Conditions: Nonalcoholic Steatohepatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
To evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing liver fat and/or liver biochemistry compared to placebo in patients with biopsy-proven nonalcoholic steatohepatitis

Detailed description:
JKB-121 is a long-acting small molecule that is efficacious as a weak antagonist at the TLR-4 receptor. It is a non-selective opioid antagonist which has been shown to prevent the lipopolysaccharide (LPS) induced inflammatory liver injury in a methionine/choline deficient diet fed rat model of nonalcoholic fatty liver disease. In vitro, JKB-121 neutralized or reduced the LPS-induced release of inflammatory cytokines, deactivated hepatic stellate cells, inhibited hepatic stellate cell proliferation, and collagen expression. Inhibition of the TLR4 signaling pathway may provide an effective therapy in the prevention of inflammatory hepatic injury and hepatic fibrosis in patients with nonalcoholic steatohepatitis. This study will evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing liver fat and/or liver biochemistry compared to placebo in patients with biopsy-proven nonalcoholic steatohepatitis.

Arms:
arm 1: JKB 121, 5 mg twice daily arm 2: JKB 121, 10 mg twice daily arm 3: Identical appearing placebo

Interventions: intervention 1: JKB-121: 5 mg twice daily intervention 2: JKB-121: 10 mg twice daily intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
 
A Randomized, Double-Blind, Placebo Controlled,  
Parallel-Group, Phase II trial of JKB-121 for the Treatment of  
Nonalcoholic Steatohepatitis (NASH) 
 
 
PROTOCOL NUMBER: JKB-121-001 
 
DUKE IRB PROTOCOL NUMBER:  Pro00062677 
 
FDA IND NUMBER:    IND 124,082 
 
STUDY MEDICATION:  JKB-121 (nalmefene hydrochloride) 
 
SPONSOR: Investigator Initiated Study 
 
PRINCIPLE INVESTIGATOR: Manal F. Abdelmalek, MD, MPH 
 
 
 
SPONSOR FOR STUDY DRUG:  
TaiwanJ Pharmaceuticals Co., Ltd. 
Zhupei, Hsinchu County 302  
Taiwan. 
 
PROTOCOL VERSION:   
Version 4.0 
,  
Date March 2, 2016 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information belonging to TaiwanJ Pharmaceutical. The 
information contained in this document, particularly unpublished data, is the property of, or under 
the control of TaiwanJ Pharmaceuticals (TaiwanJ) and is provided to you in confidence for review 
by you, your staff and an applicable Institutional Review Board.  Except as may be otherwise 
agreed to in writing, by accepting or reviewing these materials, you agree to hold such information 
in confidence and not to disclose it to others (except where required by applicable law), nor to use 
it for unauthorized purposes. Except to the extent necessary to obtain informed consent from those 
person to whom the investigational products may be administered, disclosure of any of the 
information to others required written authorization from TaiwanJ Pharmaceuticals. 
 
 
 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 2 of 60 
TABLE OF CONTENTS 
Protocol Section 
                         Page 
CRO and Sponsor Personnel and Contact Information 
 
  4 
1.0 
Protocol Synopsis 
 
  5
 
1.1 Table of Events 
 
12 
2.0  
List of Abbreviations 
 
13 
3.0 
Background 
 
15 
 
3.1    Nonalcoholic Steatohepatitis 
 
15 
 
3.2    Toll-Like Receptor 4 
 
16 
 
3.3    Obesity, Insulin resistance and TLR-4 
 
16 
 
3.4    Endotoxemia, LPS, and NASH 
 
17 
 
3.5    JKB-121 
 
17 
4.0 Study Conduct Statement 
 
18 
5.0 Study Objective and Endpoints 
 
18 
 
5.1  Objectives 
 
18 
 
5.2   Endpoints 
 
18 
6.0 Study Design 
 
19 
  
6.1    Duration of the Study 
 
19 
      
6.2    Sponsor’s Termination of Study 
 
20 
      
6.3    Reasons for Withdrawal 
 
20 
7.0 Study Population 
 
21 
 
     7.1    Number of subjects 
 
21 
 
7.2    Assignment of Subject Numbers 
 
21 
8.0 Subject Selection 
 
22 
  
8.1   Subject Inclusion Criteria 
 
22 
          8.2    Subject Exclusion Criteria 
 
22 
9.0 Study Medication 
 
24 
  
9.1   Study Medication Identification 
 
24 
  
9.2   Justification for the dose chosen 
 
24 
  
9.3   Rationale for the placebo group 
 
25 
  
9.4   Study medication packaging and labeling 
 
25 
  
 
9.4.1   Storage and Stability 
 
25 
  
 
9.4.2   Drug Preparation / Administration / Dispensing 
 
26  
  
9.5   Drug Accountability 
 
26 
 
10.0 Schedule of Events 
 
26 
  
10.1 Tests and Evaluation 
 
26 
 
  
10.2 Schedule of Visits and Procedures Table 
 
27 
  
10.3 Study Procedures 
 
28 
  
 
10.3.1   Subject Enrollment and Treatment Assignment 
 
28 
  
 
10.3.2   Screening Period 
 
28 
  
 
10.3.3   Enrollment Visit (Day 1) 
 
29 
  
 
10.3.3.1  PK Substudy  
 
30 
  
10.4 Treatment Assessments 
 
30 
  
 
10.4.1   Visit 2 (week 2) 
 
30 
  
 
10.4.2   Visit 3, 4, 6, and 7 (week 4, 8, 16, and 20) 
 
31 
  
 
10.4.3   Visit 5 (week 12) 
 
32 
  
 
  10.4.4   End of Treatment Visit 8 (week 24) 
 
32 
10.4.5  Follow-up visit 9 (week 28) 
 
33 
  
 
10.4.6   Assessments for Early Discontinuation from Study 
 
34 
  
 
10.4.7   Criteria for Discontinuation of Study Treatment 
 
34 
  
10.5  Pregnancy 
 
35 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 3 of 60 
  
10.6   Occurrence of Hepatocellular Carcinoma in Patients with NAFLD 
 
36
10.7   Death 
 
36 
  
10.8   Withdrawal of Consent 
 
36 
11.0 Study Assessments 
37 
  
11.1  Clinical Efficacy Endpoints 
 
37 
  
11.2   Safety Assessments 
 
37 
  
 
11.2.1  Clinical Safety Assessments 
 
37 
  
           11.2.2  Laboratory Safety Assessments 
 
37 
 
  
11.3   Pharmacokinetics and Exposure/ Response Assessments 
 
37 
  
11.4  Communication of Laboratory Results to Sites 
 
37 
  
11.5  Study interventions 
 
38 
12.0 Adverse Events: Definitions and Management 
 
39 
  
12.1     Definitions 
 
39 
        12.1.1 Pre-dosing signs and symptoms 
 
39 
  
12.2    Adverse Events 
 
39 
  
12.3    Classification of Events as Serious 
 
39 
 12.3.1   Immediate Reporting of Serious Events 
 
41 
  
 
12.3.2   Reporting of Serious Events to Regulatory Agencies 
 
42 
  
 
12.3.3   Guidelines for Determining Relationship Causality of Adverse Events  
42 
  
       12.3.4   Guidelines for Determining Severity of Adverse Events 
 
42 
  
12.4  Toxicity Management Guidelines 
 
43  
  
12.5  Emergency Procedures 
 
44 
  
 
12.5.1  Emergency Decoding 
 
44 
13.0 Statistical Considerations 
 
44 
  
13.1 Sample Size Calculation 
 
44 
  
13.2 General Statistical Methodology 
 
44 
  
 
13.2.1  Analysis of Continuous Variable 
 
45 
  
 
13.2.2. Analysis of Categorical Variables 
 
46 
  
 
13.2.3. Analysis of Time to Event Variables 
 
46 
  
13.4   Analyses 
 
46 
  
13.5   Interim Analysis Plan 
 
48 
  
13.6   Medical Monitoring and Independent Data Reviewing Board 
 
48 
14.0 Quality Control and Quality Assurance 
 
48 
15.0 Data Handling and Record Keeping 
 
48 
  
15.1   Case Report Forms 
 
48 
  
15.2   Record Retention 
 
49 
16.0 Ethics 
 
 
49 
  
16.1   Institutional Review Board/Independent Ethics Committee 
 
49 
  
16.2   Ethical Conduct of the Trial 
 
49 
16.3   Subject Information and Consent 
 
50 
17.0   Sponsor Discontinuation Criteria 
 
50 
18.0   Dissemination and Publication of Results 
 
50 
19.0   References 
 
51 
Signed Agreement of Study Protocol 
 
53 
Appendix I:  World Medical Association Declaration of Helsinki 
 
54 
Appendix II:  Histologic Scoring System for Nonalcoholic Fatty Liver Disease 
 
60 
 
 
 
 
 
 
 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 4 of 60 
A Randomized, Double-Blind, Placebo Controlled,  
Parallel-Group, Phase II Trial of JKB-121 for the Treatment of  
Nonalcoholic Steatohepatitis (NASH) 
 
Protocol Number: JKB-121-001 Version 4.0 (Amendment 2) 
CRO PERSONNEL 
Principle Investigator 
Manal F. Abdelmalek, MD, MPH 
Associate Professor of Medicine 
NAFLD Clinical Research Program 
Division of Gastroenterology and Hepatology  
Duke University 
 
SAE/EMERGENCY CONTACT INFORMATION 
 
SERIOUS ADVERSE EVENT REPORTING 
 
Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
MEDICAL MONITOR /EMERGENCY CONTACT INFORMATION 
Cynthia Moylan, MD 
Duke University  
NAFLD Clincal Research Program 
Phone:  919-684-6274 (NASH) 
After Hours:  919-684-8111  
Cynthia.moylan@dm.duke.edu 
 
SPONSOR PERSONNEL 
 Sponsor 
TaiwanJ Pharmaceuticals Co., Ltd.  
Rm D207, No. 2, Sec.  2, 
Shengyi Rd.,  
Zhubei City, Hsinchu County 30261, Taiwan 
Tel:886-3-658-7721   
Sponsor Contact  
Edwin Wu, PhD 
Strategic Advisor 
TaiwanJ Pharmaceuticals Co, Ltd 
Tel: (919) 270-8904 
Regulatory Manager 
Joanna Huang,                              
TaiwanJ Pharmaceuticals Co., Ltd.  
No.5, Ln. 362, Jiaxing Rd.,  
Zhubei City, Hsinchu County 302 Taiwan    
Business Hours Tel:  886-886-3-658-772 
Before / After Hours: Tel: 886-963-772-658 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 5 of 60 
 
1.  
PROTOCOL SYNOPSIS 
NAME OF PRINCIPAL INVESTIGATOR: 
Manal F. Abdelmalek, MD, MPH 
 
PROTOCOL NUMBER: 
JKB121-001 (Version 4.0) 
 
IND 124,082 
NAME OF SPONSOR 
TaiwanJ Pharmaceuticals Co., Ltd 
NAME OF FINISHED PRODUCT: 
JKB-121  
NAME OF ACTIVE INGREDIENT: 
Nalmefene hydrochloride 
Study Title  
A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II 
Trial of JKB-121 for the Treatment of Nonalcoholic Steatohepatitis (NASH). 
Lead Investigator: 
Manal F. Abdelmalek, MD, MPH 
Duke University 
Number of Centers: 
Approximately 12 sites—United States only  
Study Phase 
II 
Study Objectives: 
Primary Objectives: 
 
 
 
Secondary Objective: 
To evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 
mg twice daily and 10 mg twice daily) in reducing liver fat  compared to 
placebo.   
 
The secondary objectives are  
 
Determine the pharmacokinetic profile of JKB-121 in NASH 
 
Assess the impact of treatment with JKB-121 on metabolic markers 
 
Assess the impact of treatment on liver enzymes (serum ALT) over 
24 weeks. 
 
Establish the recommended dose for future NASH treatment studies. 
 
To evaluate changes of NASH related biomarkers such as 
adiponectin, leptin, ghrelin, TNF-alpha, TGF-beta, hyaluronic acid and 
MMP-2.  
Exploratory Objective 
Investigate the impact of treatment of potentially relevant inflammatory and 
metabolic biomarkers associated with NASH 
Study Endpoints: 
Primary Endpoints: 
 
 
 
 
Safety:  Incidence and severity of adverse events and changes in vital signs 
and clinical laboratory tests 
 
Efficacy:  Comparative changes in  
 
Mean changes from baseline in the percentage fat content of the liver 
measured by magnetic resonance imaging (MRI) at week 24.  
Secondary Endpoints: 
  
Pharmacokinetics: 
 
Serum concentration of JKB-121 over time including but not limited to 
maximum observed concentrations (Cmax), minimum observed 
concentation (Cmin) and area under the concentration time curve 
(AUC) and if feasible half-life (t½) 
Metabolic markers:  
 
Body mass index (BMI) 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 6 of 60 
 
HbA1c and the homeostatic model assessment of insulin resistance 
(HOMA-IR)  
 
Serum lipid profile: total cholesterol, triglycerides, low density 
lipoprotein (LDL) and high density lipoprotein (HDL) fractions.  
Liver Function: 
 
Mean change from baseline in serum ALT at week 24. 
 
Mean serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT) 
at weeks 4, 8, 12, 16, 20, and 24. 
 
Proportion of subjects whose ALT level at week 24 is within normal 
range defined as < 20 U/L for women and < 30 U/L for men. 
Exploratory Outcome  
Measures:  
 
Mean serum concentrations of lipopolysaccharide (LPS), c-reactive 
protein (CRP), cytokeratin (CK)-18 fragments, proinsulin c-peptide, 
glucagon-like polypeptide (GLP-1) and adiponectin. 
 
