
Always 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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xxxvii Arena U, Lupsor Platon M, Stasi C, Moscarella S, Assarat A, Bedogni G, Piazzolla V, et el. Liver stiffness is 
influenced by a standardized meal in patient with chronic hepatitis C virus at different stages of fibrotic evolution. 
Hepatology 2013;58:65:-75 
 
 
 
 
 
 
 
 
 
 

SAP_003.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A Phase 2, Randomized Double-Blind, Placebo- 
Controlled, Multi-Center Study to Assess the Efficacy, 
Safety and Tolerability of Oral LPCN 1144 in Subjects 
with Nonalcoholic Steatohepatitis (NASH) 
Protocol Number: 
LPCN 1144-18-002 
Protocol Version/Date: 
Version 1.0 / 6 June 2019 
Version 2.0 / 3 September 2019 
Version 3.0 / 7 January 2020 
 
Investigational Product: LPCN 1144 (Testosterone Undecanoate for NASH) 
 
 
Sponsor: 
Lipocine Inc. 
675 Arapeen Drive, Suite 202 
Salt Lake City, Utah 84108 
 
 
SAP Version/Date: 
Version 2.0 / 16 March 2021 
 
CONFIDENTIAL 
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 
 
 




Lipocine Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
LPCN 1144-18-002 
 
Version 2.0, 16 March 2021 
Page 3 of 34 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
30 October 2020 
Original signed version 
2.0 
16 March 2021 
Added DXA analysis for Week 20 
database lock 
 
 


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Statistical Analysis Plan 
LPCN 1144-18-002 
 
Version 2.0, 16 March 2021 
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TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 8 
2 
Study Overview ................................................................................................................... 8 
2.1 
Study Objectives .......................................................................................................... 8 
2.1.1 
Primary Objective ................................................................................................. 8 
2.1.2 
Secondary Objectives ........................................................................................... 8 
2.1.3 
Safety Objectives .................................................................................................. 8 
2.2 
Study Design ............................................................................................................... 8 
2.2.1 
Overview ............................................................................................................... 8 
2.2.2 
Randomization and Blinding ................................................................................. 9 
2.2.3 
Study Drug ............................................................................................................ 9 
2.2.4 
Sample Size Determination ..................................................................................10 
2.3 
Study Outcome Measures ...........................................................................................10 
2.3.1 
Primary Outcome Measures ................................................................................10 
2.3.2 
Key Secondary Outcome Measures .....................................................................10 
2.3.3 
Other Secondary Outcome Measures ..................................................................10 
3 
Statistical Methodology ......................................................................................................11 
3.1 
General Considerations ..............................................................................................11 
3.1.1 
Analysis Day ........................................................................................................11 
3.1.2 
Analysis Visits ......................................................................................................11 
3.1.3 
Definition of Baseline ...........................................................................................12 
3.1.4 
Summary Statistics ..............................................................................................12 
3.1.5 
Multiple Comparison/Multiplicity ...........................................................................12 
3.1.6 
Handling of Dropouts and Missing Data ...............................................................13 
3.1.7 
The Impact of Coronavirus Disease 2019 (COVID-19) .........................................13 
3.2 
Analysis Populations ...................................................................................................13 
3.2.1 
Intent-to-Treat (ITT) Analysis Dataset ..................................................................13 
3.2.2 
Modified Intent-to-Treat (mITT) Analysis Dataset .................................................13 
3.2.3 
Per-Protocol (PP) Analysis Datasets ....................................................................13 
3.2.4 
Safety Analysis Dataset .......................................................................................14 
3.3 
Subject Data and Study Conduct ................................................................................14 
3.3.1 
Subject Disposition ..............................................................................................14 
3.3.2 
Protocol Deviations ..............................................................................................14 
3.3.3 
Analysis Populations ............................................................................................15 
3.3.4 
Demographic and Baseline Characteristics ..........................................................15 
3.3.5 
Medical History ....................................................................................................15 
3.3.6 
Concomitant Medications .....................................................................................16 
3.3.7 
Study Drug Exposure and Compliance ................................................................16 
3.4 
Efficacy Assessment ...................................................................................................17 
3.4.1 
Primary Efficacy Outcome Measures ...................................................................17 


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3.4.2 
Key Secondary Efficacy Outcome Measures .......................................................19 
3.4.3 
Other Secondary Efficacy Outcome Measures .....................................................21 
3.4.4 
Subgroups ...........................................................................................................26 
3.5 
Quality of Life Assessment ..........................................................................................27 
3.5.1 
Functional Activity Questionnaire (NHANES III) ...................................................28 
3.5.2 
Health-Related Quality of Life (HR-QOL) measured by Short Form-36 ................28 
3.5.3 
Chronic Liver Disease Questionnaire (CLDQ) ......................................................28 
3.5.4 
Patient Global Impression of Severity (PGI-S) .....................................................28 
3.5.5 
Patient Global Impression of Change (PGI‑C)......................................................28 
3.5.6 
Sexual Desire and Distress Questionnaire ...........................................................29 
3.5.7 
International Prostate Symptom Score (I-PSS) ....................................................29 
3.6 
Safety Assessment .....................................................................................................29 
3.6.1 
Adverse Events (AEs) ..........................................................................................29 
3.6.2 
Clinical Laboratory Tests .....................................................................................30 
3.6.3 
Vital Signs ............................................................................................................30 
3.6.4 
Fibroscan .............................................................................................................31 
3.6.5 
Gait Speed ...........................................................................................................31 
3.6.6 
Hand Grip Strength Test ......................................................................................31 
3.6.7 
Cardiovascular Risk Evaluation ...........................................................................31 
3.6.8 
Other Safety Assessments ...................................................................................31 
4 
Data and Safety Monitoring Board (DSMB) ........................................................................31 
5 
Analysis Timing ..................................................................................................................32 
5.1 
Primary Analysis Reviews ...........................................................................................32 
5.2 
Week 20 Analysis Reviews .........................................................................................32 
5.3 
Interim Analysis ..........................................................................................................32 
6 
Changes from Protocol-Specified Statistical Analyses .......................................................33 
7 
Programming Specifications ..............................................................................................34 
 
 
 


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Statistical Analysis Plan 
LPCN 1144-18-002 
 
Version 2.0, 16 March 2021 
Page 6 of 34 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AUDIT 
Alcohol Use Disorders Identification Test 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
Alpha SMA 
Alpha-Smooth Muscle Actin 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice Daily 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
BSAP 
Bone Specific Alkaline Phosphatase 
BUN 
Blood Urea Nitrogen 
CBG 
Cortisol Binding Globulin 
CK 
Creatine Kinase 
CLDQ 
Chronic Liver Disease Questionnaire 
COVID-19 
Coronavirus Disease 2019 
CP 
Child Pugh 
CRN 
Clinical Research Network 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
cT1 
Corrected T1 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHT 
Dihydrotestosterone 
DILI 
Drug-Induced Liver Injury 
DRE 
Digital Rectal Examination 
DSMB 
Data and Safety Monitoring Board 
DXA 
Dual Energy X-ray Absorptiometry 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
ECG 
Electrocardiogram 
ELF™ 
Enhanced Liver Fibrosis Panel 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulating Hormone 
GFR 
Estimated Glomerular Filtration Rate 
GGT 
Gamma Glutamyl Transferase 
HA 
Hyaluronic Acid 
HDL-C 
High-Density Lipoprotein Cholesterol 
HOMA 
Homeostasis Model Assessment 
HSP47 
Heat-Shock Protein 47 
HR-QOL 
Health-Related Quality of Life 
INR 
International Normalized Ratio 
I-PSS 
International-Prostate Symptom Score 
ITT 
Intent-to-Treat 


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CONFIDENTIAL 
Statistical Analysis Plan 
LPCN 1144-18-002 
 
Version 2.0, 16 March 2021 
Page 7 of 34 
 
Abbreviation 
Definition 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LH 
Luteinizing Hormone 
LLOQ 
Low Limit of Quantification 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAR 
Missing at Random 
MCP-1 
Monocyte Chemotactic Protein-1 
MELD 
Model for End-Stage Liver Disease 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-Model Repeated-Measures 
MNAR 
Missing not at Random 
MRI-PDFF 
Magnetic Resonance Imaging - Proton Density Fat Fraction 
NAB 
Neutralizing Antibody 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
PIIINP  
N-terminal propeptide of type III collagen 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PP 
Per Protocol 
PT 
Prothrombin Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SHBG 
Sex Hormone Binding Globulin 
SF-36 
Short Form 36 Health Survey 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
T 
Testosterone 
TB 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TFLs 
Tables, Figures, and Listings 
TGF-Beta 
Transforming growth Factor-Beta 
TIMP-1 
Tissue inhibitor of metalloproteinase 1 
TNF-alpha 
Tissue Necrosis Factor-alpha 
TSH 
Thyroid Stimulating Hormone 
TU 
Testosterone Undecanoate 
WHO 
World Health Organization 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
 
 
 


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Statistical Analysis Plan 
LPCN 1144-18-002 
 
Version 2.0, 16 March 2021 
Page 8 of 34 
 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number 
LPCN 1144-18-002.  The SAP will be finalized prior to database lock.  Any deviations from the 
SAP after database lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
• 
To evaluate the change in hepatic fat fraction from Baseline to Week 12 based on magnetic 
resonance imaging-proton density fat fraction (MRI-PDFF) measurements in LPCN 1144 
(Oral Testosterone (T)) treated subjects. 
2.1.2 Secondary Objectives 
• 
To evaluate whether 36 weeks of treatment with LPCN 1144 lowers nonalcoholic 
steatohepatitis (NASH) activity as determined from hepatic histology in adult men with 
NASH. 
• 
To evaluate the change in hepatic fat fraction from baseline to Week 36 based on MRI-
PDFF measurements in LPCN 1144 treated subjects 
2.1.3 Safety Objectives 
• 
To assess tolerability of oral LPCN 1144 in the study population. 
2.2 Study Design 
2.2.1 Overview 
This is a proof of concept, Phase 2, randomized, double-blind, placebo controlled, three arm 
study in adult men with biopsy confirmed NASH.  The study will be conducted across multiple 
centers in the United States. 
Subjects will be randomized in 1:1:1 ratio to receive one of the following treatments:  
• 
Treatment A: Oral LPCN 1144 total daily dose of 450 mg testosterone undecanoate (TU) 
administered as BID  
• 
Treatment B: Oral LPCN 1144 d-alpha tocopherol formulation, total daily dose of 450 mg 
TU administered as BID  
• 
Treatment C: Oral matching placebo administered as BID  
There are four phases of study: 
• 
Screening Phase for Subject requiring testosterone/androgen washout up to 12 weeks 
(12 weeks following intramuscular androgen injections; 4 weeks following topical or 
buccal androgens; 3 weeks following oral androgens). 
• 
Screening Phase for eligibility assessments (8 weeks prior to randomization) 


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• 
Randomization Phase (one visit) 
• 
Treatment Phase (eight visits) 
• 
Follow-up (one visit) 
Subjects will undergo a screening period to determine study eligibility.  As a part of screening, 
liver biopsies will be performed for subjects who have not had a liver biopsy within 4 months of 
Screening Visit 1.  Adult male subjects with histologic evidence of NASH will be enrolled into the 
study.  Baseline fat fraction will be measured by MRI-PDFF in eligible subjects.  If a subject is 
unable to undergo MRI-PDFF or DXA imaging due to health condition (e.g. claustrophobia, 
difficulty holding breath during the procedure, etc.), the missing MRI-PDFF will be treated as 
missing data, and the subject will be allowed to proceed to randomization or continue therapy 
upon investigator and medical monitor approval. 
Eligible subjects will be randomized to one of the three treatment arms.  The treatment phase 
will be for a duration of 36-weeks (not including screening and follow up periods) with 
assessments of liver biopsies, hepatic fat fraction, liver enzymes, lipid levels and other safety 
parameters.  Safety and tolerability will be assessed throughout the study.  A follow-up visit will 
be performed to assess adverse events, complete patient reported questionnaires including 
Patient Global Impression of Change (PGI-C), collect a urinalysis sample, and to obtain blood 
samples for clinical laboratory tests including, lipid panel, hematology panel, metabolic and 
renal function panel, hepatic panel, testosterone, and hormones and related markers. 
The procedures of each visit are provided in Schedule of Activities (SOA) in the section 2.3 of 
the protocol. 
2.2.2 Randomization and Blinding 
All subjects meeting the inclusion criteria and not meeting any of the exclusion criteria will be 
enrolled into the study.  Subjects meeting the enrollment criteria will be randomly assigned to 
one of the three treatment arms in a 1:1:1 ratio.  The randomization will be carried out by central 
assignment.  The study is a blinded study; therefore, all the randomization codes will be 
centrally maintained and no data from the randomization will be available to Sponsor, contract 
research organization (CRO) operations team, medical monitors, monitors or any site staff.  The 
treatment assigned to the study subject will not be available to anyone except pre-identified 
study personnel.   
All randomization codes will be centrally assigned and stored.  Each subject will receive a 
unique treatment ID that does not directly associate with the treatment assigned. 
2.2.3 Study Drug 
LPCN 1144 is an oral capsule formulation of TU administered as 225 mg TU two times a day for 
a total daily dose of 450 mg TU.  Two different formulations of LPCN 1144 will be evaluated, 
along with placebo. 
All subjects should be instructed to take Treatment A (225 mg TU per dose), B (225 mg TU per 
dose), or C (placebo) twice daily, approximately 12 hours apart, approximately 30 minutes after 
morning and evening meals, with water.  If a dose is missed, the subjects should take it as soon 
as they remember (within 4 hours of missed dose).  If second dose is not taken within 16 hours 
of the first dose of the day, the subject should skip that dose and resume dosing at 24 hours 


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Statistical Analysis Plan 
LPCN 1144-18-002 
 
Version 2.0, 16 March 2021 
Page 10 of 34 
 
past the last dose.  If a subject is switched to a reduced dose, the subject should take the dose 
in the morning, approximately 30 minutes after the morning meal, with water. 
2.2.4 Sample Size Determination 
This is a proof of concept Phase 2 study aimed at evaluating the LPCN 1144 as potential 
therapeutic agent in the treatment and / or management of NASH.  The total planned sample 
size was approximately 75 subjects.  The sample size for the study was not based on any 
statistical considerations but based on similar Phase 2 studies in this therapeutic area. 
Based on the recruitment status, the initial target of 75 randomized subjects can not be 
achieved.  Therefore, Lipocine decided to end randomization by September 15th 2020.  Based 
on screening data to-date, approximately 55 subjects will be randomized in the study.  With 55 
subjects, the study will still be sufficiently powered (i.e, at least 80% power for each active arm 
vs. placebo and at least 90% power for pooled active arms vs. placebo) to detect a treatment 
difference of 5% in the primary outcome measure (change in MRI-PDFF from baseline at 
Week 12) assuming a common standard deviation of 5% at a 2-sided 0.05 significance level. 
2.3 Study Outcome Measures 
2.3.1 Primary Outcome Measures 
• 
Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated 
subjects after 12 weeks of treatment.  
2.3.2 Key Secondary Outcome Measures 
• 
Change in nonalcoholic fatty liver disease (NAFLD) activity evaluated via a standardized 
scoring of liver biopsies at baseline and after 36 weeks of treatment in LPCN 1144 treated 
subjects. 
• 
Change in fibrosis evaluated via NASH clinical research network (CRN) fibrosis score of 
liver biopsies at baseline and after 36 weeks of treatment in LPCN 1144 treated subjects. 
2.3.3 Other Secondary Outcome Measures 
• 
Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 
treated subjects after 12 weeks of treatment.   
• 
Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated 
subjects after 36 weeks of treatment.   
• 
Relative change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 
treated subjects after 36 weeks of treatment.   
• 
NAFLD resolution of subjects who at baseline is at least 5% of hepatic fat fraction with a 
decrease to less than 5% at end of study.  
• 
Resolution of NASH on overall histopathological reading. 
• 
Change in individual NAS component scores (inflammation, ballooning, steatosis) in 
LPCN 1144 treated subjects after 36 weeks of treatment.  
• 
Resolution of inflammatory liver on overall histopathological reading. 
• 
Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score).  


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• 
Change and relative change in anthropometric measurements (weight, body mass index 
(BMI), waist to hip ratio, waist circumference, triceps skin fold thickness, upper arm 
circumference) in LPCN 1144 treated subjects. 
• 
Change and relative change in insulin resistance (assessed by Homeostasis Model 
Assessment (HOMA)) and Hemoglobin A1c (HbA1c) in LPCN 1144 treated subjects. 
• 
Changes and relative changes in liver enzymes aspartate transaminase (AST), alanine 
transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), Total 
Bilirubin (TB) and Creatine Kinase (CK) in LPCN 1144 treated subjects. 
• 
Changes and relative changes in non-invasive markers of fibrosis and steatosis including 
cytokines, leptin, fibrosis markers, and lipid profile in LPCN 1144 treated subjects. 
• 
Changes and relative changes in lipid parameters (triglycerides, very low-density lipoprotein 
cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein 
cholesterol (LDL-C), non-HDL cholesterol and free fatty acids) in LPCN 1144 treated 
subjects. 
• 
Changes in Functional Activity, Health-Related Quality of Life (HR-QOL) as measured by 
Short Form-36 (SF-36), Patient Global Impression of Severity (PGI-S), PGI-C, and Chronic 
Liver Disease Questionnaire (CLDQ) and Sexual desire and distress questionnaires in 
LPCN 1144 treated subjects. 
• 
Changes in laboratory parameters (clinical chemistry, hematology and urinalysis) in 
LPCN 1144 treated subjects. 
• 
Subjects achieving relative reduction ≥ 30% hepatic fat fraction based on MRI-PDFF 
measurements. 
• 
Subjects achieving relative reduction ≥ 23% hepatic fat fraction based on MRI-PDFF 
measurements. 
• 
Change in fibrosis status evaluated via the paired biopsies after 36 weeks of treatment in 
LPCN 1144 treated subjects. 
• 
Change in FibroNest scores evaluated indepently by PharmaNest after 36 weeks of 
treatment in LPCN 1144 treated subjects if data available. 
• 
Changes in DXA scan parameters in LPCN 1144 treated subjects. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1.  There 
will be no Day 0. 
3.1.2 Analysis Visits 
For efficacy parameters with limited scheduled visits (FibroScan, liver biopsy, and ELF and its 
components), the analysis visits will be assigned according to the scheduled visit.  Note that for 