Relative levels of inflammatory cytokines, interferon gamma (IFN-γ), 
and tumor necrosis factor alpha (TNF-α) 
 
Relative levels of regulatory T cells in the peripheral blood 
mononuclear cells (PBMC) samples including CD4, CD8, CD 25, Fox 
P3, NKT, and CD62 T cells. 
Methodology: 
Study design Randomized double blind, placebo control 3-arm parallel group, multi-dose 
single center study 
Study duration Up to 28 days for screening, 24 weeks of treatment and 28 days of follow-up. 
Subjects terminating study drug will be followed-up post-treatment for 28 
days. 
Number of Subjects: 
 
The study will aim to recruit 60 subjects, randomized 1:1:1 
Stratification:  
 
Treatment allocation will be stratified by known diagnosis of diabetes status. 
Nondiabetic status will be defined as HbA1c ≤ 6.0 and absence of any 
medications to treatment diabetes.  Diabetic status will be defined as HbA1c 
> 6.0 and/or requiring medication for treatment of diabetes mellitus. 
Study Drug:  JKB-121 oral tablet 
Control Group Placebo to match 
Dose Regimens Arm A: 5 mg JKB-121 twice daily. 
Arm B: 10 mg JKB-121 twice daily 
Arm C: Matching placebo twice daily 
 
All treatment dose regimens are administered per orally 
Administration: 
Schedule: 
Twice daily for 24 weeks 
 
 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 7 of 60 
Study Population: Adults with biopsy-proven nonalcoholic steatohepatitis (NASH) 
Inclusion Criteria: 
 
1. Age ≥ 18 years 
2. Provision of written informed consent 
3. Biopsy-proven NASH within 12 months prior to randomization verified 
by central pathology reading with:  
 
NASH activity score (NAS) of 4 or more 
 
10% or more macrovesicular steatosis 
 
cytologic ballooning score of at least 1 point 
 
hepatic fibrosis of at least 1 point 
 
hematoxylin and eosin (H&E) stained slides and/or paraffin 
block available for independent assessment 
4. ALT > 40 U/L for women and > 60 U/L for men at screening and at 
least once in the previous 12 months. 
5. MRI with > 6% hepatic steatosis 
6. HbA1c of ≤ 9.0 
7. Lipid lowering agents (i.e. statins) and allowable antidiabetic 
treatment (i.e. metformin or sulfonylurea) must be stable at screening 
and during the study.  
8. Agree to use of effective contraceptive measures if female of child 
bearing potential. 
Exclusion Criteria: 
1. Any chronic liver disease other than NASH (i.e., drug-induced, viral 
hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary 
sclerosing cholangitis, hemochromatosis, A1AT deficiency, Wilsons 
disease) 
2. Cirrhosis, as assessed clinically or histologically (fibrosis stage 4) 
3. Presence of vascular liver disease 
4. BMI ≤ 25 kg/m2 
5. Excessive alcohol use (> 20 g/day) within the past 2 years 
6. AST or ALT > 250 U/L  
7. Type 1 diabetes mellitus 
8. Bariatric surgery in the past 5 years. 
9. Weight gain or weight loss of > 5% in past 6 months or > 10% change 
in past 12 months.  
10. Contraindication to MRI 
11. Inadequate venous access 
12. HIV antibody positive, hepatitis B surface antigen positive (HBsAg), or 
HCV RNA positive.  
13. Receiving an elemental diet or parenteral nutrition 
14. Chronic pancreatitis or pancreatic insufficiency 
15. Any history of complications of cirrhosis (i.e. ascites, hepatic 
encephalopathy, or portal hypertensive bleeding), even if absent or 
optimized with medical management at time of screening 
16. Concurrent conditions: 
a) Inflammatory bowel disease 
b) Unstable angina, myocardial infarction, transient ischemic events, 
or stroke within 24 weeks of screening 
c) Ongoing infectious, immune mediated disease within previously 1 
years 
d) Any malignant disease (other than basal cell carcinoma of the 
skin) within previous 2 years 
e) Prior solid organ transplant 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 8 of 60 
f) Any other concurrent condition which, in the opinion of the 
investigator, could impact adversely on the subject participation or 
the interpretation of the study data. 
17. Concurrent medications including: 
a) Anti-NASH therapy(s) initiated after the liver biopsy diagnosing 
NASH.  Anti-NASH therapies include S-adenosyl methionine 
(SAMe), milk thistle, and vitamin E.   
b) Antidiabetic medication which may impact NASH histology 
initiated after the liver biopsy diagnosing NASH including 
thiazolidinediones (glitazones), dipeptidyl peptidase 4 inhibitors 
(gliptins) or glucagon-like peptide 1 analogs.  
c) Immune modulatory agents including systemic steroids, 
methotrexate, anti-TNF-α therapies (infliximab, adalimumab, 
etanercept) or anti-integrin therapy (namixilab).  
d) UGT2B7 enzyme inhibitors (e.g., diclofenac, fluconazole, 
medroxyprogesterone acetate, meclofenamic acid) 
e) UGT2B7 inducers (e.g., dexamethasone, phenobarbital, 
rifampicin, omeprazole)  
f) Chronic opioid use within 28 days prior to screening (Day -28) 
18. Self-reported or known marijuana or illicit drug use within 28 days 
before the screening 
19. The following laboratory abnormalities: 
a) HbA1c > 9.0% 
b) Neutrophil count  < 1.0 x 109 / L 
c) Platelets < 100  109 / L 
d) Hemoglobin < 10 g/dl 
e) Albumin < 3.5 g 
f) International normalized ratio (INR) >1.3 
g) Any elevation of total bilirubin above normal (unless Gilbert’s 
syndrome or extrahepatic source as denoted by increased 
indirect bilirubin fraction). 
h) Serum creatinine > 1.5 mg/dl 
i) Creatinine clearance ≤ 50 ml/minute calculated by Crockroft-
Gault. 
20. Pregnancy or breastfeeding. 
21. Women, of childbearing age, who are not willing to practice effective 
contraception (i.e., barrier, oral contraceptives, or past medical history 
of hysterectomy) for the 48-week duration of the trial and for 1 month 
after the last  administration of the drug.   Women with documented 
(not reported) oophorectomy or hysterectomy are considered sterile. 
Women with tubal ligation are at small risk and should have 
pregnancy test at screening.  
22. Participation in an investigational drug study within past 30 days. 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 9 of 60 
Study Procedures and 
Visit Schedule: 
 
Refer to Table 1 for the schedule of study procedures. 
 
Subjects who provide voluntary written informed consent will be screened for 
eligibility. Subjects meeting all the inclusion and none of the exclusion criteria 
will be eligible to participate. 
 
The maximum time on study drug for each subject is 24 weeks with an 
additional 4 weeks of follow-up.  
 
Eligible subjects will be randomized at the baseline visit to receive one of 
three study treatments twice daily for a period of 24 weeks.  Each subject will 
return for assessment and required study procedures on days 14, 28 and 
every 4 weeks thereafter until week 24.  A final follow-up visit will be 
conducted at week 28 if the subject ceases treatment at week 24.  
 
Investigational product dispensing and accounting will be conducted on a 4 
week basis.  
 
The actual visit schedule will be as follows: 
 
Screening period, culminating in randomization (screening 
assessments must be completed no more than 4 weeks prior to 
enrollment.  
 
Baseline visit and every 4 weeks afterward for total of 24 weeks 
 
Week 8, 16 and 24 (± 4 days) visits will include measure of metabolic 
(glucose, lipids, glycosylated hemoglobin, HOMA-IR, C-reactive 
protein etc.) 
 
Week 12 and 24 (± 4 days) will include measures of hepatic steatosis 
and exploratory measures (i.e. CK-18, adiponection, leptin, ghrelin, 
TNF-, TGF-, hyaluronic acid, cytokines, and MMP-2 etc)  
 
Follow-up visit at week 28 (±4 days).  
 
Unscheduled or early withdrawal visits may be necessary.  
Safety Assessment 
 
Safety Parameters:  
 
 
 
 
 
 
 
 
 
 
 
Other Parameters: 
The following measures of safety and tolerability will be conducted at 
screening, baseline and every 4 weeks during the study: 
 
Adverse event monitoring 
 
Physical examination including vital signs 
 
Safety laboratory assessments 
 
Treatment compliance 
 
Urine pregnancy test (women only) 
 
The following measures of safety and tolerability will be conducted at 
screening, baseline and every 12 weeks during the study: 
 
Electrocardiogram (EKG) 
 
Urinalysis 
 
The following measures of immunological profile will be explored in this 
study: 
 
Insulin resistance (HOMA-IR, insulin and glucose levels,HbA1c) 
 
Lipid levels 
 
Special laboratory functions panel include CK-18, adiponectin, leptin, 
ghrelin, TNF-, TGF-β, hyaluronic acid, and MMP-2. 
 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 10 of 60 
Statistical Considerations: 
Sample Size 
Determination: 
 
An approximate total of 60 subjects will be enrolled.  Subjects will be 
randomized into three treatment groups in a ratio of Group 1 (5 mg twice 
daily): Group 2 (10 mg twice daily): Group 3 (placebo twice daily) = 1:1:1.  No 
empirical power calculation is performed. The sample size is based on the 
best medical judgment. 
 
The power to detect a difference between placebo and active treatment with 
respect to change from baseline in liver fat content and serum ALT has been 
determined for a sample size of 20 patients per arm to assess safety and 
potential efficacy.  Fat quantification by MRI is very sensitive with as small as 
a 5% detectable change in fat quantification.  
 
Further, since the endpoint is the change from baseline, plausible estimates 
of the degree of correlation between pre-and post-baseline measurements 
will be incorporated into the variance estimates.  Given the wide range of 
results observed in the literature, several “what-if” scenarios were examined.  
As such, the current sample size was considered sufficient for the 
exploratory objectives of the study for the given range of plausible treatment 
effects and variance estimates.  Due to the exploratory objects of the 
protocol, no adjustment for the two co-primary endpoints was made.  
Additionally, there will be no adjustments for multiple comparisons between 
the 3 treatment groups.  
 
Assuming the observed difference between two treatment groups is 20%, 
then the 95% confidence interval for the true mean is given by (2.5%, 37.5%) 
with 20 subjects in each group.  
 
Fat Liver Content Change from Baseline: 
The current sample size of 20 subjects per group should yield approximately 
85% power to detect a treatment effect of at least  5% with respect to the 
difference in the mean change from baseline between one of the JKB-121 
treatment groups and placebo  
 
ALT change from Baseline: 
Patients will be stratified into treatment arms based on threshold of baseline 
elevation of ALT (i.e. ALT < 2x ULN and ALT ≥ 2 x ULN, but < 5 x ULN).  The 
current sample size of 20 subjects per group should yield approximately 73% 
power to detect a treatment effect of at least 30 U/L assuming a SE of 50 U/L 
(α= 0.05; two tailed; unpaired t-test).  The SD of 50 U/L for the change from 
baseline endpoint was derived assuming SDs of 40 for the pre-and post-
baseline measurements with a correlation of 0.25.  
 
Sample size and power estimates have not been adjusted for multiple 
comparisons or multiple endpoints, dropouts or stratifications. 
 
The analysis of each primary endpoint will be based on a linear model that 
incorporates the baseline measures as a covariate, the stratification factor 
and randomization treatment group.  Pairwise comparisons of each active 
treatment group to control will be conducted vial linear contrasts. 
 


JKB121 
 
                         March 2, 2016 
TaiwanJ Pharmaceuticals 
Phase II NASH STUDY 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                               CONFIDENTAL                                                   Page 11 of 60 
Statistical Analysis 
The populations for analysis will be as follows: 
 
Full Analysis Set (FAS) for Efficacy:  includes all subjects who received at 
least one dose of study medication.  Only subjects with clear documentation 
that no study medication was received may be excluded.  In the event of 
allocation errors, subjects will be analyzed for efficacy according to the 
treatment to which they were randomized.  
 
Safety Analysis Set: includes all subjects who received at least one dose of 
study medication.  Only subjects with clear documentation that no study 
medication was received may be excluded.  In the event of treatment 
allocation errors, subjects will be analyzed for efficacy according to the 
treatment in which they were randomized.  
 
Per Protocol Analysis Set includes all subjects who complete 24 weeks of 
study treatment and have MRI and ALT measured at baseline and at week 
24 and no major protocol violations, determined prior to break of the 
treatment blind.  
 
All hypotheses will be tested for statistical significance with two-tailed p-
values. Results of all tests will be considered statistically significant if their p-
value is less than or equal to 0.05, except results of the tests for interaction 
will be considered statistically significant if the p-value is less than or equal to 
0.10 
 
Efficacy: 
The primary endpoint of this study is the safety and potential efficacy of two 
dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing 
liver fat compared to placebo.   
The secondary endpoint of the study is the time to remission (TTR) is defined 
as time in weeks from randomization to liver aminotransferase remission as 
defined as two consecutive ALT values within normal range (< 20 U/L for 
women and < 30 U/L for men) or a 20% reduction from the baseline during 
study period. A Cox proportional hazard model will be used to compare the 
TTR duration between treatment arms.  
Median duration of TTR and the hazard ratio with 95% confidence limits will 
be estimated using Kaplan-Meier survival methodology.  TTR from 
randomization will be compared using estimates from the Kaplan-Meier 
survival curves.  A detailed comparison of the treatment effects will be 
analyzed by fitting a Cox proportional hazard model with baseline variables 
as covariates to assess the benefit-risk ratio. 
Safety: 
The primary safety endpoints will be the rates of patients who experience (1) 
one or more AEs; (2) SAEs; and (3) AEs leading to discontinuation of study 
medication. Treatment effect will be explored by inspection of observed 
means or rates for the dose groups within each treatment regimen. Other 
safety parameters such as laboratory test, vital signs, and other safety 
related variables will be summarized regarding each scheduled visit. Shift 
tables will be presented for laboratory values based on the reference 
laboratory normal ranges.  