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Version 2.0, 16 March 2021 
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subjects who early terminate, liver biopsy will only be obtained and used in analyses if the 
withdrawal is after Week 16, and within 56 days (or 8 weeks) after the last dose of study drug.  
For FibroScan, and ELF and its components, if the early term collection is >56 days (or 8 
weeks) after the last dose of study drug, it will not be used in analyses. 
For MRI-PDFF, dual-energy absorptiometry (DXA) scan and other efficacy parameters, 
scheduled visits will be assigned to analysis visits as recorded on the CRF.  Unscheduled and 
early termination visits will be assigned to analysis visits according to the following visit 
windows: 
Analysis Visit 
Target Analysis Day Low Analysis Day 
High Analysis Day 
Week 4 
29 
2 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
99 
Week 16 
113 
100 
127 
Week 20 
141 
128 
155 
Week 24 
169 
156 
183 
Week 30 
211 
184 
225 
Week 36 
253 
226 
259 
Note: for subjects who early terminate, MRI-PDFF will only be used if the withdrawal is after 
Week 4, and within 56 days (or 8 weeks) after the last dose of study drug.  For other efficacy 
parameters, if the unscheduled collection or early term collection is >56 days after the last 
dose of study drug, it will not be used in analyses.   
Within an analysis visit window, the measurement from the scheduled visits will be used if 
available.  If no scheduled visit occurs, the measurement from the visit closest to the defined 
target analysis day within the window will be used.  If there is more than one measurement with 
equal distance to the defined target analysis day, the latter will be used.  If no visits occur within 
a visit window, the measurement for this visit will be treated as missing. 
3.1.3 Definition of Baseline  
Pre-dose measurements on Day 1 will be considered the baseline values.  If the measurement 
at this visit is not available, the last measurement prior to the first dose of study drug may be 
used as the baseline value unless it is stated otherwise.  The scheduled baseline visits for MRI-
PDFF, FibroScan, liver biopsy, DXA scan, questionnaires, gait speed and hand grip are 
Screening Visits from Day -56 to -1.  The scheduled baseline visits for other variables are Day 
1. 
3.1.4 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, minimum, maximum. 
3.1.5 Multiple Comparison/Multiplicity 
For the primary outcome measure, if the difference between the mean change in MRI-PDFF 
from baseline at Week 12 of the pooled active treatment groups compared to the placebo group 
is statistically significant, a step-down procedure will be followed to test the individual 


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Version 2.0, 16 March 2021 
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LPCN  1144 dose groups compared to each other and compared to placebo.  The following 
testing order will be employed:  
1) LPCN 1144 versus placebo 
2) LPCN 1144 d-alpha tocopherol formulation versus placebo 
3) LPCN 1144 d-alpha tocopherol formulation versus LPCN 1144 
A two sided p-value of less than or equal to 0.05 will be considered statistically significant.  No 
adjustments for the additional analysis or multiple comparisons will be applied for secondary 
outcome measure analysis; however, any significant findings must be interpreted taking into 
account the strength of the finding and its biologic plausibility. 
3.1.6 Handling of Dropouts and Missing Data 
Missing data will be reported as such.  Raw data will be subjected to a statistical screen for 
outliers using commonly accepted procedures. 
3.1.7 The Impact of Coronavirus Disease 2019 (COVID-19) 
COVID-19 pandemic may impact the conduct of the study from different aspects including 
quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product, or other considerations if site personnel or trial subjects become 
infected with COVID-19. 
3.2 Analysis Populations 
3.2.1 Intent-to-Treat (ITT) Analysis Dataset 
The ITT Analysis Dataset is defined as all randomized subjects.  The ITT Analysis Dataset will 
be the primary analysis dataset for the analysis of efficacy data. 
3.2.2 Modified Intent-to-Treat (mITT) Analysis Dataset 
The mITT Analysis Dataset is defined as all randomized subjects who took at least one dose of 
study drug and have at least 4 weeks of on-treatment data with non-missing baseline and 
Week 12 MRI-PDFF. 
3.2.3 Per-Protocol (PP) Analysis Datasets 
The 12-Week PP Analysis Dataset is defined as subjects in the ITT Analysis Dataset who took 
at least one dose of study drug and complied with the protocol sufficiently to ensure that the 
data is likely to represent the effects of study intervention.  The following criteria will be 
evaluated for compliance to the protocol prior to unblinding of the treatment allocation: 
• 
Valid hepatic fat fraction measured by MRI-PDFF at Baseline and Week 12; 
• 
No major eligibility criterion violations; 
• 
Did not discontinue study drug prior to Week 4; 
• 
Subjects compliance to study drug during 12-week treatment period; 
• 
Not taken any prohibited concomitant medication during 12-week treatment period; 
• 
No other substantial protocol violations during 12-week Treatment Period. 


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The 36-Week PP Analysis Dataset is defined as subjects in the ITT Analysis Dataset who took 
at least one dose of study drug and complied with the protocol sufficiently to ensure that the 
data is likely to represent the effects of study intervention.  The following criteria will be 
evaluated for compliance to the protocol prior to unblinding of the treatment allocation: 
• 
Valid hepatic fat fraction measured by MRI-PDFF at Baseline and Week 36; 
• 
No major eligibility criterion violations; 
• 
Did not discontinue study drug prior to Week 28; 
• 
Subjects who are <80% or >120% compliant with study drug during the treatment period; 
• 
Not taken any prohibited concomitant medication during the treatment period; 
• 
No other substantial protocol violations during the treatment period. 
The 36-Week PP Analysis Dataset - Biopsy will be defined with similar criteria with valid liver 
biopsy at Baseline and Week 36. 
A list of subjects with major protocol deviations leading to exclusion from the 12-Week PP 
Analysis Dataset, the 36-Week PP Analysis Dataset and the 36-Week PP Analysis Dataset - 
Biopsy will be finalized prior to unblinding the randomized treatment assignments. 
3.2.4 Safety Analysis Dataset 
The Safety Analysis Dataset is defined as all subjects who took at least one dose of study drug.  
All safety data will be analyzed using the Safety Analysis Dataset.  In the event that a subject 
takes the wrong study drug (i.e., did not take the randomized study drug), the actual treatment 
received will be used for analysis. 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Counts and percentages of subjects who were screened (signed informed consent), participated 
in the optional Washout, discontinued early during screening (screen failures), and randomized 
will be summarized in total based on all screened subjects.  Reasons for early discontinuation 
will also be summarized.  In addition, discontinuation due to COVID-19 impact will be 
summarized. 
Counts and percentages of subjects who were randomized, started study drug, discontinued 
early from the study, completed Week 12, and completed the study will be summarized by 
treatment, pooled active treatment (two formulations of LPCN 1144), and in total based on all 
randomized subjects.  Reasons for early discontinuation will also be summarized.  In addition, 
early discontinuation from the study due to COVID-19 impact will be summarized. 
3.3.2 Protocol Deviations 
Protocol deviations will be defined in the Protocol Deviation Plan.  Counts and percentages of 
subjects with CSR reportable protocol deviations by deviation category will be summarized by 
treatment, pooled active treatment (two formulations of LPCN 1144), and in total based on all 
randomized subjects.  All protocol deviations and COVID-19 related protocol deviations will be 
listed. 


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3.3.3 Analysis Populations 
Counts and percentages of subjects in each analysis set will be summarized by treatment, 
pooled active treatment (two formulations of LPCN 1144), and in total based on all randomized 
subjects. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) and age categories (<65 years, ≥65 years) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI (kg/m2) and BMI categories (<30 kg/m2, ≥30 kg/m2) 
• 
Waist circumference (cm) 
• 
Hip circumference (cm) 
• 
Waist-to-hip ratio 
• 
Diabetes mellitus Type 1 and Type 2 diagnosis  
• 
Hypertension diagnosis  
• 
Hepatic fat fraction (%) by MRI-PDFF and MRI-PDFF categories (≥5%, ≥8%, and ≥10%) 
• 
Liver Biopsy Inclusion Criteria (Stage 1 fibrosis with NAS ≥ 4 with at least 1 point each in 
inflammation and ballooning, Stage 2-3 fibrosis with at least 1 point in inflammation) 
• 
Fibrosis stage 
• 
NAS and NAS components  
• 
Liver fibrosis (kPa) 
• 
CAP (dB/m) 
• 
Total testosterone (ng/dL) 
• 
Hemoglobin A1c (%) 
• 
ALT (U/L) 
• 
AST (U/L) 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of subjects as appropriate by treatment, pooled active treatment (two 
formulations of LPCN 1144), and in total for all randomized subjects and each defined analysis 
population. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 22.0.  Counts and percentages of 
subjects with medical history by system organ class and preferred term will be summarized by 
treatment, pooled active treatment (two formulations of LPCN 1144), and in total based on all 
randomized subjects. 