JKB121  
 
             Version 4.0 
TaiwanJ Pharmaceuticals                                                                                NASH Protocol 
March 2, 2016 
Manal F. Abdelmalek, MD, MPH                                                                     CONFIDENTAL 
          
 Page 12 of 60 
1.1 TABLE OF EVENTS 
 
Screening 
Period 
Enrollment 
Treatment period 
End of 
Treatment 
Follow-up  
Visit 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
up to 4 wks 
0 
2 
4 
8 
12 
16 
20 
24 
28 
Day (Visit Window) 
-1 to -28 
1 
14 (±4) 
28 (±4) 56 (±4) 84 (±4) 112 (±4) 140 (±4) 
168 (±4) 
196 (±4) 
Determination of eligibility  
X 
X 
 
 
 
 
 
 
 
 
Review of medical history  
X 
X 
 
 
 
 
 
 
 
 
Obtain informed consent  
X 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
X 
X 
X 
X 
 
  
 
Managing drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum hCG (if applicable) 
X 
 
 
 
 
 
 
 
 
 
Urine hCG (if applicable)  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid panel 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Glycosylated hemoglobin  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
HOMA-IR 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
 
 
 
 
X 
 
 
X 
X 
Electrocardiogram 
X 
 
 
 
 
X 
 
 
X 
 
Liver biopsy (if prior biopsy > 12 mo) 
X 
 
 
 
 
 
 
 
 
 
PK study 
 
 X* 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse events ** 
 
X** 
X 
X 
X 
X** 
X 
X 
X** 
X 
 
 
 
 
 
 
 
 
 
 
 
MRI for hepatic steatosis 
X 
 
 
 
 
X 
 
 
X 
 
CK-18 
 
X 
 
 
 
X 
 
 
X 
X 
Stored serum for exploratory measures 
and noninvasive biomarkers of fibrosis 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
 
 
 
X 
* Frequent sampling PK study on Day 1 for Substudy subjects only.  All patients to have a pre-dose trough level drug measures (6 ml blood ) at treatment Weeks 8, 16, and 24 (Visits 4, 6, and 8). 
** Hospital Anxiety and Depression Scale and Columbia Suicide Severity Scale  


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 13 of 60 
2. 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE  
 
Adverse event  
ALD   
Alcoholic liver disease 
ALT  
 
Alanine aminotransferase  
AST 
 
Aspartate aminotransferase 
BUN 
 
Blood urea nitrogen 
CFR   
Code of Federal Regulations  
CK-18  
Cytokeratin 18 
CRF   
Case report form  
CRO   
Contract research organization  
CTCAE  
Common terminology criteria for adverse events 
EC  
 
Ethics committee  
EKG   
Electrocardiogram  
FDA   
Food and Drug Administration  
GCP   
Good Clinical Practice  
GGT   
Gamma-glutamyl transferase 
ß-HCG  
ß-human chorionic gonadotropin  
HBsAg  
Hepatitis B surface antigen 
HCV   
Hepatitis C virus  
HIV  
 
Human immunodeficiency virus 
HSC 
 
Hepatic stellate cells 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
IB  
 
Investigator’s brochure  
ICF  
 
Informed consent form  
ICH  
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDRB   
Independent Data Review Board  
IL 
 
Interleukin 
IND  
 
Investigational new drug  
INR 
 
International normalized ratio 
IRB  
 
Institutional Review Board  
ITT  
 
Intent-to-treat  
KO 
 
Knock-out 
LDH 
 
Lactate dehydrogenase 
LPS 
 
Lipopolysaccharide 
MedDRA  
Medical dictionary for regulatory activities  
MCD  
Methionine choline deficient  
MCP-1  
Monocyte chemotactic protein 1 
MMP-1 
Matrix metallopeptidase 2 
MRI 
 
Magnetic resonance imaging 
NAFLD 
Nonalcoholic fatty liver disease 
NASH  
Nonalcoholic steatohepatitis 
NASH CRN 
Nonalcoholic Steatohepatitis Clinical Research Network 
NCI  
 
National Cancer Institute 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 14 of 60 
NFK-β  
Nuclear factor-kappa beta  
SAE   
Serious adverse event  
TNF-  
Tumor necrosis factor alpha 
TLR-4  
Toll like receptor 4 
TIR 
 
Toll/IL-1 receptor 
TLR 
 
Toll-Like Receptors 
TTR   
Time to remission 
 
 
 
 
 
 
 
 
 
 
 
 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 15 of 60 
3.0   BACKGROUND  
3.1 
Nonalcoholic Steatohepatitis (NASH) 
The emerging epidemic of obesity and metabolic syndrome has contributed to the increased 
prevalence of nonalcoholic steatohepatitis (NASH) as what is now considered to be the leading 
cause of chronic liver disease in the Western World [1].   An estimated 25% of the industrialized 
world has hepatic steatosis and fatty liver, an entity that has been termed nonalcoholic fatty liver 
disease (NAFLD).  NAFLD encompasses a spectrum of liver pathology with different clinical 
prognoses.  The simple accumulation of triglyceride within hepatocytes (hepatic steatosis) is on 
the most clinically-benign extreme of the spectrum.  On the opposite, most clinically-ominous 
extreme, are cirrhosis and primary liver cancer.  The risk of developing cirrhosis is extremely 
low in individuals with chronic hepatic steatosis, but increases as steatosis becomes 
complicated by histologically-conspicuous hepatocyte death and inflammation, i.e., nonalcoholic 
steatohepatitis (NASH).  NASH affects approximately 20-25% of all NAFLD patient, which 
equates approximately 6.0% of the overall population [2].   NASH resembles alcoholic liver 
disease but occurs in people who drink little or no alcohol [3].   
Most subjects with NAFLD are asymptomatic. The diagnosis is often made when abnormal liver 
aminotransferases or features of fatty liver are noted during an evaluation performed for other 
reasons.   NAFLD may also be diagnosed during the work-up of vague right upper quadrant 
abdominal pain, hepatomegaly, or an abnormal appearing liver at time of abdominal surgery.   
The association of NAFLD with obesity, diabetes, hypertriglyceridemia, hypertension, and 
cardiovascular disease is well known.   NAFLD is an independent risk factor for metabolic 
syndrome and type 2 diabetes mellitus [4].  In addition, approximately 50-90% of patients with 
obesity may have NAFLD while 50% of patients with diabetes may have biopsy proven NASH 
and are at increased risk for progressive hepatic fibrosis and cirrhosis [5, 6].   
The mechanisms underlying NAFLD pathogenesis and progression are not entirely clear.  The 
best-understood mechanisms pertain to hepatic steatosis.  Hepatic steatosis results when 
hepatocyte mechanisms for triglyceride synthesis (e.g., lipid uptake and de novo lipogenesis) 
overwhelm mechanisms for triglyceride disposal (e.g., degradative metabolism and lipoprotein 
export), leading to accumulation of fat (i.e., triglyceride) within hepatocytes.  Obesity stimulates 
hepatocyte triglyceride accumulation by altering the intestinal microbiota to enhance both 
energy harvest from dietary sources and intestinal permeability.  Reduced intestinal barrier 
function increases hepatic exposure to gut-derived products which stimulate liver cells to 
generate inflammatory mediators that inhibit insulin action and cause oxidative or inflammatory 
stress.  Increased delivery of triglyceride precursors (e.g., fatty acids and diacylglycerols) and 
metabolic by-products (e.g., reactive oxygen species) may damage hepatocytes, leading to 
hepatocyte lipotoxicity.  Lipotoxicity also triggers the generation of other factors (e.g., 
inflammatory cytokines, hormonal mediators) that deregulate systems that normally maintain 
hepatocyte viability and result in progressive chronic liver injury. 
Weight reduction with diet and exercise is the only therapeutic strategy that has been shown to 
be beneficial in NASH.  Unfortunately, most patients are unable to achieve and maintain the 
required lifestyle change for any significant period of time.  Bariatric surgery is effective for 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 16 of 60 
weight loss, but has not been specifically assessed as a treatment for NASH and may be 
contraindicated in those patients with advanced liver disease attributable to NAFLD. Insulin 
sensitizing agents such as metformin and glitazones have been used experimentally with some 
limited evidence of short term benefit; however, the benefits are not sustained.  Experimental 
approaches under clinical evaluation in patients with NASH include antioxidants, newer 
antidiabetic medications and antifibrotic agents. In two pilot trials, pentoxifylline [7, 8], which 
inhibits Tumor necrosis factor alpha (TNF-) production, was reported to show beneficial effects 
in improving aminotransferase levels, hepatic steatosis, fibrosis and necroinflammation among 
patients with NASH.  Currently, there are no FDA-approved treatments for NAFLD and NASH. 
3.2 Toll-Like Receptor 4   
Toll-like receptor 4 (TLR-4) is a cell surface, type 1 trans-membrane protein that recognizes 
bacterial lipopolysaccharides (LPS) and endotoxins, among other ligands, a key mediator of the 
release of proinflammatory cytokines and inflammatory responses, and a member of TLR family 
which are mainstays of the innate immune system and best known for their role in host 
defenses against infections.  Lipopolysaccharide (LPS), an endotoxin, is a specific agonist for 
TLR-4. Activation of inflammatory signaling pathways is of central importance in the 
pathogenesis of alcoholic liver disease (ALD) and NASH.  Recent studies demonstrated that 
Toll-like receptors, the sensors of microbial and endogenous danger signals, are expressed and 
activated in innate immune cells as well as in parenchymal liver cells involved in hepatic fibrosis 
(hepatic stellate cells and Kupffer cells) and thereby contribute to ALD and NASH [9]. The 
importance of gut-derived endotoxin and its recognition by TLR4 in the liver, the significance of 
TLR-induced intracellular signaling pathways and cytokine production as well as the contribution 
of TLR-4 signaling to the induction of liver fibrosis and to the progression of liver pathology 
suggest that a TLR-4 antagonist for therapeutic target for the treatment of chronic liver disease 
[10].  
3.3 Obesity, Insulin resistance and TLR-4  
Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the 
development of obesity-related insulin resistance. TLR-4 is a key mediator of pro-inflammatory 
responses. Mice lacking TLR-4s are protected from diet-induced insulin resistance and 
inflammation.  Mice deficient in hepatocyte TLR-4 (TLT4KO) exhibit improved glucose 
tolerance, enhanced insulin sensitivity and ameliorated hepatic steatosis despite the 
development of obesity after a high-fat diet (HFD) challenge [11]. Furthermore, TLR4KO mice 
have reduced macrophage content in white adipose tissue, as well as decreased tissue and 
circulating inflammatory markers. TLR4 are activated by fatty acids and endotoxinemia (a 
marker of gut permeability), features of both obesity and metabolic syndrome, resulting in 
activation of nuclear factor-kappa beta (NFK-β) and increased release of inflammatory 
biomediators such as IL-6, IL-1, TNF-α, and monocyte chemotactic protein-1 (MCP-1), which 
play a role in the pathophysiology of obesity and metabolic syndrome [12] 
Such data indicate that the activation of TLR-4 on hepatocytes contributes to obesity-associated 
inflammation and insulin resistance, and suggest that targeting hepatocyte TLR-4 might be a 
useful therapeutic strategy for the treatment of type 2 diabetes [13].  Given the very strong 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 17 of 60 
association of metabolic syndrome and obesity in that pathogenesis of NAFLD and NASH, 
targeting TLRs can potentially forestall the end-organ complication of insulin resistance 
syndrome, including the development obesity-related chronic liver disease.  
3.4 Endotoxemia, LPS and NASH  
Emerging data have shown a close association between compositional changes in gut 
microbiota and the development of NAFLD [14, 15]. The change in gut microbiota may alter 
nutritional absorption and storage. In addition, gut microbiota are a source of TLR ligands, and 
their compositional change can also increase the amount of TLR ligands delivered to the liver. 
TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-
liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD [16]. 
The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been 
considered a potential underlying mechanism of obesity and NAFLD, but the role of these 
microbiota in NAFLD remains unknown [17].  Several reports have demonstrated that certain 
gut microbes are associated with the development of obesity and NAFLD. For instance, a 
decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut 
permeability, which allows the leakage of bacterial components. Interventions to increase 
Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD.  In children, 
the levels of Escherichia were significantly increased in NASH compared with those in obese 
control. Escherichia can produce ethanol, which promotes gut permeability [18]. Another 
possibility by which the altered intestinal microbiota may promote obesity and fatty liver is an 
increase in LPS-containing microbiota [19] and increased intestinal permeability to LPS [20].  
Bacterial LPS stimulates Kupffer cells and participates in the pathogenesis of hepatic 
fibrogenesis [21].  Thus, normalization of gut microbiota using probiotics or prebiotics is a 
promising treatment option for NAFLD.  In addition, TLR signaling in the liver is activated, and 
its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To 
date, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis 
of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment.  Thus, 
plausible evidence exists to support the use of a TLR-4 antagonist in the treatment of NASH.  
3.5 JKB-121 
JKB-121, a methylenemorphinandiol compound, is a long-acting small molecule that is 
efficacious as a weak antagonist at the TLR-4 receptor, thus reducing the likelihood of affecting 
the innate immune system.  It is an off-patent FDA-approved drug (as a non-selective opioid 
antagonist) with no known safety issues.   
JKB-121 has been shown to prevent the LPS induced inflammatory liver injury in a 
methionine/choline deficient (MCD) diet fed rat model of NAFLD [22].  In vitro, JKB-121 
neutralized or reduced the LPS-induced release of IL-6 and IL-12 in murine macrophages, 
deactivated hepatic stellate cells (HSCs), inhibited HSCs proliferation, collagen expression  and 
α-SMA expression in cultured HSCs (spontaneously activated) [23]. In vivo, JKB-121 
neutralized the stimulated release of TNF-a, IL-6, and IL-18 by LPS/D-Gal in mice.  Moreover, 
JKB-121 also neutralized LPS-induced p38 phosphorylation and TNF-α in isolated rat Kupffer 
cells [22].  The data supports that JKB-121, a TLR4 antagonist, exhibits the potential for treating 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 18 of 60 
NASH.  Based on the evidence reviewed above, inhibition of the TLR4 signaling pathway may 
provide an effective therapy in the prevention of inflammatory hepatic injury in NAFLD, the 
progression to NASH and fibrosis, and ultimately cirrhosis. 
4.  STUDY CONDUCT STATEMENT 
This study will be conducted in compliance with the protocol, according to current United States 
federal regulations (21, Code of Federal Regulations [CFR] Parts 50, 56 and 312D) and the 
principles of International Conference on Harmonization (ICH) (ICH E6 1997) Good Clinical 
Practice (GCP), Food and Drug Administration (FDA) guidelines and the Declaration of Helsinki.  
5.  STUDY OBJECTIVES AND ENDPOINTS 
 
5.1 
Objectives 
5.1.1 Primary Objective 
To evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily 
and 10 mg twice daily) in reducing liver fat compared to placebo.   
 