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3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the World Health Organization (WHO) Drug Dictionary version 2019G B3.  
For summary purposes, the medication will be reported in both the prior and concomitant 
medications if the end date of a prior medication occurs after treatment starts; otherwise, 
medications will be considered prior medications if they stopped prior to the first dose of study 
drug and concomitant medications if they were taken at any time after the first dose of study 
drug (i.e. started prior to the first dose of study drug and were ongoing or started after the first 
dose of study drug). 
Counts and percentages of subjects taking prior and concomitant medications by ATC class and 
preferred term will be summarized separately by treatment, pooled active treatment (two 
formulations of LPCN 1144), and in total based on the Safety Analysis Dataset.  Furthermore, 
counts and percentages of subjects with changes in baseline dose of blood pressure medication 
or introduction of new blood pressure medication by ATC class and preferred term will be 
summarized separately by treatment, pooled active treatment (two formulations of LPCN 1144), 
and in total based on the Safety Analysis Dataset.  The use of any prior medication or 
concomitant medication will be listed for all randomized subjects. 
3.3.7 Study Drug Exposure and Compliance 
Days of exposure to study drug will be calculated as: 
date of very last dose of study drug - date of very first dose of study drug + 1 
Note that the exposure calculation is intended to describe the length of time a subject was 
exposed to study drug and therefore does not take study drug interruptions into account.  Days 
of exposure to study drug will be summarized by treatment based on the Safety Analysis 
Dataset with descriptive statistics and with counts and percentages of subjects with exposure in 
the following categories: 
• 
>0 to ≤4 weeks (1 – 28 days) 
• 
>4 to ≤8 weeks (29 – 56 days) 
• 
>8 to ≤12 weeks (57 – 84 days) 
• 
>12 to ≤16 weeks (85 – 112 days) 
• 
>16 to ≤20 weeks (113 – 140 days) 
• 
>20 to ≤24 weeks (141 – 168 days) 
• 
>24 to ≤30 weeks (169 – 210 days) 
• 
>30 to ≤36 weeks (211 – 252 days) 
• 
>36 weeks (>252 days) 
The total days of actual dosing and days of interrupted therapy will also be captured. 
Days of actual dosing will be calculated as: 
date of very last dose of study drug - date of very first dose of study drug + 1 - days of 
interruption 


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Days of interruption will be calculated as: 
Sum of (date of restarting dosing of study drug - date of last dose of study drug before stopping 
- 1) 
Percent compliance to the study drug regimen will be calculated as  
100 x number of actual capsules taken / number of expected capsules taken 
Where the number of actual capsules taken = number of capsules dispensed – number of 
capsules returned, and the number of expected capsules taken = (date of last dose – date of 
first dose + 1) x 2 capsules per day. 
If study drug is not returned, the number of capsules returned will be considered 0 for the 
compliance calculation.  If subject has dose reduced to 1 capsule per day, the number of 
expected capsules taken = (last dose date of 2 capsules per day – date of first dose + 1) x 2 
capsules per day + (date of last dose – start date of 1 capsule per day + 1) x 1 capsule per day. 
The percent compliance to the study drug regimen during the 12-week treatment period and the 
36-week treatment period will be summarized by treatment, and pooled active treatment (two 
formulations of LPCN 1144) based on the Safety Analysis Dataset with descriptive statistics and 
with counts and percentages of subjects with compliance in the following categories: 
• 
<80% 
• 
80-120% 
• 
>120% 
3.4 Efficacy Assessment 
Efficacy data will be summarized and analyzed by randomized treatment, and pooled active 
treatment (two formulations of LPCN 1144) based on the ITT Analysis Dataset unless otherwise 
specified.   
3.4.1 Primary Efficacy Outcome Measures 
The primary efficacy outcome measure will be the change in hepatic fat fraction based on MRI-
PDFF measurements from baseline to Week 12. 
Change in fat fraction by MRI-PDFF = Week 12 - Baseline 
Relative (percent) change in fat fraction by MRI-PDFF = 100 x (Week 12 - Baseline) / Baseline 
MRI-PDFF imaging will be performed at Screening, Week 12, and Week 36/Early Terminate 
(ET).  Summary statistics at all scheduled visits for the values, change from baseline and 
relative change from baseline will be provided.  The summary will also be repeated based on 
the mITT and PP Analysis Datasets.  Mean and mean changes will be plotted over time.  
Waterfall plots will be provided for relative changes at Week 12 and Week 36. 
3.4.1.1 
Primary Analysis 
The primary efficacy outcome measure will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group as a factor and baseline hepatic fat fraction (%) based 
on MRI-PDFF measurements as a covariate.  The 2 active arms (two formulations of LPCN 
1144) will be pooled and compared to placebo.  The treatment effect estimate, 95% CI and p 


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values will be provided.  The two formulations of LPCN 1144 will also be compared to each 
other and compared to placebo independently using linear contrasts.  Multiple imputation will be 
performed if MRI-PDFF is missing at baseline and/or Week 12 in the ITT Analysis Dataset.  The 
SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  BASE: Baseline fat fraction by MRI-PDFF 
  CHG: Change from baseline to Week 12 in fat fraction by MRI-PDFF 
**********************************************************************;  
proc mixed;  
  class TREATMENT;  
  model CHG = TREATMENT BASE;  
  lsmeans TREATMENT / cl alpha = 0.05;  
  estimate "LPCN 1144 450 mg: Placebo" TREATMENT -1 1 0 /cl;  
  estimate "LPCN 1144 450 mg d-alpha : Placebo" TREATMENT -1 0 1 /cl; 
  estimate "LPCN 1144 450 mg d-alpha : LPCN 1144 450 mg" TREATMENT 0 -1 1 
/cl; 
run; 
The Shapiro-Wilk normality test will be performed for the residuals from the model above.  If the 
p-value <0.01, non-parametric analyses using Wilcoxon rank sum test may be explored. 
Multiple Imputation (MI) Method: 
Missing primary efficacy outcome measure will be handled using the Missing at random (MAR) 
multiple imputation method. 
The multiple imputation procedure will be conducted by two parts: PROC MI and PROC 
MIANALYZE. 
• 
Multiple imputation will be used to impute missing data and will be implemented using SAS® 
PROC MI:  Missing data may be the result of missing hepatic fat fraction (%) assessed by 
MRI-PDFF at any time point including baseline and/or week 12, or the result of patients 
discontinuing treatment prior to Week 12.  MAR will be assumed.  The imputation model will 
include the subject demographics, and baseline and Week 12 hepatic fat fraction assessed 
by MRI-PDFF.  Missing data will be imputed 100 times to generate 100 complete data sets.  
The seed will be 98765.  The fully conditional specification method will be used.  The 100 
complete data sets will then be analyzed using the same analysis method as the one used 
to analyze the primary outcome measure.   
The SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  BASE: Baseline fat fraction by MRI-PDFF 
  WEEK12: Week 12 fat fraction by MRI-PDFF 
  AGEGR: 1 (< Median Age), 2 (>= Median Age) 
  RACEGR: 1 (White), 2 (Non-white) 
  WGTBLGR: 1 (< Median Weight), 2 (>= Median Weight) 
**********************************************************************;  


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proc mi seed=98765 nimpute=100 minimum=(. . . . 0 0) maximum=(. . . . 100 
100);  
  class TREATMENT AGEGR RACEGR WGTBLGR;  
  FCS reg(BASE WEEK12);  
  var TREATMENT AGEGR RACEGR WGTBLGR BASE WEEK12;  
run; 
• 
The results from the 100 fitted models will be combined using SAS® PROC MIANALYZE:  
The estimate of the treatment difference and standard error from the analysis will be analyzed 
by PROC MIANALYZE to obtain the overall estimate of treatment difference, as well as the 
confidence interval and p-value for the hypothesis testing. 
The SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 m), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  ESTIMATE: Estimated reatment difference from 100 fitted models 
  STDERR: Standard error of the estimate 
**********************************************************************;  
proc mianalyze; 
    by TREATMENT; 
    modeleffects ESTIMATE; 
    stderr STDERR; 
run; 
If the model fails to converge, exclusion of subject demographics will be considered.   
3.4.1.2 
Sensitivity Analyses 
The primary analysis will be repeated on observed data using the mITT and 12-Week PP 
Analysis Datasets.  No imputation will be performed.  
Tipping-point analysis approach may be used to explore the robustness of the primary analysis 
results using the multiple imputation method.  The assumptions in this sensitivity analysis are 
“missing not at random” for dropouts in the active treatment group and “missing at random” for 
dropouts in the placebo group.  A penalty of delta ranging from 0% to 40% (or higher if 
necessary) by intervals of 2%, will be added to the imputed values at Week 12 in each active 
treatment group while the fix penalty delta = 0% will be used in the placebo group (delta = 0% 
corresponds to the missing at random assumption).   
3.4.2 Key Secondary Efficacy Outcome Measures 
The key secondary efficacy outcome measures are  
• 
Change in NAFLD activity evaluated via a standardized scoring of liver biopsies from 
baseline to Week 36  
• 
Change in fibrosis evaluated via NASH CRN fibrosis score of liver biopsies at baseline 
and after 36 weeks of treatment in LPCN 1144 treated subjects.   
The NAS ranges from 0 to 8 (highest activity) and is calculated as the sum of three components 
of the standardized histologic feature scoring system for liver biopsies: 
NAS   =    Steatosis score (0-3) + 