5.1.2 Secondary Objective(s) 
The secondary objectives are:  
 Determine the pharmacokinetic profile of JKB-121 in NASH 
 Assess the impact of treatment with JKB-121 on metabolic markers 
 Assess the impact of treatment on liver enzymes (serum ALT) over 24 weeks. 
 Establish the recommended dose for future NASH treatment studies. 
 To evaluate changes of NASH related biomarkers such as adiponectin, leptin, ghrelin, 
TNF-alpha, TGF-beta, hyaluronic acid and MMP-2. 
5.1.3 
Exploratory Object(s) 
Investigate the impact of treatment of potentially relevant inflammatory and metabolic 
biomarkers associated with NASH. 
5. 2 
Endpoints  
 
5.2.1 Primary Endpoint 
The primary endpoint of this study is safety and potential efficacy of two dose levels of JKB-121 
(5 mg twice daily and 10 mg twice daily) in reducing liver fat compared to placebo.   
 
5.2.2 Secondary Endpoint(s) 
The secondary endpoint of the study is time to remission (TTR).   TTR is defined as time in 
weeks from randomization to liver function remission as defined as two consecutive ALT values 
within normal range (< 20 U/mL for woman and < 30 U/L for men) or 20% reduction from the 
baseline during study period.  
 
TTR rate in ALT at the end of the treatment period. 
 
Assess the  pharmacokinetic profile of JKB-121 in NASH 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 19 of 60 
 
Change on metabolic markers associated with NASH 
 
Change in  liver enzymes (serum ALT) over 24 weeks. 
 
Change of NASH related biomarkers such as adiponectin, leptin, ghrelin, TNF-alpha, 
TGF-beta, hyaluronic acid and MMP-2. 
 
6. 
STUDY DESIGN 
This is a randomized, double-blind, placebo controlled, parallel-group, phase II trial of JKB-121 
in treating subjects with biopsy-proven NASH. 
 
Subjects will be randomized at study entry to placebo twice daily, 5 mg twice daily, or 10 mg 
twice daily of JKB-121 orally to improve NASH with regard to biochemical and MRI/MRS 
features of NASH in a 1:1:1 ratio. 
• 
Treatment Group 1:  placebo twice a day orally  
• 
Treatment Group 2:  5mg of JKB-121 twice a day orally  
• 
Treatment Group 3:  10 mg of JKB-121 twice a day orally  
The maximum time on study drug for each subject is 24 weeks with an additional 4 weeks of 
follow-up.  
 
This allocation is shown diagrammatically in Figure 1  
 
Figure 1: Study Schema 
 
 
 
 
Screening for 4 weeks 
Randomization 
Treatment for 24 weeks 
Follow-up for 4 weeks 
 
 
 
 
Placebo 
 
 
Placebo 
 
 
6.1 
Duration of the Study 
 
Subjects will be on treatment for up to 24 weeks.  Subjects who experience adverse reaction will 
discontinue study drug but will continue to complete all protocol-specified follow-up visits, 
assessments and evaluations.  They will then continue to be followed up for the remaining 
duration of the study. Unless otherwise recommended by the Independent Data Review Board 
(IDRB) or regulatory authorities, the study will continue until it accrues a minimum of 60 subjects 
complete the study.   
 
Screening 
Randomization 
5 mg twice daily 
Placebo 
10 mg twice daily 
Off treatment 
follow-up 
Start 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 20 of 60 
Until formal conclusion of the study, subjects, investigators and all site study personnel will be 
remain blinded as to treatment allocation, except in the event of a medical emergency which 
necessitates unblinding.  
 
6.2 
Sponsor’s Termination of Study  
Although TaiwanJ Pharmaceuticals has the intention of completing the study, the company 
reserves the right to discontinue the study at any time for clinical or administrative reasons. If ≥ 
30% of subjects received study treatments has a hepatic AE of > Grade 3 or a non-hepatic, 
drug-related AE of ≥ Grade 3, then the study will be terminated. 
 
6.3   
Reasons for Subject Withdrawal 
Any subject may withdraw his or her consent at any time.  
Subjects will be monitored carefully during the study. Any subject who experiences an increase 
in ALT value greater than 3X baseline during the treatment period will be monitored weekly. If 
ALT values increase to greater than 5X the baseline ALT will be rechecked within 48 hours and 
if value remains > 5X baseline, the subject will be withdrawn from the study. The subject will 
then be followed, and ALT, AST, prothrombin time, and total bilirubin will be monitored every 2 
weeks thereafter until the value that led to the subject’s discontinuation of therapy has returned 
to the baseline value (Baseline for prothrombin time and total bilirubin is the value obtained at 
the screening). 
Other reasons for withdrawal from the study may include, but are not limited to the following: 
 
Subject is in violation of the protocol, defined as refusal or inability to adhere to 
prescribed dosing and/or follow-up regimen. 
 
Subject is lost to follow-up. 
 
Subject experiences a serious or intolerable AE that, in the medical opinion of the 
principal investigator, warrants discontinuation. 
 
Subject has laboratory safety assessments that reveal clinically significant worsening 
from baseline values. 
 
Subject develops, during the course of the study, symptoms or conditions listed in the 
exclusion criteria. 
 
Subject requires a medication that is prohibited by the protocol. 
 
Investigator or TaiwanJ Pharmaceuticals requests an early discontinuation of the trial for 
any reason. 
 
The investigator may also withdraw a subject upon the request of TaiwanJ Pharmaceuticals or if 
TaiwanJ Pharmaceuticals terminates the study. Upon occurrence of a serious or intolerable AE, 
the principal investigator will confer with TaiwanJ Pharmaceuticals. If a subject is discontinued 
because of an AE, the event will be followed until it is resolved or until the principal investigator 
or sub-investigator deems the event to be chronic or the subject to be stable. 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 21 of 60 
6.3.1 Handling of Withdrawals  
Subjects should be encouraged to complete all study procedures; however, all subjects are free 
to withdraw from the study at any time. Subject participation in the trial may be stopped at any 
time at the discretion of the investigator or at the request of TaiwanJ Pharmaceuticals.  
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by the 
investigator in the source documents and on the relevant page of the CRF. Whenever possible, 
all subjects who withdraw from the study prematurely will undergo all end-of-study (Visit 8) and 
follow-up (Visit 9) assessments. Subjects who fail to return for final assessments will be 
contacted by the site in an attempt to have them comply with the protocol. Follow-up 
assessment for early withdrawals will be attempted through 2 documented telephone calls to the 
subject followed by 1 registered letter. All attempted contacts should be detailed thoroughly in 
the source documentation. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or serious adverse 
event (SAE). In any case, every effort must be made to undertake protocol-specified safety 
follow-up procedures. 
6.3.2 Replacements 
Subjects who are withdrawn from the study will not be replaced. 
 
7. STUDY POPULATION 
7.1. Number of Subjects 
A target of 60 subjects will be enrolled. It is envisioned that recruitment of subjects will occur at 
approximately 12 sites. Subjects who discontinue treatment per protocol or withdraw consent 
after initiating treatment will not be replaced. Any subject who fails a screening investigation 
may, at the discretion of the investigator, be re-tested, providing that they remain able to 
complete screening assessments within the protocol-specified screening period (up to 4 weeks). 
7.2. Assignment of Subjects Numbers 
Patients will be randomized in the order in which they are enrolled into this double-blind study 
by using a computer-generated randomization schedule.  TaiwanJ Pharmaceuticals will prepare 
the schedule prior to the start of the study.  This number will designate which allocated 
treatment a patient will receive.  The randomization schedule will be a ratio of 1:1:1 to one of the 
following three treatment groups: 
 
JKB-121 5 mg tablet twice daily orally 
 
JKB-121 10 mg tablet twice daily orally 
 
Placebo as tablet twice daily orally 
The patient number will be used to identify the patient throughout the duration of the study and 
will be used on the CRF. 
 
 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 22 of 60 
8. SUBJECT SELECTION 
This clinical trial can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate. All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular subject.  
Eligibility criteria may not be waived by the investigator and are subject to review in the case of 
a Good Clinical Practices (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with TaiwanJ site management or study management 
personnel (see protocol cover page) prior to enrollment. 
8.1. Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:  
1. Age ≥ 18 years 
2. Provision of written informed consent 
3. Biopsy-proven NASH within 12 months prior to randomization as reviewed by central 
pathologist with:  
• 
NASH activity score (NAS) of 4 or more 
• 
10% or more macrovesicular steatosis 
• 
cytologic ballooning score of at least 1 point 
• 
hepatic fibrosis of at least 1 point 
• 
hematoxylin and eosin (H&E) stained slides and/or paraffin block available for 
independent assessment 
4.   ALT > 40 U/L for women and > 60 U/L for men at screening and at least once in the 
previous 12 months. 
5. MRI with > 6% hepatic steatosis 
6. HbA1c of ≤ 9.0 
7. Lipid lowering agents (i.e. statins) and allowable antidiabetic treatment (i.e. metformin or 
sulfonylurea) must be stable at screening and during the study.  
8.  Agree to use of effective contraceptive measures if female of child bearing potential. 
8.2. Subject Exclusion Criteria 
1. The presence of any of the following will exclude a subject from study enrollment: Any 
chronic liver disease other than NASH (i.e., drug-induced, viral hepatitis, autoimmune 
hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, 
A1AT deficiency, Wilsons disease) 
2. Cirrhosis, as assessed clinically or histologically 
3. Presence of vascular liver disease 
4. BMI ≤ 25 kg/m2 
5. Excessive alcohol use (> 20 g/day) within the past 2 years 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 23 of 60 
6. AST or ALT > 250 U/L.   
7. Type 1 diabetes mellitus 
8. Bariatric surgery in the past 5 years. 
9. Weight gain or weight loss of > 5% in past 6 months or > 10% change in past 12 months.  
10. Contraindication to MRI 
11. Inadequate venous access 
12. HIV antibody positive, hepatitis B surface antigen positive (HBsAg), or HCV RNA 
positive.  
13. Receiving an elemental diet or parenteral nutrition 
14. Chronic pancreatitis or pancreatic insufficiency 
15. Any history of complications of cirrhosis (i.e. ascites, hepatic encephalopathy, or portal 
hypertensive bleeding), even if absent or optimized with medical management at time of 
screening 
16. Concurrent conditions: 
a) Inflammatory bowel disease 
b) Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24 
weeks of screening 
c) Ongoing infectious, immune mediated disease within previously 1 years 
d) Any malignant disease (other than basal cell carcinoma of the skin) within previous 2 
years 
e) Prior solid organ transplant 
f) Any other concurrent condition which, in the opinion of the investigator, could impact 
adversely on the subject participating or the interpretation of the study data. 
17. Concurrent medications including: 
a) Anti-NASH therapy(s) initiated after the liver biopsy diagnosing NASH.  Anti-NASH 
therapies include S-adenosyl methionine (SAMe), milk thistle, and vitamin E.   
b) Antidiabetic mediation which may impact NASH histology initiated after the liver 
biopsy diagnosing NASH including thiazolidinediones (glitazones), dipeptidyl 
peptidase 4 inhibitors (gliptins) or glucagon-like peptide 1 analogs.  
c) Immune modulatory agents including systemic steroids, methotrexate, anti-TNF-α 
therapies (infliximab, adalimumab, etanercept) or anti-integrin therapy (namixilab).  
d) UGT2B7 enzyme inhibitors (e.g., diclofenac, fluconazole, medroxyprogesterone 
acetate, meclofenamic acid) 
e) UGT2B7 inducers (e.g., dexamethasone, phenobarbital, rifampicin, omeprazole)  
f) Chronic opioid use within 28 days prior to screening (Day -28) 
18. Self-reported or known marijuana or illicit drug use 30 days before the screening 
19. The following laboratory abnormalities: 
a) HbA1c > 9.0% 
b) Neutrophil count  < 1.0 x 109 / L 
c) Platelets < 100  109 / L 
d) Hemoglobin < 10 g/dl 
e) Albumin < 3.5 g 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 24 of 60 
f) International normalized ratio (INR) > 1.3 
g) Any elevation of bilirubin above normal (unless Gilbert’s syndrome or extrahepatic 
source as denoted by increased indirect bilirubin fraction). 
h) Serum creatinine > 1.5 mg/dl 
i) Creatinine clearance ≤ 50 ml/minute calculated by Crockroft-Gault 
20. Pregnancy or breastfeeding. 
21. Women, of childbearing age, who are not willing to practice effective contraception (i.e., 
barrier, oral contraceptives, or past medical history of hysterectomy) for the 48-week 
duration of the trial and for 1 month after the last administration of the drug. Women with 
documented (not reported) oophorectomy or hysterectomy are considered sterile. 
Women with tubal ligation are at small risk and should have pregnancy test at screening.  
22. Participation in an investigational drug study within past 30 days. 
 
9. 
STUDY MEDICATION  
9.1 
Study Medication Identification  
Investigational drug supplies will be provided by TaiwanJ Pharmaceuticals and will consist of 
the following three treatment arms: 
1. 
Placebo tablet twice daily 
2. 
JKB-121 5mg tablet twice daily 
3. 
JKB-121 10mg tablet twice daily 
9.1.1 Investigational Drug 
JKB-121 is a tablet which contains nalmefene (as hydrochloride) in different strength of 5mg, 
10mg and with GRAS (generally recognized as safe) excipients.  The tablet is white to off white, 
round and plain biconvex tablet. 
9.1.2 Reference Drug:  
Placebo will be supplied as a similar appearing tablet which also contains lactose.  
9.2   Justification for the dose chosen   
JKB-121 is effective at a dose of 1 mg/kg in reducing elevated serum liver enzyme ALT in D-
Gal/LPS mouse model (Szabo et al. Alcohol Clin Exp Res 2005). Using the FDA guidelines 
(fda/cder/guidance/5541fnlcln1.doc 07/06/05, page 29), 1 mg/kg dose in mouse corresponds to 
6.4 mg for an 80 Kg patient. In light of these results, the JKB-121 doses at 5, and 10 mg bid 
have been chosen, based on safety and potential efficacy, as the ideal doses for this study. 
The overall previous human safety profile of chronically administered nalmefene is very positive. 
Trials on alcohol dependence were conducted with once or twice a day tablet, while those on 
pruritus were treated with tablet twice or three times a day. The duration of testing in at least 
one study in cholestatic pruritus patients lasted for over 26 months at 10 mg and higher twice 
daily, while maximal dose of 120 mg bid was given to 2 patients for 4 months. The daily 
administered doses in these trials were 2 to 12 times higher than the 5mg and 10 mg bid in 
proposed JKB-121 IND application (Refer to Investigational Brochure pages 15-17). 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 25 of 60 
 
9.3   Rationale for a placebo group 
In order to assess the efficacy of an agent in NASH, a placebo-arm is needed to determine its 
relative efficacy in improving NASH histology beyond that achieved with a placebo [24]. 
Currently, there are no FDA approved therapies for NASH. The recently completed PIVENS trial 
for NASH [25] did not find either vitamin E or pioglitazone to be uniformly effective. The study 
demonstrated that 43% of vitamin E treated patients and 34% of pioglitazone treated patients 
met a pre-determined histological endpoint compared to 19% of placebo treated patients (P = 
0.001 and P = 0.04 for each drug respectively) [25].  Previous non-randomized and pilot studies 
have shown the efficacy of several agents such as ursodiol [26] and betaine [27] in the 
treatment of NASH, but follow-up randomized, placebo controlled studies failed to show 
improvement in liver histology in patients with NASH beyond that observed in placebo groups. 
To have the highest quality of evidence to test our hypothesis, the proposed JKB-121 NASH 
trial is a randomized, double-masked, placebo-controlled study design. As there is no proven 
pharmacologic therapy for NASH, using a placebo for comparative purposes is justified. 
 