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     Lobular inflammation score (0-3) +  
     Hepatocyte ballooning score (0-2) 
Fibrosis score evaluated via NASH CRN includes 5 stages: F0, F1 (F1a, F1b, F1c), F2, F3 and 
F4. 
Biopsy will be performed at Screening and Week 36/ET.  Values and changes from baseline in 
NAS and fibrosis will be summarized descriptively, as well as the counts and percentages of 
subjects by treatment group, and pooled active treatment (two formulations of LPCN 1144).   
The analysis will include both improvement in NAS and fibrosis, and numerical change in NAS 
and fibrosis based on the ITT.  The missing value at Week 36 in ITT will be imputed by last-
observed-carried-forward (LOCF) method.  The analysis will be repeated on the 36-Week PP 
Analysis Dataset – Biopsy, and no imputation will be performed. 
3.4.2.1 
Improvement in NAS and Fibrosis 
The definition of improvement in NAS after treatment as the key secondary outcome measure 
requires the following three conditions: 
• 
No worsening of the fibrosis feature score. 
• 
Improvement by at least 1 point in the hepatocyte ballooning feature score. 
• 
Either: 
1. Improvement in NAS by 2 or more points spread across at least two of the NAS 
components, OR 
2. Post-treatment NAS is 3 points or less. 
Similarly, improvement in fibrosis will be defined as improvement in liver fibrosis greater than or 
equal to one stage using the NASH CRN fibrosis score with no worsening of ballooning, 
inflammation, or steatosis. 
The analysis for improvement of NAS will only include subjects with a baseline hepatocyte 
ballooning score of 1 or 2.  Improvement in NAS and fibrosis from baseline to Week 36/LOCF 
will be analyzed as a binary outcome (improved vs. not improved).  Counts and percentages of 
subjects will be presented by treatment group.  The binary outcomes will be compared using 
Fisher’s exact test.  The SAS sample code is listed: 
 ***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  RESPONDER: 0 (Non-Improvement), 1 (Improvement) 
**********************************************************************;  
proc freq;   
  tables TREATMENT*RESPONDER / fisher;   
run;  
If concerns about confounding arise,, a logistic regression model with treatment group as a 
factor and baseline value as a covariate will be used.  The odds ratio, 95% confidence interval, 
and p-value from the logistic regression will be provided.  Missing value will be imputed as not 
improved for both methods.  The SAS sample code is listed: 


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***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  BASE: Baseline NAS/fibrosis 
  RESPONSE: 0 (Non-Improvement), 1 (Improvement) 
**********************************************************************;  
proc logistic;   
  class TREATMENT;   
  model RESPONSE (event='1') = TREATMENT BASE / link=logit  
        clodds=wald orpvalue;   
  oddsratio TREATMENT /diff=ref;  
run;  
3.4.2.2 
Numerical Change in NAS and Fibrosis 
Mean changes from baseline to Week 36/LOCF in NAS and fibrosis will be analyzed by an 
ANCOVA model with treatment group as a factor and baseline value as a covariate.  LS means 
vs placebo, 95% confidence intervals and p-values will be presented.   
Addtionally, median changes in NAS and fibrosis will be analyzed by Wilcoxon rank sum test 
with Hodges-Lehmann method.  Median difference, 95% confidence intervals and p-values will 
be presented.  No imputation will be performed.  The SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  CHG: Change from baseline to Week 36 in NAS/fibrosis 
**********************************************************************;  
proc npar1way alpha=.05 wilcoxon hl; 
  class TREATMENT; 
  var CHG; 
run;  
3.4.3 Other Secondary Efficacy Outcome Measures 
3.4.3.1 
Change and Relative Change in Hepatic Fat Fraction based on MRI-PDFF 
• 
Relative change in hepatic fat fraction based on MRI-PDFF measurements in 
LPCN 1144 treated subjects after 12 weeks of treatment.   
• 
Change in hepatic fat fraction based on MRI-PDFF measurements in LPCN 1144 treated 
subjects after 36 weeks of treatment.   
• 
Relative change in hepatic fat fraction based on MRI-PDFF measurements in 
LPCN 1144 treated subjects after 36 weeks of treatment. 
The three outcome measures are the change from baseline at Week 36 and the relative change 
from baseline at Week 12 or 36, which will be analyzed using ANCOVA model in a manner 
similar to the primary analysis of the primary outcome measure. 
A mixed-model repeated-measures (MMRM) will be used for analyzing the change and relative 
change from baseline to Week 12 and 36 for the ITT analysis population and repeated on the 
mITT and PP analysis populations.  No imputation will be performed.  The factors in the model 
will be treatment group, visit, and the treatment group by visit interactions, and the covariate will 
be baseline value. An unstructured covariance matrix will be used (TYPE=UN).  The sample 
SAS code can be found below: 


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***********************************************************************  
  USUBJID: Unique subject identifier 
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  BASE: Baseline fat fraction by MRI-PDFF 
  VISIT: Week 12, Week 36 
  CHG: Change from baseline to Week 36 in fat fraction by MRI-PDFF 
**********************************************************************;  
proc mixed;   
  class USUBJID TREATMENT VISIT;   
  model CHG = TREATMENT BASE VISIT TREATMENT*VISIT;   
  Repeated VISIT / TYPE=UN sub=USUBJID;   
  lsmeans VISIT*TREATMENT / cl pdiff slice=VISIT;   
run;   
3.4.3.2 
NAFLD Resolution  
• 
NAFLD resolution of subjects who at baseline is at least 5% with a decrease to less than 
5% at end of study.  
Resolution of NAFLD at Week 12 or 36 is defined as MRI-PDFF at baseline ≥ 5% and MRI-
PDFF at Week 12 or 36 < 5%.  Counts and percentages of subjects will be presented by 
treatment group, and pooled active treatment (two formulations of LPCN 1144).  The logistic 
regression model with treatment group as a factor and baseline MRI-PDFF value as a covariate 
will be used.  The odds ratio, 95% confidence interval, and p-value will be provided.  Missing 
value will be imputed as non-resolution.   
3.4.3.3 
NASH Resolution  
Resolution of NASH on overall histopathological reading is defined as  
• 
Resolution of steatohepatitis on overall histopathological reading (defined as NAS score 
of 0-1 for inflammation, 0 for ballooning, and any value for steatosis) and no worsening 
of liver fibrosis on NASH CRN fibrosis score.  
OR 
• 
Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score) and no worsening of steatohepatitis (defined as no increase in NAS for 
ballooning, inflammation, or steatosis) 
The analysis for resolution of NASH will only include subjects with a baseline NAS ≥ 4 with 
lobular inflammation score ≥1 and hepatocyte ballooning score ≥1 and any value for steatosis 
score.   
Counts and percentages of subjects will be presented by treatment group, and pooled active 
treatment (two formulations of LPCN 1144).  Fisher’s exact test will be used for the analysis at 
Week 36/LOCF.  Odds ratios (vs Placebo), 95% confidence intervals and p-values will be 
provided.  Missing value will be imputed as non-resolution.   
3.4.3.4 
Inflammatory Liver Resolution 
Resolution of inflammatory liver on overall histopathological reading is defined as  
• 
NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis at Week 
36/ET and no worsening of fibrosis.   


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OR 
• 
Improvement in liver fibrosis greater than or equal to one stage and no increase in NAS 
for ballooning, inflammation, or steatosis 
The analysis for inflammatory liver resolution will only include subjects with a baseline lobular 
inflammation score >1 and baseline hepatocyte ballooning score >0 and any value for steatosis 
score regardless of total NAS score.   
Counts and percentages of subjects will be presented by treatment group, and pooled active 
treatment (two formulations of LPCN 1144).  Fisher’s exact test will be used for the analysis at 
Week 36/LOCF.  Odds ratios (vs Placebo), 95% confidence intervals and p-values will be 
provided.  Missing value will be imputed as non-resolution.   
3.4.3.5 
NAS component scores  
• 
Change in individual NAS component scores (inflammation, ballooning, steatosis) in 
LPCN 1144 treated subjects after 36 weeks of treatment.  
Biopsy will be performed at Screening and Week 36/ET.  Values and changes from baseline in 
individual NAS component scores will be summarized descriptively.  The changes in individual 
NAS component scores will be analyzed by an ANCOVA model with treatment group as a factor 
and baseline value as a covariate.  LS means vs placebo, 95% confidence intervals and p-
values will be presented.  The missing value will be imputed by LOCF method.   
3.4.3.6 
Liver Fibrosis Stage 
• 
Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score).  
Counts and percentages of subjects will be presented by treatment group, and pooled active 
treatment (two formulations of LPCN 1144).  Fisher’s exact test will be used for the analysis at 
Week 36/LOCF.  The odds ratio (vs Placebo), 95% confidence interval, and p-value will be 
provided.  Missing value will be imputed as non-improved. 
3.4.3.7 
Liver Enzymes 
Liver enzymes (AST, ALT, ALP, GGT, TB and CK) will be collected at each visit. 
Values for baseline and for values and changes from baseline will be presented for each 
scheduled visit.  Mean and mean changes will be plotted over time.  The change and relative 
change from baseline to Weeks 4, 8, 12, 16, 20, 24, 30 and 36 will be analyzed using a MMRM.  
No imputation will be performed.  The factors in the model will be treatment group, visit, and the 
treatment group by visit interactions, and the covariate will be baseline value.  An unstructured 
covariance matrix will be used (TYPE=UN).   
3.4.3.8 
Subjects achieving absolute reduction ≥  17 U/L in ALT at Week 12 with ALT > ULN at baseline. 
Counts and percentages of subjects will be presented by treatment group, and pooled active 
treatment (two formulations of LPCN 1144) at Week 12.  Fisher’s exact test will be used for the 
analysis at Week 12.  The odds ratio (vs Placebo), 95% confidence interval, and p-value will be 
provided.  The analysis will be performed on the observed data without imputation. 