9.4 
Study Medication Packaging and Labeling 
Study drug will be labeled in accordance with GMP and all applicable regulations. 
The label will include full manufacturing details, storage instructions and caution statements. 
Study drug will be dispensed to subjects at each scheduled visit, or at specific pharmacy visits, 
according to the dispensing practices prevailing at the site pharmacy. 
Figure 1 
Sample Drug Bottle Label 
 
9.4.1 Storage and Stability 
Study medication must be stored according to labeled storage conditions, and in a secure place 
in the research facility.  This study product must not be used outside the context of this protocol.  
Under no circumstances should the investigator or site personnel supply product to other 


JKB121        
 
March 2, 2016 
TaiwanJ Pharmaceuticals  
         NASH Protocol 
Version 4.0 
Manal F. Abdelmalek, MD, MPH                         CONFIDENTAL 
 
  Page 26 of 60 
investigators or clinics, or allow the drug supplies to be used other than as directed by this 
protocol without prior authorization from TaiwanJ Pharmaceuticals. 
9.4.2 Drug Preparation/Administration/Dispensing 
Each patient will receive one bottle of study medication at each visit during the treatment period.  
Bottles will contain single panel label. One part of the label, containing study and patient 
information is attached to the carton.  Directions on the bottles will indicate the following:  
• 
JKB-121 is for oral use. 
• 
The tablet should be swallowed whole. 
• 
The tablet should not be divided or crushed because nalmefene may cause skin 
sensitivity when in direct contact with the skin Take one tablet within 12 hours of the 
initial dose, but no sooner than 8 hours after initial dose. 
 
9.5 
Drug Accountability 
Adequate records on receipt, use, return, loss or other disposition of medication must be 
maintained.  A specific drug accountability form supplied by TaiwanJ Pharmaceuticals or 
computer records used by the pharmacy at the investigational site, can be used to provide drug 
accountability information.  Drug compliance will be based on pill count.  Paper diaries will be 
provided to subjects, reviewed at each visit, signed by study coordinator or investigator. Other 
required data includes relevant dates, quantities, and patient identification (subject number and 
initials) for patients who receive study.  Patients will be instructed to return all unused study 
medication to the investigator, in the original bottles. 
At the end of the study, all unused products will be collected and counted by the local 
Investigational Drug Pharmacy monitor or designee and destroyed according to institutional 
pharmacy policies and procedures.  
 
10. 
SCHEDULE OF EVENTS 
10.1 
Tests and Evaluations 
No subject may be permitted to undergo any protocol-specified investigations or interventions in 
this study until they have provided a signed, dated, written informed consent.  
All tests and evaluations must be performed prior to that day’s administration of study drug 
treatment. Subjects should undergo all tests and evaluations specified in the protocol, 
regardless of whether they remain on study drug. Insofar as possible, all blood samples should 
be collected at approximately the same time of day in each visit, in order to minimize diurnal 
variation 
The required procedures for patient evaluation at each study visit are outlined in the study. 
Schedule of Visits and Procedures are in Sections 10.2 and detail items in section 10.3 through 
10.4.8.  Detailed instructions for specific procedures are presented in Section 11. 
 
10.2 
Schedule of Visits and Procedures:  Detailed in Table 10.2.1 
 


JKB121  
 
             Version 4.0 
TaiwanJ Pharmaceuticals                                                                                NASH Protocol 
March 2, 2016 
Manal F. Abdelmalek, MD                                                                                                            CONFIDENTAL    
 Page 27 of 60 
10.2.1. Visit Schedule Table 
 
Screening 
Period 
Enrollment 
Treatment period 
End of 
Treatment 
Follow-up  
Visit 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
up to 4 wks 
0 
2 
4 
8 
12 
16 
20 
24 
28 
Day (Visit window) 
-1 to -28 
1 
14 (±4) 
28 (±4) 56 (±4) 84 (±4) 112 (±4) 140 (±4) 
168 (±4) 
196 (±4) 
Determination of eligibility  
X 
X 
 
 
 
 
 
 
 
 
Review of medical history  
X 
X 
 
 
 
 
 
 
 
 
Obtain informed consent  
X 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
X 
X 
X 
X 
 
  
 
Managing drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum hCG (if applicable) 
X 
 
 
 
 
 
 
 
 
 
Urine hCG (if applicable)  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid panel 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Glycosylated hemoglobin  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
HOMA-IR 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
 
 
 
 
X 
 
 
X 
X 
Electrocardiogram 
X 
 
 
 
 
X 
 
 
X 
 
Liver biopsy (if prior biopsy > 12 mo) 
X 
 
 
 
 
 
 
 
 
 
PK study 
 
X* 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse events** 
 
X** 
X 
X 
X 
X** 
X 
X 
X** 
X 
 
 
 
 
 
 
 
 
 
 
 
MRI for hepatic steatosis 
X 
 
 
 
 
X 
 
 
X 
 
CK-18 
 
X 
 
 
 
X 
 
 
X 
X 
Stored serum for exploratory measures  
and noninvasive biomarkers of fibrosis 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
 
 
 
X 
* Frequent sampling PK study on Day 1 for Substudy subjects only.  All patients to have a pre-dose trough level drug measures (6 ml blood ) at treatment Weeks 8, 16, and 24 (Visits 4, 6, and 8). 
** Hospital Anxiety and Depression Scale and Columbia Suicide Severity Scale 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 28 of 60
10.3 Study Procedures 
Complete study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Table 10.2.1 and described in the text that follows.  
Any deviation from protocol procedures should be documented.  
 
10.3.1 Subject Enrollment and Treatment Assignment 
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug kit 
assignment from investigational drug pharmacy or IVRS/IWRS system. Patients will be stratified 
into treatment arms based diabetes status.  
 
10.3.2 Screening Period (within 4 weeks before randomization) 
Prior to performing any study procedures, an informed consent form will be reviewed and signed 
by each subject.  Subjects will be screened within 4 weeks before starting study treatment to 
determine eligibility for participation in the study, unless otherwise noted below.  Subjects who 
fail to meet eligibility due to an abnormal laboratory results (other than what is otherwise 
explained by NAFLD alone) may undergo retesting of the abnormal laboratory test during the 
screening window.  This will be done at the discretion of the investigator and with prior approval 
from the Sponsor or Medical Monitor.  
Sufficient time should be allowed for all screening laboratory studies to be resulted prior to 
scheduling subject for MRI testing.  The following will be performed and documented at 
screening:  
 Obtain subject screening number  
 Obtain medical history and complete physical examination 
 Record vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
 Record height, weight and body mass index 
 Study pathologist to review screening liver biopsy (within 12 months of screening) for 
confirmation and staging of NASH as defined by NASH Clinical Research Network 
(NASH CRN) Grading and Staging System [28]. 
 MRI to be performed and study radiologist to review and confirm > 6% hepatic steatosis 
for inclusion 
 Review concomitant medications that the subject has taken within 30 days prior to 
screening. 
 Assess and record pre-dosing signs / symptoms 
 Determine study eligibility 
 Electrocardiogram 
 Liver biopsy may be performed if subject has historical biopsy c/w NASH and biopsy is > 
12 months of screening or subject at increased risk for NASH (increased liver enzymes 
with > 3 features of metabolic syndrome) 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 29 of 60
 Urinalysis 
 Urine drug screen for amphetamine, cocaine and opiate drug screening 
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including:  alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), albumin, alkaline phosphatase, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), magnesium, phosphorus, potassium, sodium, total and direct bilirubin, 
protein, uric acid, and gamma-glutamyl transferase (GGT). 
3. Fasting glucose and insulin level for HOMA-IR 
4. Glycosylated hemoglobin 
5. Prothrombin time and International normalized ratio (INR) 
6. Serum pregnancy test (only for women of childbearing potential).  
7. HCV RNA 
8. HBsAg 
9. Serum and plasma samples for non-invasive biomarkers related to liver injury 
pathophysiology and/or TLR-4 pathway 
 Record any adverse events occurring after signing the consent form 
 
10.3.3 Enrollment Visit (Day 1, Visit 1) 
Subjects returning to the clinic for randomization at Day 1 must be in a fasted state for at least 8 
hours prior to sample collection prior dosing for this visit, which is a requirement for some of the 
blood test that will be performed as noted below.   
Subjects will be randomized to study drug kit assignment and receive their Subject Identification 
Number prior to the first dose of study drug being administered.  The following will be performed 
for all subjects who meet the inclusion criteria and not of the exclusion criteria 
 
Confirm that the subject continues to be eligible for participation 
 
Record vital signs 
 
 
Record weight 
 
Physical examination 
 
Hospital Anxiety and Depression Scal and Columbia Suicide Severity Scale 
Questionnaires. 
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including:  ALT, AST, albumin, alkaline phosphatase, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, sodium, total and direct bilirubin, protein, uric acid, 
and GGT. 
3. Fasting glucose and insulin level for HOMA-IR 
4. Lipid panel 
5. Glycosylated hemoglobin 
6. Urine pregnancy test (only for women of childbearing potential).  


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 30 of 60
7. Serum and plasma samples for non-invasive biomarkers related to liver injury 
pathophysiology and/or TLR-4 pathway 
8. ELF™ test—Subjects must be an a fasted state prior to the sample collection 
9. FibroSURE/ FibroMAX/ FibroTest—Subject must be in a fasted state prior to 
the sample collection 
10. Additional blood sample needs to be collected for pharmacokinetic study. 
 
Counsel subjects on weight loss, diet and exercise 
 
Record any adverse events occurring after signing of the informed consent form 
 
Record all medications that the subject has taken since prior visit  
 
Dispense study drug 
 
10.3.3.1 
PK 
Substudy 
Subjects 
Only: 
From 
volunteered 
subjects for 
intensive 
pharmacokinetic studies:  Blood samples will be obtained prior to 12 hour dosing (predose 
and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12,  and 24 (next day) hours post 
dose administration in three volunteered subjects from each treatment group (5 mg and 10 
mg bid).  Additional pre-dose blood sample for trough PK level at Day 1, weeks 8, 16, and 
24 will be collected for assessment of steady state PK analysis as well as biomarker study.  
Biosample collection and handling procedures will be detailed before the implementation of 
the study. These will be based on information obtained from a validated analytical method 
for nalmefene with respect to its stability, handling, and storage conditions of the 
biosamples.  
Six mL of blood will be collected from fasting (at least 8 hours) subjects on Day 1 prior to 
dosing, and during Visits 4, 6, and 8 for measurements of the plasma concentrations of JKB-
121. In a subset of volunteers who consent to participate in PK Substudy,blood samples will 
be collected on Day 1 pre-dose and at each sampling point post-dose for  pharmacokinetic 
evaluation as described in Section 10.3.2. 
 
10.4 
Treatment Assessments 
10.4.1 Visit 2 (Week 2 ± 4 days) 
Subject may be in a nonfasted state for this visit.  Starting with week 2, subjects will return to the 
investigative site every 4 weeks during the treatment phase of the protocol for 24 weeks.  
During the Week 2 visit (+/- 4 days), the subject will return to the investigational site and the 
following will be completed: 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 31 of 60
 
Verify the study drug was administered correctly 
 
Document drug accountability and any problems with drug administration in the source 
documents. 
 
Record vital signs 
 
Record weight 
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including:  ALT, AST, albumin, alkaline phosphatase, 
bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, 
LDH magnesium, phosphorus, potassium, sodium, total and direct bilirubin, 
protein, uric acid, and GGT. 
 
Counsel subjects on weight loss, diet and exercise 
 
Record any adverse events occurring after signing of the informed consent form 
 
Record all medications that the subject has taken since prior visit 
 
10.4.2 Visits 3, 4, 6 and 7 (week 4, 8, 16 and 20 ± 4 days) 
Subjects must be in a fasted state for at least 8 hours prior to sample collection at these visits, 
which is a requirement for some of the blood tests that will be performed as noted below.  The 
following will be performed for all subjects who meet the inclusion criteria and not of the 
exclusion criteria 
 
Verify the study drug was administered correctly 
 
Document drug accountability and any problems with drug administration in the 
source documents. 
 
Record vital signs 
 
Physical examination 
 
Record weight 
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including: ALT, AST, albumin, alkaline phosphatase, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, sodium, total and direct bilirubin, protein, uric acid, 
and GGT. 
3. Fasting glucose and insulin level for HOMA-IR 
4. Lipid panel 
5. Glycosylated hemoglobin 
6. Urine pregnancy test (only for women of childbearing potential).  
7. Additional trough (pre-dose) blood sample needs to be collected for 
pharmacokinetic study at visits 4 (week 8) and 6 (week 16). 
 
Counsel subjects on weight loss, diet, and exercise 
 
Record any adverse events occurring after signing of the informed consent form 
 
Record all medications that the subject has taken since prior visit 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 32 of 60
10.4.3 Visit 5 (week 12 ± 4 days)   
Subjects must be in a fasted state for at least 8 hours prior to sample collection at this visit, 
which is a requirement for some of the blood tests that will be performed as noted below:  
 
Verify the study medication  
 
Document drug accountability and any problems with drug administration in the 
source documents. 
 
Record vital signs 
 
Physical examination 
 
Record weight 
 
Electrocardiogram 
 
Hospital Anxiety and Depression Scale and Columbia Suicide Severity Scale 
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including: ALT, AST, albumin, alkaline phosphatase, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, sodium, total and direct bilirubin, protein, uric acid, 
and GGT.  
3. Fasting glucose and insulin level for HOMA-IR 
4. Lipid panel 
5. Glycosylated hemoglobin 
6. Urine pregnancy test (only for women of childbearing potential) 
7. Serum and plasma samples for non-invasive biomarkers related to liver 
injury pathophysiology and/or TLR 4 pathway 
8. ELF test—Subjects must be an a fasted state prior to the sample collection 
9. FibroSURE/ FibroMAX/ FibroTest—Subject must be in a fasted state prior to 
the sample collection  
10. Urinalysis  
11. Sample collection/storage for CK-18 and exploratory measures 
12. Perform MRI for quantitation of hepatic fat 
 
Counsel subjects on weight loss, diet and exercise 
 
Record any adverse events occurring after signing of the informed consent form 
 
Record all medications that the subject has taken since prior visit 
10.4.4 End of Treatment Visit 8 (week 24 ± 4 days) 
Subjects must be in a fasted state for at least 8 hours prior to sample collection at these visits, 
which is a requirement for some of the blood tests that will be performed as noted below.  If a 
subject has discontinued treatment, every attempt should be made to have the subject return to 
the site and complete the procedures / assessments that are required at the End of Treatment 
Visit (Week 24) and the Follow-up Visit (Week 28).  The following will be performed for all 
subjects who meet the inclusion criteria and not of the exclusion criteria 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 33 of 60
 
Verify the study drug was administered correctly 
 
Document drug accountability and any problems with drug administration in the 
source documents. 
 
Record vital signs 
 
Physical examination 
 
Record weight 
 
Electrocardiogram 
 
Urinalysis 
 
Hospital Anxiety and Depression Scale and Columbia Suicide Severity Scale 
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including:  ALT, AST, albumin, alkaline phosphatase, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, sodium, total and direct bilirubin, protein, uric acid, 
and GGT/ 
3. Fasting glucose and insulin level for HOMA-IR 
4. Lipid panel 
5. Glycosylated hemoglobin 
6. Urine pregnancy test (only for women of childbearing potential).  
7. Serum and plasma samples for non-invasive biomarkers related to liver injury 
pathophysiology and/or TLR-4 pathway 
8. ELF test—Subjects must be an a fasted state prior to the sample collection 
9. FibroSURE/ FibroMAX/ FibroTest—Subject must be in a fasted state prior to 
the sample collection 
10. Additional blood sample needs to be collected for pharmacokinetic study 
 
Counsel subjects on weight loss, diet and exercise 
 
MRI for quantification of hepatic fat 
 
Record any adverse events occurring after signing of the informed consent form 
 
Record all medications that the subject has taken since prior visit 
 
10.4.5 Follow-up Visit 9 (week 28 ± 4 days) and Exit Interview 
Subjects must be in a fasted state for at least 8 hours prior to sample collection at these visits, 
which is a requirement for some of the blood tests that will be performed as noted below.  If a 
subject has discontinued treatment, every attempt should be made to have the subject return to 
the site and complete the procedures / assessments that are required at the End of Treatment 
Visit (Week 24) and the Follow-up Visit (Week 28).  The following will be performed for all 
subjects who meet the inclusion criteria and not of the exclusion criteria 
 
Verify the study drug was administered correctly 
 
Document drug accountability and any problems with drug administration in the 
source documents. 
 
Record vital signs 
 
Physical examination 
 
Record weight 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 34 of 60
 
Complete blood samples for: 
1. Complete blood count with differential 
2. Blood chemistry including:  ALT, AST, albumin, alkaline phosphatase, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, sodium, total and direct bilirubin, protein, uric acid, 
and GGT. 
3. Fasting glucose and insulin level for HOMA-IR 
4. Lipid panel 
5. Glycosylated hemoglobin 
6. Urinalysis 
7. Urine pregnancy test (only for women of childbearing potential).  
8. Serum and plasma samples for non-invasive biomarkers related to liver injury 
pathophysiology and/or TLR-4 pathway 
9. ELF test—Subjects must be an a fasted state prior to the sample collection 
10. FibroSURE/ FibroMAX/ FibroTest—Subject must be in a fasted state prior to 
the sample collection 
 
Counsel subjects on weight loss, diet and exercise 
 
Record any adverse events occurring after signing of the informed consent 
formRecord all medications that the subject has taken since prior visit 
 
10.4.6 Assessments for Early Discontinuation from Study 
 
Subjects discontinuing early should have an End of Treatment Visit performed, if 
possible and then have a Follow-up Visit 4 weeks later 
 
10.4.7 Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances 
 
Intercurrent illness that would, in the judgment of the investigator, affect 
assessment of clinical status to a significant degree 
 
Any concern for drug-induced liver injury as defined by change from baseline 
liver aminotransferases according to the following criteria: 
• 
ALT or AST > 10 x ULN  
• 
ALT or AST > 5 x ULN for more than 2 weeks 
• 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 
• 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant abdominal pain, fever, rash or 
eosinophilia (> 5%).  
 
Unacceptable toxicity, as defined in the toxicity management section of the 
protocol, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the 
subject’s best interest. 
 
Subject request to discontinue for any reason 
 
Subject noncompliance 
 
Pregnancy during the study 
 
Sponsor discretion 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 35 of 60
 
Discontinuation of the study at the request of TaiwanJ. Pharmaceuticals,  
any Regulatory Authorities or an IRB/IEC.  
 
10.5 
Pregnancy 
An effective method of birth control must be used during the course of the study, in a manner 
such that the risk of birth control failure is minimized.  Prior to enrollment, study candidates who 
are women of childbearing potential or men whose partners are women of child bearing 
potential must be advised of the importance of avoiding pregnancy during trial participation and 
the potential risk factors for an unintentional pregnancy.  All women of childbearing potential 
must have a negative pregnancy test within 72 hours prior to receiving JKB-121 per the 
eligibility criteria.  The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of human chorionic gonadotropin (HCG).  If the pregnancy test is positive, the patient must 
not receive JKB-121 and may not be enrolled in the study. 
Women of childbearing potential is defined as females who have experienced menarche and 
who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy), are not postmenopausal (defined as amenorrhea 12 consecutive 
months or women on hormone replacement therapy with a documented serum follicle 
stimulating hormone level > 35 mIU/mL).  Even women who are using oral, implanted, or 
injectable contraceptive hormones or mechanical products, such as an intrauterine device or 
barrier methods (diaphragm, condoms, spermicides), to prevent pregnancy, who are practicing 
abstinence, and who have a sterile partner (e.g., vasectomy) should be considered of child 
bearing potential. 
All study participants should be instructed to contact the investigator immediately if they suspect 
they or their partner might be pregnant (e.g., missed or late menstrual period) at any time during 
study participation. 
In the case of pregnancy, JKB-121 will be discontinued and protocol-required procedures for 
study discontinuation and follow-up must be performed on the patient unless contraindicated by 
pregnancy (e.g., x-ray studies).  Other appropriate pregnancy testing and assessment as would 
otherwise be standard for care should follow. 
In the event of a subject becoming pregnant during the study, they must immediately and 
permanently discontinue study drug. However, such subjects should be encouraged to continue 
completing all scheduled visits, evaluations and assessments as per the protocol, with the 
exception of radiological assessments such as MRI.  
Every attempt should be made to ascertain the outcome of the pregnancy. The investigator will  
report the pregnancy to Medpace Clinical Safety within 24 hours of being notified. Medpace 
Clinical Safety will then forward the Exposure In Utero form to the investigator for completion.  
In the event of a subject’s partner becoming pregnant, the subject may continue to receive study 
drug per protocol, but all efforts should be made to ascertain the outcome of the partner’s 
pregnancy. The pregnancy should be reported to the CRO on the appropriate form as described 
above. 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 36 of 60
10.6 
Occurrence of Hepatocellular Carcinoma in Patients with NAFLD 
Any liver tumor occurrence will, in all cases, be diagnosed at the site according to local standard 
of care practices. In the event of a suspected tumor, subjects should undergo any confirmatory 
investigations that may be required. 
These confirmatory investigations should be performed as soon as possible and in all cases 
within 21 days of diagnosis. All confirmatory investigations, including any additional scans that 
may be required, will be the responsibility of the study site. 
If, after performing any confirmatory investigations that may be required, the diagnosis of 
malignancy is confirmed, the subject should immediately and permanently cease administration 
of study drug. Subjects with confirmed malignancy may then receive any other therapies or 
treatment modalities that their attending physicians consider appropriate.  
However, such subjects should be encouraged to remain in the study and complete all 
scheduled visits, evaluations and assessments as per the protocol. If the subject elects not to 
participate in remaining visits, they should be strongly encouraged to complete a ‘premature 
withdrawal’ visit or early discontinuation visit as detailed in Section 10.4. 
 
10.7 
Death 
In the event of a death on study, the investigator should complete the ‘death’ page of the Case 
report form (CRF), including the date and reason of death. All attempts should be made to 
secure access to any autopsy findings and to retrieve the patient compliance diary. The cause 
of death must be immediately notified to the CRO as a serious adverse event as described in 
Section 12.1 and, if applicable, to institutional review boards and / or local regulatory authorities, 
even if the death is considered to be due liver-related mortality. 
 
10.8 
Withdrawal of Consent 
If a subject voluntarily elects to discontinue participation in the study, administration of study 
drug must be immediately and permanently ceased. However, such subjects should be 
encouraged to continue completing all scheduled visits, evaluations and assessments as per 
the protocol. If a subject elects not to participate in remaining visits, they should be strongly 
encouraged to complete a ‘premature withdrawal’ visit, encompassing: 
 
Recording of adverse events 
 
Review of concomitant medications and therapies 
 
Physical examination and vital signs 
Completion of end of treatment visit at time of withdrawal 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 37 of 60
11.0  STUDY ASSESSMENTS 
11.1   Clinical Efficacy  Endpoints 
The clinical endpoints of this study is time to remission (TTR). TTR is defined as time in weeks 
from randomization to improvement in hepatic steatosis as measured b MRI and liver function 
remission as defined as two consecutive ALT values within normal range (< 20 U/mL for woman 
and < 30 U/L for men) or 20% reduction from the baseline during study period.  
11.2 Safety Assessments 
11. 2.1 Clinical Safety Assessments 
Physical examination and vital signs will be assessed monthly. Subjects must sit quietly for 5 
minutes before having their pulse and blood pressure recorded. 
All adverse events will be collected from the onset of study drug treatment. Serious adverse 
events are to be reported immediately to the CRO. Pre-dosing signs and symptoms will be 
recorded in the screening section of the CRF. 
11.2.2 Laboratory Safety Assessments 
All laboratory tests following randomization will be performed by a study approved laboratory 
service. Samples will be drawn at sites and forwarded under appropriate conditions to the 
approved laboratory. The laboratory will communicate all test results to site study personnel. 
The Laboratory Assessing Physician will immediately notify sites of any values which lie outside 
pre-specified ranges. Screening samples, prior to initiation of study drug, may be analyzed at 
site. 
Sites will be immediately notified of any test results that lie outside of pre-specified ranges. Site 
personnel will not be expected to transcribe results from the laboratory into the CRF, although 
abnormal results that are considered clinically significant should be entered in the CRF as 
adverse events. Screening assessments, prior to initiation of study drug, may be performed at 
sites. Sites are discouraged from performing additional routine investigations locally, but site 
personnel are permitted to perform any investigations at any time that may be necessary to 
safeguard patient welfare.  
11.3 Pharmacokinetics and Exposure/Response Assessments 
Pharmacokinetics of JKB-121 will be assessed by measuring the plasma concentrations of JKB-
121 at the steady state (Day 1) in three subjects in each treatment dose, i.e. 5 mg and 10 mg 
twice daily with the agreement of the patients. The exposure/response relationship of JKB-121 
will be explored by measuring the plasma concentrations of JKB-121 in the sparse samples 
collected in all subjects and correlating them with the changes from baseline in ALT. 
11.4 Communication of Laboratory Results to Sites 
All laboratory results will be communicated directly to sites by fax or other means.  All laboratory 
results which equate to an NCI CTCAE grade 3 or above toxicity will be escalated for internal 
medical review by the contract research organization and/or medical monitor. 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 38 of 60
11.5 Study interventions 
Peripheral blood collection: Blood will be collected venipuncture.  Serum and plasma will be 
collected for assessing non-invasive biomarkers related to NAFLD / NASH as well as liver 
fibrosis (i.e. CK-18, adiponectin, leptin, TNF-α, TGF-β, hyaluronic acid, and MMP-2).  MRI 
Procedures as detailed in Section 11.3. 
Magnetic Resonance Imaging (MRI)  
The purpose of the magnetic resonance imaging (MRI) exam is to quantify the hepatic proton 
density fat fraction non-invasively in participants who participate in the study.  The fat fraction is 
the proportion of mobile protons in liver tissue attributable to fat and thus is a non-invasive MR-
based assessment of liver triglyceride concentration. To quantify the fat fraction, the MRI exam 
will use a fast spoiled gradient recalled echo sequence that uses a low flip angle to reduce T1 
bias, acquires multiple echoes after a single excitation to measure and correct for T2*decay, 
and uses spectral modeling to address fat-water and fat-fat signal interference effects. The 
proposed MRI technique measures hepatic fat fraction accurately in human subjects at 1.5T or 
3T and across different vendors. The technique provides high within-examination and between-
examination precision. Linearity is maintained across the entire relevant biological range from 
<1% to >40% hepatic fat fraction. The technique is robust to minor variations in acquisition 
parameters, including those that may be encountered during usage in a clinical trial.  The echo 
sequence proposed for imaging-based hepatic fat fraction quantification can be implemented on 
any up-to-date clinical scanner and thus can be used at any clinical centers with access to such 
a scanner. Moreover, the technique is imaging based and covers the whole liver, thus providing 
information on both the quantity and distribution of hepatic fat fraction. MRI is currently the most 
accurate noninvasive technique to quantify hepatic fat fraction. 
Percutaneous Liver Biopsy  
The purpose of the liver biopsy within 12 months of screening is to ensure the presence of 
NASH and the absence of cirrhosis prior to randomization.  The histologic features of liver injury 
(ie. necroinflammation, ballooned hepatocytes) and hepatic fibrosis is best assessed by liver 
biopsy as this remains the “gold-standard” for grading and staging NASH.  The ideal target 
population “at risk” for disease progression, and thus, the appropriate cohort of subjects for 
investigational therapies are those patients with histologic evidence of NASH with hepatic 
fibrosis. Due to the early phase of investigation and the interdeterminate safety of JKB-121 in 
patietns with cirrhosis, subjects with histologic features of cirrhosis (stage 4 fibrosis) and/or any 
history of hepatic decompensation attributable to cirrhosis will be excluded. The screening liver 
biopsy should be considered for patients with known history of NASH and for whom historical 
liver biopsy is in excess of 12 months.  Given the dynamic changes in NASH which may occur 
due to life-style changes alone and the reassurance of targeting patient with histologic features 
of NASH, only patients with biopsy-proven NASH within 12 months of screening will be enrolled. 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 39 of 60
12. 
ADVERSE EVENTS: DEFINITIONS AND MANAGEMENT 
At the time of written informed consent, the subject must be given the name and telephone 
number of personnel at the study site who can be contacted in the event of an emergency or to 
report any medical symptom or untoward medical occurrence that is of concern to the subject. 
Investigators will closely monitor the subject for adverse events.  
All adverse events reported by the subject or observed by study site personnel from time of 
informed consent until completion of the study or premature withdrawal must be recorded in the 
subject’s CRF as per the CRF instructions. Adverse events are to be recorded regardless of 
relationship to study drug. Information to be recorded will include, but not be limited to, 
relationship of the event to study drug and severity of the event. These terms are defined in 
Sections 12.4.5.5 &12.4.5.6 below. Specific instructions for management of adverse events will 
be reviewed with study site personnel by the Clinical Monitor prior to study start. 
12.1 
Definitions 
12.1.1 Pre-Dosing Signs and Symptoms 
For the purposes of this study, any sign (including a clinically significant laboratory result) or 
medical diagnosis noted by medical personnel, or symptom reported by the subject that occurs 
from the time the subject signs the informed consent to the start of study drug treatment is 
considered to be  preexisting and should not be reported as an adverse event unless it worsens 
subsequent to the start of study drug treatment. 
12.1.2 Adverse Events 
For the purposes of this study, any sign (including a clinically significant laboratory result) or 
medical diagnosis noted by medical personnel, or symptom reported by the subject, regardless 
of relationship to investigational drug, that is treatment-emergent is considered to be an adverse 
event.   
TaiwanJ Pharmaceuticals defines treatment-emergent are defined as follows:  
1) 
Has onset any time after the start of investigational drug treatment OR 
2) 
Has worsened since the event was previously reported (this includes worsening 
of signs, symptoms, abnormal laboratory values, or diagnoses that were present 
prior to the first dose of investigational drug but then worsened any time after the 
start of investigational drug treatment) 
 