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3.4.3.9 
Lipid Profile 
Lipid profile (total cholesterol, triglycerides, VLDL-C, HDL-C, LDL-C, and free fatty acids) will be 
collected at Day 1, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 30, Week 
36 and Week 38. 
Non-HDL cholesterol will be calculated as Total Cholesterol - HDL-C. 
Values for baseline and for values and changes from baseline will be presented for each 
scheduled visit.  The change and relative change from baseline to Weeks 4, 8, 12, 16, 20, 24, 
30 and 36 will be analyzed using a MMRM.  No imputation will be performed.  The factors in the 
model will be treatment group, visit, and the treatment group by visit interactions, and the 
covariate will be baseline value.  An unstructured covariance matrix will be used (TYPE=UN).   
For the relative change in triglycerides, the MMRM specified above will be performed on the log-
transformed data, and the results will be back-transformed. 
3.4.3.10 Fibrosis and Steatosis Biomarkers  
Fibrosis and steatosis biomarkers including ELF [and its components Hyaluronic Acid (HA), N-
terminal propeptide of type III collagen (PIIINP), Tissue inhibitor of metalloproteinase 1 (TIMP-
1)], Transforming growth Factor-Beta (TGF-Beta), Tissue Necrosis Factor-alpha (TNF-alpha) 
will be collected at Day 1 and Week 36/ET. 
Values for baseline and for values and changes from baseline will be presented for Week 36.  
ANCOVA model with treatment group as a factor and baseline value as a covariate will be used 
for analyzing the change and relative change from baseline to Week 36.  LS means vs placebo, 
95% confidence intervals and p-values will be presented.  The missing value will be imputed by 
LOCF method. 
3.4.3.11 Insulin Resistance (assessed by HOMA) and HbA1c 
Insulin Resistance (assessed by HOMA) and HbA1c will be collected at Day 1, Week 12 and 
Week 36/ET. 
Values for baseline and for values and changes from baseline will be presented for each 
scheduled visit.  ANCOVA model with treatment group as a factor and baseline value as a 
covariate will be used for analyzing the change and relative change from baseline to Week 12, 
and the change and relative change from baseline to Week 36.  LS means vs placebo, 95% 
confidence intervals and p-values will be presented.  The missing value will be imputed by 
LOCF method.  The same ANCOVA model will be repeated on the observed data without 
imputation. 
3.4.3.12 Anthropometric Measurements 
The anthropometric measurements include weight, BMI, waist to hip ratio, waist circumference, 
triceps skin fold thickness, upper arm circumference.  The measurements of weight, and waist 
and hip circumference will be performed at Screening, Day 1, Week 4, Week 8, Week 12, Week 
16, Week 20, Week 24, Week 30, and Week 36.  The measurements of triceps skin fold 
thickness, and mid upper arm circumference will be performed at Screening, Week 12, and 
Week 36.   
Values for baseline and for values and changes from baseline will be presented for each 
scheduled visit.   


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The change and relative change from baseline to Weeks 4, 8, 12, 16, 20, 24, 30 and 36 in 
weight, BMI, waist to hip ratio, and waist circumference will be analyzed using a MMRM.  No 
imputation will be performed.  The factors in the model will be treatment group, visit, and the 
treatment group by visit interactions, and the covariate will be baseline value.  An unstructured 
covariance matrix will be used (TYPE=UN).   
ANCOVA model with treatment group as a factor and baseline value as a covariate will be used 
for analyzing the change and relative change from baseline to Week 12, and the change and 
relative change from baseline to Week 36 in the triceps skin fold thickness, and upper arm 
circumference.  LS means vs placebo, 95% confidence intervals and p-values will be presented.  
The missing value will be imputed by LOCF method.  The same ANCOVA model will be 
repeated on the observed data without imputation. 
3.4.3.13 Subjects achieving relative reduction ≥ 30% or 23% hepatic fat fraction based on MRI-PDFF 
measurements. 
Counts and percentages of subjects will be presented by treatment group, and pooled active 
treatment (two formulations of LPCN 1144) at Week 12 and Week 36.  A logistic regression 
model with treatment group as a factor and baseline value as a covariate will be used.  The 
odds ratio, 95% confidence interval, and p-value from the logistic regression will be provided.  
Missing value will be imputed as not improved for both methods. 
3.4.3.14 Fibrosis Status Evaluated via the Paired Biopsies 
The following analysis will be performed if data available. 
A direct comparison of a patient’s two biopsies to each other at the end of study can provide a 
complimentary assessment of the difference between the two biopsies and allow a qualitative 
determination of intra grade or intrastage changes.  Paired biopsies from each patient will be 
randomly sorted and assigned as either A or B.  The pathologist will be unaware of which biopsy 
is which.  The assessment will be made as better, worse or same for the changes in Fibrosis 
and the three components including Steatosis, Lobular Inflammation and Ballooning. 
Counts and percentages of subjects will be presented by treatment group, and pooled active 
treatment (two formulations of LPCN 1144).  Cochran-Mantel-Haenszel (CMH) test will be used 
for the analysis and the row mean scores differ p-value will be provided.  The sample SAS code 
can be found below: 
***********************************************************************  
  TREATMENT: 0 (Placebo), 1 (LPCN 1144 450 mg), or 
             2 (LPCN 1144 450 mg, d-alpha tocopherol formulation) 
  RESPONSE: -1 (Worse), 0 (Same), 1 (Better), 
**********************************************************************;  
proc freq order=data; 
  tables Treatment*Response / cmh score=modridit; 
  weight count; 
  ods output cmh=cmh; 
run; 
3.4.3.15 FibroNest Scores Evaluated by PharmaNest 
The following analysis will be performed if data available. 


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Values for baseline and for values and changes from baseline will be presented for each 
scheduled visit.  ANCOVA model with treatment group as a factor and baseline value as a 
covariate will be used for analyzing the change from baseline to Week 36.  LS means, 95% 
confidence intervals and p-values will be presented.  The missing value will be imputed by 
LOCF method. 
3.4.3.16 Dual-energy X-ray Absorptiometry (DXA) Scan 
DXA scan including whole body lean mass, appendicular lean mass, fat mass, and bone 
mineral density will be performed at Screening, Week 20 and Week 36. 
DXA scan parameters will be defined/calculated as below: 
Values for baseline and for values, change and relative change from baseline will be presented 
at each scheduled visit by DXA scan parameters.  ANCOVA model with treatment group as a 
factor and baseline value as a covariate will be used for analyzing the change and relative 
change from baseline to Week 20, and the change and relative change from baseline to Week 
36.  LS means vs placebo, 95% confidence intervals and p-values will be presented.  The 
missing value will be imputed by LOCF method.  The same ANCOVA model will be repeated on 
the observed data without imputation. 
Counts and percentages of subjects, who have an increase from baseline in whole body lean 
mass and decrease from baseline in whole body fat mass, will be presented by treatment group, 
and pooled active treatment (two formulations of LPCN 1144) at Week 20 and Week 36.  
Fisher’s exact test will be used for the analysis at Week 20 and Week 36.  The odds ratio (vs 
Placebo), 95% confidence interval, and p-value will be provided.  The analysis will be performed 
on the observed data without imputation. 
3.4.4 Subgroups 
The analyses of the primary outcome measure will be performed for the following subgroups: 
• 
Subjects with baseline liver fat ≥ 5%; 
• 
Subjects with baseline liver fat ≥ 8%; 
• 
Subjects with baseline liver fat ≥ 10%; 
• 
Baseline serum total Testosterone level (< median, ≥ median, < 300 ng/dL, ≥ 300 ng/dL); 
• 
Diabetes Status at Screening = Type 1 or 2;  
DXA PARAMETERS  
MICL TEST CODE 
MICL TEST NAME 
MICL TEST UNITS 
Whole Body Lean Mass 
TBC_TotLean_Mass 
Total Lean Mass 
g 
Appendicular Lean Mass 
calculated as:  
Appendicular Lean Muscle Mass = TBC_R_ArmLean_Mass + 
TBC_L_ArmLean_Mass + TBC_R_LegLean_Mass + 
TBC_L_LegLean_Mass 
g 
TBC_R_ArmLean_Mass 
Right Arm Lean Mass 
g 
TBC_L_ArmLean_Mass 
Left Arm Lean Mass 
g 
TBC_R_LegLean_Mass 
Right Leg Lean Mass 
g 
TBC_L_LegLean_Mass 
Left Leg Lean Mass 
g 
 
TBC_TotFat_Mass 
Total Fat Mass 
g 
Whole Body Fat Mass 
Total_FNeck_BMD   
Total Femoral Neck BMD 
g/cm2 
Bone Mineral Density 
(Femoral) 
Total_Spine_BMD 
Total Spine BMD 
g/cm2 
Bone Mineral Density (Lumbar) 
 
 
 


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• 
Baseline ALT > ULN;  
• 
Baseline BMI >=30 kg/m2; and  
• 
Ethnicity = Hispanic or Latino.  
The analyses of the primary outcome measure may be evaluated for the COVID-19 subgroup 
as needed. 
The analyses of the key secondary outcome measures will be performed for the following 
subgroups: 
• 
Baseline Inflammation >=1 and Ballooning >=1  for the improvement in NAS;  
• 
Baseline NAS ≥ 4 for the improvement in NAS; and  
• 
Baseline fibrosis stage (F1, F2-3) for the improvement in Fibrosis. 
The analyses of the other outcome measure - Relative Change in Hepatic Fat Fraction based 
on MRI-PDFF will be performed for the following subgroups: 
• 
Subjects with baseline liver fat ≥ 10%; and 
• 
Ethnicity = Hispanic or Latino.  
The analyses of the other secondary outcome measure - Liver Enzymes will be performed for 
the following subgroups: 
• 
Baseline ALT > ULN 
3.5 Quality of Life Assessment 
Functional Activity, HR-QOL (SF-36) and CLDQ questionnaires will be administered at 
Screening and Week 36.  PGI-S and Sexual desire and distress questionnaires will be 
administered at each study visit except Day 1 and Week 38.  PGI-C questionnaire will be 
administered at Week 12 Week 36 and Week 38.  I-PSS questionnaire will be administered at 
Screening, Week 12 and Week 36.  AUDIT (interview version) and Skinner Alcohol 
questionnaire will be administered at Screening.  AUDIT-C questionnaire will be administered at 
Week 12. 
Quality of life data will be summarized and analyzed by randomized treatment, and pooled 
active treatment (two formulations of LPCN 1144) based on the ITT Analysis Dataset unless 
otherwise specified.   
Values and changes from baseline in Functional Activity, HR-QOL (SF-36), CLDQ and I-PSS 
will be presented at each scheduled visit and baseline by domain or total score.  Values and 
changes from baseline in PGI-S, PGI‑C, and sexual desire and distress questionnaires will be 
presented at each scheduled visit and baseline by item.  All questionnaires responses will be 
listed.  
For HR-QOL (SF-36) and CLDQ questionnaires, an ANCOVA model with treatment group as a 
factor and baseline value as a covariate will be used for analyzing the change from baseline to 
Week 36.  LS means vs placebo, 95% confidence intervals and p-values will be presented.  No 
imputation will be performed. 


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3.5.1 Functional Activity Questionnaire (NHANES III) 
The questionnaire has 19 items grouped into eight domains: Vigorous work (PAQ 605, 610, 
615), Moderate work (PAQ 620, 625, 630), Travel (PAQ 635, 640, 645), Vigorous recreation 
(PAQ 650, 655, 660), Moderate recreation (PAQ 665, 670, 675), Sitting (PAQ 680), Physically 
activity (PAQ 706), and Sedentary behavior (PAQ 710, 715).   
3.5.2 Health-Related Quality of Life (HR-QOL) measured by Short Form-36 
The SF-36 questionnaire is to measure functional health and well-being from the subject’s point 
of view.  It consists of eight health domains in the table below.  These health domain scales 
contribute to the physical health and mental health summary measures.   
The scores are weighted sums of the questions in each domain. All the scores can range from 0 
- 100.  Higher scores represent better health.  The Physical Component Summary (PCS) was 
calculated by positively weighting the 4 subscales in the physical domain (PF, RP, BP, and GH) 
and the remaining psychological domain subscales negatively. In contrast, the Mental 
Component Summary (MCS) was calculated by positively weighting the 4 mental domain 
subscales (VT, SF, RE, and MH) and negatively weighting the 4 physical domain subscales.  
The domain scores are derived using an uncorrelated factor solution.  The correlated PCS and 
MCS are derived from an obliquely rotated factor solution and adjusted by 1998 US general 
population norms, age and gender. 
Domains 
Number of Items 
Items 
Physical Functioning (PF) 
10 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
Role-Physical (RP) 
4 
13, 14, 15, 16 
Bodily Pain (BP) 
2 
21, 22 
General Health (GH) 
5 
1, 33, 34, 35, 36 
Vitality (VT) 
4 
23, 27, 29, 31 
Social Functioning (SF) 
2 
20, 32 
Role-Emotional (RE) 
3 
17, 18, 19 
Mental Health (MH) 
5 
24, 25, 26, 28, 30 
3.5.3 Chronic Liver Disease Questionnaire (CLDQ) 
The questionnaire has 29 items grouped into six domains: AS, FA, SS, AC, EF and WO.  Items 
are scored by a 7-point rating scale from 1 (All of the time) to 7 (None of the time). 
Domains 
Number of Items 
Items 
Abdominal Symptoms (AS) 
3 
1, 5, 17 
Fatigue (FA) 
5 
2, 4, 8, 11, 13 
Systemic Symptoms (SS) 
5 
3, 6, 21, 23, 27 
Activity (AC) 
3 
7, 9, 14 
Emotional Function (EF) 
8 
10, 12, 15, 16, 19, 20, 24, 26 
Worry (WO) 
5 
18, 22, 25, 28, 29 
3.5.4 Patient Global Impression of Severity (PGI-S) 
It is a single question asking the patient to rate the overall impression of their health on a 5-point 
scale of 1 (None) to 5 (Very severe). 
3.5.5 Patient Global Impression of Change (PGI‑C) 
It is a single question asking the patient to rate the overall status on a 7-point scale of 3 (Very 
much better) to -3 (Very much worse). 


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3.5.6 Sexual Desire and Distress Questionnaire 
Daily Rating is a single question asking the patient to rate the level (degree) of sexual desire 
today on a 6-point scale of 0 (None at all) to 5 (Very high).  Weekly Rating is a single question 
asking the patient to rate the feeling of being bothered by low sexual desire over the past 7 days 
on a 5-point scale of 0 (Never) to 4 (Always).   
3.5.7 International Prostate Symptom Score (I-PSS) 
The questionnaire has two parts: International Prostate Symptom Score with 7 items and 
Quality of Life Due to Urinary Symptoms with 1 item.  Total IPSS score ranges from 0 to 35, 
which can be categorized as mild (0 - 7), moderate (8 -19) and severe (20 - 35).  The quality of 
life assessment index L ranges from 0 (Delighted) to 6 (Terrible). 
3.6 Safety Assessment 
Safety data will be summarized by actual treatment received, and pooled active treatment (two 
formulations of LPCN 1144) based on the Safety Analysis Dataset. 
3.6.1 Adverse Events (AEs) 
AEs will be captured from the date of informed consent through study completion.  All AEs will 
be coded to system organ class and preferred term using MedDRA version 22.0. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that start during a unique 
treatment or that already exist before the start of that unique treatment but worsen in severity or 
relationship to the unique treatment during the treatment. 
Adverse events of special interest (AESIs) include cardiovascular events, drug induced liver 
(DILI) events and elevated hematocrit related to plasma volume depletion. 
An overview of TEAEs will be provided including counts and percentages of subjects with the 
following: 
• 
Any TEAEs (overall and by maximum severity) 
• 
Any study drug related TEAEs (overall and by maximum severity) 
• 
Any TEAEs of special interest (cardiovascular, DILI and elevated hematocrit) 
• 
Any treatment-emergent serious AEs (TESAEs) 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any TEAEs leading to premature discontinuation from the study 
• 
Any TEAEs leading to death 
Counts and percentages of subjects will also be presented by system organ class and preferred 
term for each of the categories in the overview. 
Listings will be presented specifically for all AEs, AESIs, SAEs and deaths, TESAEs and AEs 
leading to premature discontinuation from the study. 