12.1.3 Classification of Events as Serious 
As soon as a subject has given written informed consent to participate in the study, any 
abnormal sign (including the clinical manifestations of an abnormal laboratory result) or medical 
diagnosis noted by medical personnel, or symptom reported by the subject regardless of 
whether or not the subject has received investigational drug is to be classified by the 
investigator as either a serious or non-serious event using the following definition: 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 40 of 60
Events are classified as serious if they meet any of the following criteria (in accordance with 21 
United States Code of Federal Regulations Part 312.32 and the recommendations of the 
International Conference on Harmonization (ICH) [Federal Register, October 7, 1997, Vol 62, 
No. 194, pp 52239-45]): 
 
Any death 
 
Any life-threatening event, i.e., an event that places the subject, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
 
Any event that requires or prolongs in-patient hospitalization  
 
Any event that results in persistent or significant disability/incapacity 
 
Any congenital anomaly/birth defect diagnosed in a child of a subject who 
participated in this study and received investigational drug 
 
Other medically important events that in the opinion of the investigator may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above  
A new diagnosis of cancer should also be considered serious and should be reported on the 
Serious Adverse Event (SAE) form. In the case of a death on study, the immediate cause of 
death should be notified as an SAE. 
Overdose and pregnancy are not in and of themselves adverse events or SAEs. However, if 
there are subsequent adverse events or SAEs as a result of overdose or pregnancy, these 
events should be captured on the adverse event and SAE forms, as appropriate.  
Note: A pre-scheduled or elective procedure or a routinely scheduled treatment shall not be 
considered an SAE, even if the subject is hospitalized, provided the site stipulates that:  
a) the pre-scheduled elective procedure or routinely scheduled treatment was scheduled 
prior to obtaining the subject’s consent to participate in the clinical trial, 
b) the condition requiring the pre-scheduled elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress between the subject’s 
consent to participate in the clinical trial and the time of the procedure or treatment, and  
c)   the pre-scheduled elective procedure or routinely scheduled treatment is the sole reason 
for admission and intervention.  
However, if complications occur during procedures or surgeries, they are considered to be 
adverse events and should be recorded. Any adverse event classified as serious must be 
reported immediately to the CRO via the electronic data capture (EDC) system. \. 
In the event of a medical emergency when knowledge of the subject’s treatment assignment 
would influence the subject’s clinical care, the principal investigator must contact the Medical 
Monitor to describe the emergency. Only under these circumstances will unblinding of the 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 41 of 60
subject’s treatment assignment be authorized. Refer to Section 12.4 for emergency decoding 
procedures. 
12.3.1 Immediate Reporting of Serious Events 
The study sponsor must immediately be made aware of events classified as SERIOUS in order 
to adhere to all applicable laws and regulations for reporting serious events. Therefore, it is the 
investigator’s responsibility to ensure the following: 
Initial Reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to Medpace Clinical Safety within 24 hours 
of the knowledge of the occurrence (this refers to any adverse event that meets any of the 
aforementioned serious criteria). All serious adverse events that the investigator considers 
related to study drug occurring after the 30-day follow-up period must be reported to the 
Sponsor. 
To report the SAE, complete the SAE form electronically in the EDC system for the study. 
When the form is completed, Medpace 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 Safety at  
medpace-safetynotification@medpace.com or call the Medpace SAE hotline (phone number 
listed below), and fax the completed paper SAE form to Medpace (fax number 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. 
 
Safety Contact Information: 
Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until 
the condition becomes chronic in nature, stabilizes (in the case of persistent impairment) 
or the subject dies. 
 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE 
form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., subject discharge summary or autopsy reports) to Medpace Clinical 
Safety via fax or e-mail. If it is not possible to access the EDC system, refer to the 
procedures outlined above for initial reporting of SAEs.  
The investigator must also notify the local review committee, (ie. Institutional Review Board 
(IRB) or Ethics Committee (EC) as per local IRB/EC requirements. Documentation of these 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 42 of 60
reports must be kept in the site’s study files and will be checked routinely by the Clinical 
Monitor.  
Any serious event that has onset of informed consent that is unresolved at the time the subject 
permanently discontinues the study must be followed until the event resolves or until the 
subject’s clinical course has stabilized. 
12.3.2 Reporting of Serious Events to Regulatory Agencies 
After receipt of a serious adverse event report, TaiwanJ Pharmaceuticals (or CRO) will code 
and classify the serious adverse event and inform regulatory authorities, as necessary, within 
the required time frames. TaiwanJ Pharmaceuticals or the CRO will complete written safety 
reports with the assistance of the investigator and other study site personnel, and will submit the 
reports to regulatory authorities, as needed.12.3.3 Guidelines for Determining Relationship 
Causality of Adverse Events 
Not related  Any event which does not follow a reasonable temporal sequence from 
administration of study drug AND that is likely to have been produced by the subject’s 
clinical state or other modes of therapy administered to the subject 
Related 
An event that follows a reasonable temporal sequence from administration of 
study drug OR that follows a known response pattern to the suspected drug OR that is 
improved by stopping the drug or reducing the dose but recurs with re-challenge AND that 
cannot readily be explained by the subject’s clinical state or other modes of therapy 
administered to the subject 
12.3.4 Guidelines for Determining Severity of Adverse Events 
All adverse events and serious adverse events will be graded according to the NCI CTCAE 
v3.0. Any event not listed in the CTCAE will be graded as follows:-  
Grade 1 
Mild Adverse Event: symptom(s) barely noticeable to subject or does not make 
subject uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) but may be given because of personality of 
subject. 
Grade 2 
Moderate Adverse Event: symptom(s) of a sufficient severity to make subject 
uncomfortable; performance of daily activity is influenced; subject is able to continue in 
study; treatment for symptom(s) may be needed. 
Grade 3 
Severe Adverse Event: symptom(s) cause severe discomfort; symptoms cause 
incapacitation or significant impact on subject’s daily life; severity may cause cessation of 
treatment with investigational drug; treatment for symptom(s) may be given and/or subject 
hospitalized. 
Grade 4 
Life-Threatening or Disabling Adverse Event: symptom(s) symptoms pose 
significant risk to life or risk of permanent disability. 
Grade 5 
Death 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 43 of 60
12.4 Toxicity Management Guidelines 
The toxicity management will be based on DAIDS AE Grading system,  
Hepatic toxicity: 
ALL patients will have increased liver enzymes at baseline. Liver function tests will monitored 
with each visit.  For any elevated ALT 5-10.0 X ULN (Grade 3 or 4) on study drug, repeat testing 
and evaluation will be performed in 1 week. Treatment will be interrupted for drug-related Grade 
3 AE until their AE Grade is less than 3.  Liver function tests and assessment will be performed 
weekly to ensure resolution of Grade 3 AE.  Study drug may be resumed following confirmation 
of resolution of Grade 3 AE or if investigator confirms AE is keeping with patient’s underlying 
NASH. The investigator must assess whether or not Grade 3 AE is clinically or not clinically 
significant in the setting of NASH and in reference to baseline ALT levels.  Increases in liver 
enzymes > 3 x subject’s baseline will prompt retesting and patient examination within 1 week.  
Increases in liver enzymes > 5 x subject’s baseline will prompt immediate drug discontinuation 
and withdrawal from study.  For non-drug related Grade 3 AE, Investigator will perform further 
clinical management based on subject’s clinical condition and/or other biochemistry results.  
DAIDS 
Grading 
Lab Value 
 
Clinical management 
ALT * 
 
AST 
 
Bilirubin 
(total) 
 
INR 
Non Drug Related 
Drug Related 
Grade 1 1.25-2.5 x 
ULN 
and/or 1.25-2.5 x 
ULN 
and/or 1.1-1.5 x 
ULN 
 
and/or 
1.2-1.3 
Non treatment modification 
Grade 2 
2.6-5.0 x 
ULN 
and/or 2.6-5.0 x 
ULN 
and/or 1.6-2.5 x 
ULN 
 
and/or 
1.4-1.5 
Non treatment modification 
Grade 3 5.1-10.0 x 
ULN 
and/or 5.1-10.0 x 
ULN 
and/or 2.6-5.0 X 
ULN 
 
and/or 
 
1.5-2.0 
Further clinical 
management will 
be judged by 
Investigator 
Treatment 
interruption may 
be suggested by 
Investigator  
Grade 4 
> 10.0 x 
ULN 
and/or > 10.0 x 
ULN 
and/or 
> 5.0 x 
ULN 
 
and/or 
 
> 2.0 
Treatment termination and withdraw 
* Subjects with elevated ALT > 10.0 ULN will be withdrawn from this study. 
Discontinuation of treatment should be considered if: 
• 
ALT or AST > 10 x ULN 
• 
ALT or AST > 5 x ULN for more than 2 weeks 
• 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 
• 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant abdominal pain, fever, rash or eosinophilia (> 5%).  
 
Other toxicities 
For other grade ≥ 3 toxicities, if they are considered drug-related adverse event, treatment 
discontinuation will be suggested based on investigator’s judgment. If they are considered non 
drug-related AE, further clinical management will be conducted based on Investigator’s clinical 
judgment. 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 44 of 60
All adverse events occurring during the study and follow-up period should be followed until fully 
resolution or the event is considered chronic or stable. 
 
12.5 
Emergency Procedures 
In the event of a medical emergency (i.e., an event that requires Taiwan’s immediate attention 
regarding the treatment of the subject, operation of the clinical study, and/or use of study drug), 
study site personnel will immediately contact the Medical Monitor.  
The investigator will ensure that all study site personnel responsible for the subject’s medical 
care are familiar with the Medical Emergency Call number, its location and have access to it.  
Prior to the start of dosing at the site, the Clinical Monitor will review medical emergency call 
procedures with study personnel. 
12.5.1 Emergency Decoding 
As each subject is randomized into the study, his/her treatment assignment will be individually 
determined using IVRS/IWRS. This information will be kept in a secured fashion. 
In the event of a medical emergency when knowledge of the subject’s treatment assignment 
would influence the subject’s clinical care, the principal investigator must contact the Medical 
Monitor to describe the emergency. Only under these circumstances will TaiwanJ and/or 
Medical Monitor authorize unbinding of the subject’s treatment assignment. 
If a subject’s treatment assignment is unblended for a medical emergency or for regulatory 
purposes, that subject must immediately and permanently discontinue treatment with study drug 
but should remain in the study and continue the protocol specified follow-up evaluations. 
If a subject’s treatment assignment is accidentally unblended, that subject should continue 
treatment with study drug and remain in the study. The data will be included in the intent-to-treat 
data set. 
The investigator must document the reasons for the unbinding in the subject’s CRF and is 
strongly encouraged not to divulge the subject’s treatment assignment to any individuals not 
directly involved in managing the medical emergency. 
13. 
 STATISTICAL CONSIDERATIONS 
13.1 
Sample Size Calculation 
The study will need to screen approximately 100 subjects to enroll 60 patients with biopsy-
proven NAFLD who meet the study inclusion / exclusion criteria.  With 20 subjects per treatment 
group, the study will not be powered for efficacy assessment between the two doses. Based on 
precision analysis, the proposed sample size will provide the maximum error (defined as the 
half-way of the width of the 95% confidence interval for the difference (change in liver-
biochemistry) between two doses (5 mg twice daily vs 10 mg twice daily dose) allowed.  