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3.6.2 Clinical Laboratory Tests 
C-Reactive Protein, fasting glucose and insulin will be collected at Day 1, Week 12 and 
Week 36. 
Hepatic panel (TB, direct bilirubin, ALT, AST, ALP, GGT, Bile acid and CK), hematology panel 
(hematocrit, hemoglobin, prothrombin time (PT), international normalized ratio (INR)), metabolic 
and renal function panel (sodium, potassium, chloride, bicarbonate, calcium, phosphate, Blood 
Urea Nitrogen (BUN), creatinine, uric acid, albumin, total protein, estimated glomerular filtration 
rate (GFR)), testosterone assay (Total and calculated free T, SHBG), and urinalysis (Color, 
appearance, specific gravity, pH, protein, blood, ketones, urobilinogen, glucose, bilirubin, 
leukocyte esterase, nitrite) will be collected at each study visit. 
Biomarkers will be collected at Day 1 and Week 36, including Monocyte Chemotactic Protein-1 
(MCP-1), Enhanced Liver Fibrosis (ELF), [and components, Hyaluronic Acid (HA), N-terminal 
propeptide of type III collagen (PIIINP), Tissue inhibitor of metalloproteinase 1 (TIMP-1)], 
Transforming growth Factor-Beta (TGF-Beta), Tissue Necrosis Factor-alpha (TNF-alpha). 
Lipid profile (total cholesterol, triglyceride, fatty acids, VLDL-C, LDL-C, HDL-C), and hormones 
and related markers (DHT, LH, FSH, TSH, SHBG) will be collected at Day 1, Week 4, Week 8, 
Week 12, Week 16, Week 20, Week 24, Week 30, Week 36 and Week 38. 
HbA1c will be collected at Screening, Week 12 and Week 36.  
PSA and prolactin will be collected at Screening, Week 4, Week 8, Week 12, Week 16, 
Week 20, Week 24, Week 30, Week 36 and Week 38. 
Cortisol and cortisol binding globulin (CBG) will be collected at Screening, Week 4, Week 8, 
Week 12, Week 16, Week 20, Week 24, Week 30, and Week 36. 
Drug and alcohol screen will be collected at Screening, Week 4, Week 12, and Week 24. 
Serology will be collected at Screening.  
Values for baseline and for values and changes from baseline will be presented for each 
scheduled visit.  The incidence of abnormalities (as defined by normal ranges) prior to the first 
dose of study drug and after the first dose of study drug will be summarized with counts and 
percentages of subjects.  A shift table will be provided for selected laboratory tests. 
An evaluation of drug-induced serious hepatotoxicity (eDISH) plot will be provided to display 
peak serum ALT and TB levels for each subject. 
3.6.3 Vital Signs 
An abbreviated physical exam including measurements of height, weight, waist and hip 
circumference, vital signs (temperature, single measurement, respiratory rate, single 
measurement, clinic blood pressure, triplicate measurement, and pulse rate, triplicate 
measurement), examination for scleral icterus and pedal edema, and auscultation of heart and 
lungs will be performed at Day 1, Week 4, Week 8, Week 16, Week 20, Week 24, and Week 30. 
A detailed physical exam, which includes all tests in the abbreviated physical exam plus triceps 
skin fold thickness, mid upper arm circumference, and general physical findings 
(hepatosplenomegaly, peripheral manifestations of liver disease, ascites, wasting, fetor) will be 
performed at Screening, Week 12, and week 36.  A prostate digital rectal examination will be 


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performed at Screening and Week 36. Triplicate measurements will be averaged prior to 
summary. 
Values and changes from baseline will be presented at each scheduled visit and baseline by 
vital signs parameters.   
Blood pressure will be summarized for the following the subgroups: 
• 
Subjects who have a diagnosis of diabetes mellitus at baseline; 
• 
Subjects who do not have a diagnosis with hypertension and are normotensive at 
baseline; and  
• 
Subjects who have a diagnosis of hypertension at baseline and are controlled with 
medical management. 
The change and relative change from baseline to Weeks 4, 8, 12, 16, 20, 24, 30 and 36 in the 
blood pressure will be analyzed using a MMRM.  No imputation will be performed.  The factors 
in the model will be treatment group, visit, and the treatment group by visit interactions, and the 
covariate in the model will be baseline value,.  An unstructured covariance matrix will be used 
(TYPE=UN).   
3.6.4 Fibroscan 
Fibroscan imaging will be performed at Screening, Week 12, Week 24, and Week 36.   
Values and changes from baseline of liver fibrosis will be presented at each scheduled visit and 
baseline. 
3.6.5 Gait Speed 
Gait speed will be assessed at Screening and Week 36. 
Values and changes from baseline of time to complete the 10-meter walk will be presented at 
each scheduled visit and baseline. 
3.6.6 Hand Grip Strength Test 
Hand grip strength test will be assessed at Screening and Week 36. 
Values and changes from baseline will be presented at each scheduled visit by hand. 
3.6.7 Cardiovascular Risk Evaluation 
Counts and percentages of subjects will be presented by the type of cardiovascular event.  
3.6.8 Other Safety Assessments 
Other safety data will be listed.  Additionally, the subject visits impacted by COVID-19 will be 
listed. 
4 DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent DSMB, appointed by Sponsor, is responsible for monitoring the accumulated 
interim data as the trial progresses to ensure subject safety and to review efficacy.  The DSMB 
is a multidisciplinary group with a written charge provided by Sponsor.  The DSMB will include 
three or more members, at least one of whom is a hepatologist.  After the trial commences, the 


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DSMB will establish a charter and meet to review data, evaluate emerging safety information, or 
other issues. 
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled 
meetings.  Serious adverse events will be reviewed by the DSMB as they occur with the option 
of a teleconference discussion if any DSMB member so requests. 
The DSMB will also review the overall progress of the trial in terms of recruitment and data 
quality and makes a formal recommendation to Sponsor at the end of each scheduled meeting 
as to whether the trial should continue unmodified, continue with protocol modifications, or be 
stopped.  
5 ANALYSIS TIMING 
5.1 Primary Analysis Reviews 
Primary Analysis will be performed after all subjects complete the Week 12 study visit or 
withdraw priror to Week 12 study visit and the database has been locked for the analysis at 
Week 12.  
An unblinded biostatistician will be involved and send the unblinded tables to the pre-specified 
personnel only.  The unblinded individual Week 12 MRI-PDFF results will be only available for 
the unblinded personnel or team.  The individual treatments and individual Week 12 MRI-PDFF 
results must remain blinded to the study team until final data base lock and full study unblinding. 
The unblinded tables will be unblinded at the treatment group level and be limited to topline 
results for efficacy and safety (i.e. primary outcome measure, selected other secondary efficacy 
outcome measures like liver enzymes (ALT/AST), selected TEAE, selected exploratory 
endpoints).  Statistics (i.e. minimum, maximum) that could potentially unblind at the individual 
level will be removed.   
All the details will be defined in the unblinding plan. 
5.2 Week 20 Analysis Reviews 
Week 20 Analysis will be performed after all subjects complete the Week 20 study visit or 
withdraw priror to Week 20 study visit and the database has been locked for the analysis at 
Week 20.  
An unblinded biostatistician will be involved and send the unblinded tables to the pre-specified 
personnel only.  The individual treatments must remain blinded to the study team until final data 
base lock and full study unblinding. 
The unblinded tables will be unblinded at the treatment group level and be limited to results for 
DXA efficacy.  Statistics (i.e. minimum, maximum) that could potentially unblind at the individual 
level will be removed.   
All the details will be defined in the unblinding plan. 
5.3 Interim Analysis 
No interim analysis is planned.   


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6 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
Statistical methods will include pooling the 2 active arms for comparison to placebo for the 
primary outcome measure analysis in addition to the comparisons between each individual 
active arm to placebo. 
Relative changes are added in the following other secondary outcome measures: 
anthropometric measurements, insulin resistance, non-invasive markers, and lipid parameters. 
The definition of resolution of NASH is revised. 
Heat-Shock Protein 47 fibroblast marker (HSP47 fibroblast marker), and Alpha-Smooth Muscle 
Actin (Alpha SMA) are removed from biomarkers. 
The following other secondary outcome measures are added:  
• 
Resolution of inflammatory liver on overall histopathological reading. 
• 
Subjects achieving relative reduction ≥ 30% hepatic fat fraction based on MRI-PDFF 
measurements at Week 12. 
• 
Subjects achieving relative reduction ≥ 23% hepatic fat fraction based on MRI-PDFF 
measurements at Week 12. 
• 
Change in fibrosis status evaluated via the paired biopsies after 36 weeks of treatment in 
LPCN 1144 treated subjects. 
• 
Change in FibroNest scores evaluated indepently by PharmaNest after 36 weeks of 
treatment in LPCN 1144 treated subjects if data available. 
• 
Non-HDL cholesterol will be calculated. 
• 
Subjects achieving absolute reduction ≥  17 U/L in ALT at Week 12 with ALT > ULN at 
baseline. 
The following subgroup analysis are added for the primary outcome measure: 
• 
Diabetes Status at Screening = Type 1 or 2;  
• 
Baseline ALT > ULN;  
• 
Baseline BMI >=30 kg/m2; and  
• 
Ethnicity = Hispanic or Latino.  
The following subgroup analysis are added for the other outcome measure - Relative Change in 
Hepatic Fat Fraction based on MRI-PDFF: 
• 
Subjects with baseline liver fat ≥ 10%; and 
• 
Ethnicity = Hispanic or Latino.  
The following subgroup analysis are added for the other secondary outcome measure - Liver 
Enzymes: 
• 
Baseline ALT > ULN 
DXA scan parameters are added as one ofother secondary outcome measures instead of 
safety.  Week 20 analysis review is planned to review the DXA scan parameters. 


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7 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher.  All available data will be 
presented in subject data listings which will be sorted by subject and visit date as applicable.  
Detailed Programming Specifications will be provided in a separate document.