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 45 of 60
Presuming the observed difference between two treatment groups is 20%, then the 95% 
confidence interval for the true mean is given by (2.5%, 37.5%) with 20 subjects in each group.  
13.2 General Statistical Methodology 
Prior to database lock, a final detailed Statistical Analysis Plan (SAP) will be available. Results, 
when available, will be summarized into tabulations, case listings, plots, and histograms for 
comparison. 
Three major study populations are planned, modified intent-to-treat (met) population, per 
protocol (PP), and safety populations.  
Baseline variables will be ascertained for conformity among all stratification factors.  All baseline 
analysis will be based on the met population. In the met population, the subjects will be counted 
in the treatment group to which they were randomized, as long as they received at least one 
dose of study medication and have at least one return visit.   
The safety analysis will be based on the safety population. In the safety population, subjects will 
be counted in the group in which they were treated.  To assess the robustness of the study 
outcomes, a sensitivity analysis will be performed on all pertinent major efficacy variables. The 
sensitivity analysis will include and exclude patients with major study deviations and early 
withdrawals to assess the impact on the study endpoints.  
The criteria may be amended prior to unbinding of the treatment assignment for the analysis of 
data. Reasons for changes may include study conduct changes, protocol amendments, or 
changes in the appropriateness of the criteria, which may be assessed based on review of 
blinded data. 
For all analyses, all missing values due to patient early termination from the study will be not 
imputed.    
For each patient, the Baseline values will be defined as those values recorded at Day 1 prior to 
dosing or Screening, as appropriate. 
All hypotheses will be tested for statistical significance with two-tailed p-values. Results of all 
tests will be considered statistically significant if their p-value is less than or equal to 0.05, 
except for results of the tests for interaction will be considered statistically significant if the p-
value is less than or equal to 0.10.  
13.2.1. Analysis of Continuous Variables 
Continuous variables will be summarized with descriptive statistics (i.e., sample size, mean, 
standard deviation, minimum, maximum, median, and quintiles). The continuous variables will 
be analyzed using a general linear model to test the treatment effect of the changes from pre- to 
post-treatment [29]. 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 46 of 60
If the data are not transformable to symmetry, rank methods such as the Friedman rank test will 
be used. The possible transformation will be applied on the original pre- and post-treatment 
values only. 
13.2.2. Analysis of Categorical Variables 
Categorical variables will be summarized with descriptive statistics (i.e., sample size, frequency 
counts, percentage, and 95% confidence interval) and will be analyzed with CMH test adjusting 
for tumor size [30]. 
13.2.3. Analysis of Time-to-Event Variables  
Time to event variables (such as time to treatment success) will be assessed by survival 
analysis. The cumulative portion of the time-to-event variables of each treatment group will be 
determined by Kaplan-Meier estimates. Fisher's exact or chi-square test will be used to 
compare the portion of patients with the event occurring at different time intervals throughout the 
study period.  
When it is beneficial, a more precise comparison of the treatment effects will be analyzed by 
fitting a Cox proportional hazard model to assess the benefit-risk ratio.   
13.4. Analyses 
13.4.1. Efficacy Analyses  
13.4.1.1. Primary Efficacy Endpoint 
The primary endpoint of this study is assessment of safety and the change in hepatic steatosis 
as measured by MRI. 
13.4.1.2. Secondary Efficacy Endpoint 
The secondary endpoints of this study are: 
 Time to remission (TTR) is defined as time, in weeks, from randomization to liver 
function remission as defined as two consecutive ALT values within normal range (< 40 
IU/mL) during study period.  The Cox proportional hazard model with treatment and 
diabetes status as factors, will be used.  
 
ALT changes from baseline. The statistical analysis will the same as the one 
used for the primary efficacy endpoint 
 
Changes in metabolic markers and NASH related biomarkers 
13.4.2. Timing of Analyses 
 All endpoints will be analyzed at the time point when all subjects have completed the 
treatment program and at the time when all subjects have completed the study. 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 47 of 60
13.4.3. Safety Analyses 
13.4.3.1. Primary Safety Endpoints 
The rate of patients by treatment groups who experience (1) one or more adverse events (AEs); 
(2) SAEs; and, (3) AEs leading to discontinuation of study medication (4) adverse events in 
each grade of the Common Terminology Criteria for Adverse Events (CTCAE) v3.0, published 
by the National Cancer Institute will be displayed. Treatment effect will be explored by 
inspection of observed rates for the dose groups within each treatment regimen. 
Adverse events will be summarized in frequency counts by treatment group using current 
Medical Dictionary for Regulatory Activities (Mudra) terms. Summaries of AEs will be displayed:  
1. All AEs by system organ class regardless of the relationship to the study treatment;  
2. By treatment relationship (“possible, probable or definite” related vs. not related); and 
3. By maximum severity (mild, moderate, or severe). 
13.4.3.2. Other Safety Endpoints 
Change from Baseline for each interval-valued laboratory test, vital signs, and other safety 
related variables will be summarized regarding each scheduled visit. Shift tables will be 
presented for laboratory values based on the central laboratory normal ranges.  
All abnormalities deemed clinically significant by the investigator will be presented in detail and 
listed by patient identifier. The patients who have no laboratory results at the Screening or post-
Baseline visit will be excluded from the change from Baseline and shift table analyses. 
Treatment effect will be explored by inspection of observed means or rates for the dose groups 
within each treatment regimen. 
13.4.4. Sensitivity Analysis 
Sensitivity analyses of the primary efficacy variable will be conducted as described below to 
assess the robustness of the primary analysis results. In the sensitivity analysis, decreases in p-
values due to drops in power (decreasing sample sizes and increasing standard errors) will be 
distinguished from changes in the effect size. The criterion that defines substantial changes will 
be those changes that alter the effect parameter by more than one standard error. 
The sensitivity analysis will use the following algorithm: 
1. 
Subjects who are excluded from per protocol population and subjects who withdraw 
from the study at or after interim analysis will be considered as a responders or non-
responders at the end of the study according to their response status at the time of 
withdrawal. 
2. 
Subjects who drop out at the time are considered as non-responders at the time of 
withdrawal. Subjects who withdraw early, regardless of their final outcomes, will be 
considered as non-responders at the end of study 
3. 
Remaining patients assigned to treatment will be considered as responders at the end 
of study if the withdrawals occur at the end of the study and they are also responders 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 48 of 60
at the time of withdrawal and at the last visit prior to the withdrawal.  Remaining JKB-
121 patients who drop out of the study at or after interim analysis will be considered as 
JKB-121 non-responders at the end of the study if they don’t satisfy the described 
above. 
4. 
Sensitivity analysis will be performed to assess the impact of patients with significant 
protocol violations possibly leading to improved efficacy, e.g. use of concomitant 
medications.  Definitions of significant protocol violations will be described in detail in 
the statistical analysis plan before the study blind is broken. 
13.5 
Interim Analysis Plan   
No interim analysis is planned for this study, 
13.6 
Medical Monitoring and Independent Data Review Board 
A Medical Monitor, independent of TaiwanJ Pharmaceuticals, will be appointed to monitor safety 
and efficacy of the study. The medical monitor will be a hepatologist experienced in clinical trials 
in the field of NASH. The medical monitor will have statistical expertise and/or access to 
biostatistician with the contacted CRO to monitor safety as assess reported adverse events.  An 
independent Data Review Board consisting of a hepatologist and biostatistician unblinded to 
treatment allocation will be compiled to assess safety events in treatment groups as compared 
to placebo. 
 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Monitoring visits to the trial site will be made periodically during the trial to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of 
agreement with data on case report forms. The investigator/institution guarantees direct access 
to source documents by TaiwanJ Pharmaceuticals and appropriate regulatory authorities. 
The trial site may also be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), to quality assurance audits performed by TaiwanJ Pharmaceuticals, 
and/or to inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
 
15. 
DATA HANDLING AND RECORD KEEPING 
15.1 
Case Report Forms  
A case report form is required and should be completed for each included subject. The 
completed original case report forms are the sole property of TaiwanJ Pharmaceuticals and 
should not be made available in any form to third parties, except for authorized representatives 
of appropriate regulatory authorities, without written permission from TaiwanJ Pharmaceuticals. 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 49 of 60
It is the investigator's responsibility to ensure completion and to review and approve all case 
report forms. Case report forms must be signed by the investigator. These signatures serve to 
attest that the information contained on the case report forms is true. 
At all times, the investigator has final responsibility for the accuracy and authenticity of all 
clinical and laboratory data entered on the case report forms. Subject source documents are the 
physician's subject records maintained at the study site. In most cases, the source documents 
will be the hospital's or the physician's chart. In cases where the source documents are the 
hospital or the physician's chart, the information collected on the case report forms must match 
those charts. In some cases, a portion of the source documents for a given subject may be the 
case report forms. 
15.2 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or TaiwanJ Pharmaceuticals the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., case report forms and hospital records), all original signed 
informed consent forms, copies of all case report forms and detailed records of treatment 
disposition. The records should be retained by the investigator according to local regulations or 
as specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to TaiwanJ Pharmaceuticals. The investigator must obtain TaiwanJ’s written 
permission before disposing of any records. 
 
16. 
ETHICS 
16.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to obtain approval of the trial protocol and subsequent 
protocol amendments, if applicable, from the IRB/IEC. All correspondence with the IRB/IEC 
should be retained in the Investigator File. Copies of IRB/IEC approvals should be forwarded to 
TaiwanJ Pharmaceuticals. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the investigator must notify the IRB/IEC and the local TaiwanJ Pharmaceutical site 
personnel (see protocol cover page) in writing within 5 working days after the implementation. 
16.2 
Ethical Conduct of the Trial 
The trial will be performed in accordance with International Conference on Harmonization Good 
Clinical Practice guidelines and applicable regulatory requirements. 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 50 of 60
16.3 
Subject Information and Consent 
It is the responsibility of the investigator to give each subject (or the subject’s acceptable 
representative) full and adequate verbal and written information regarding the objective and 
procedures of the trial and the possible risks involved. This information must be provided to the 
subject prior to undertaking any trial-related procedure.  
The subjects must be informed about their right to withdraw from the trial at any time. Written 
subject information (included as an appendix to the protocol) must be given to each subject 
before any trial-related procedure is undertaken. The written subject information must not be 
changed without prior approval by TaiwanJ Pharmaceuticals and the IRB/IEC. Furthermore, it is 
the responsibility of the investigator to obtain signed informed consent or witnessed verbal 
consent according to applicable regulations, from all subjects, and a signature from the persons 
conducting the informed consent discussion, prior to undertaking any trial-related procedure. 
17. 
SPONSOR DISCONTINUATION CRITERIA 
TaiwanJ Pharmaceuticals reserves the right to discontinue the trial prior to inclusion of the 
intended number of subjects, but intends only to exercise this right for valid scientific or 
administrative reasons. After such a decision, the investigator must contact all participating 
subjects within 1 month. All study materials must be collected and all case report forms 
completed to the greatest extent possible. 
18. 
DISSEMINATION AND PUBLICATION OF RESULTS  
The conditions regulating dissemination of the information derived from this clinical study are 
described in the Clinical Trial Agreement. 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 51 of 60
19.0     REFERENCES: 
 
1. 
Clark, J.M., F.L. Brancati, and A.M. Diehl, Nonalcoholic fatty liver disease. 
Gastroenterology, 2002. 122(6): p. 1649-57. 
2. 
Lim, Y.S. and W.R. Kim, The global impact of hepatic fibrosis and end-stage liver 
disease. Clin Liver Dis, 2008. 12(4): p. 733-46, vii. 
3. 
Ludwig, J., et al., Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto 
unnamed disease. Mayo Clin Proc, 1980. 55(7): p. 434-8. 
4. 
Park, S.K., et al., Clinical availability of nonalcoholic fatty liver disease as an early 
predictor of type 2 diabetes mellitus in Korean men: 5-year prospective cohort study. 
Hepatology, 2013. 57(4): p. 1378-83. 
5. 
Williams, C.D., et al., Prevalence of nonalcoholic fatty liver disease and nonalcoholic 
steatohepatitis among a largely middle-aged population utilizing ultrasound and liver 
biopsy: a prospective study. Gastroenterology, 2011. 140(1): p. 124-31. 
6. 
Ismail, M.H., Nonalcoholic fatty liver disease and type 2 diabetes mellitus: the hidden 
epidemic. Am J Med Sci, 2011. 341(6): p. 485-92. 
7. 
Adams, L.A., et al., A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J 
Gastroenterol, 2004. 99(12): p. 2365-8. 
8. 
Zein, C.O., et al., Pentoxifylline improves nonalcoholic steatohepatitis: a randomized 
placebo-controlled trial. Hepatology, 2011. 54(5): p. 1610-9. 
9. 
Broering, R., M. Lu, and J.F. Schlaak, Role of Toll-like receptors in liver health and 
disease. Clin Sci (Lond), 2011. 121(10): p. 415-26. 
10. 
Petrasek, J., T. Csak, and G. Szabo, Toll-like receptors in liver disease. Adv Clin Chem, 
2013. 59: p. 155-201. 
11. 
Tsukumo, D.M., et al., Loss-of-function mutation in Toll-like receptor 4 prevents diet-
induced obesity and insulin resistance. Diabetes, 2007. 56(8): p. 1986-98. 
12. 
Jia, L., et al., Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and 
insulin resistance. Nat Commun, 2014. 5: p. 3878. 
13. 
Vila, I.K., et al., Immune cell Toll-like receptor 4 mediates the development of obesity- 
and endotoxemia-associated adipose tissue fibrosis. Cell Rep, 2014. 7(4): p. 1116-29. 
14. 
Abu-Shanab, A. and E.M. Quigley, The role of the gut microbiota in nonalcoholic fatty 
liver disease. Nat Rev Gastroenterol Hepatol, 2010. 7(12): p. 691-701. 
15. 
Compare, D., et al., Gut--liver axis: the impact of gut microbiota on non alcoholic fatty 
liver disease. Nutr Metab Cardiovasc Dis, 2012. 22(6): p. 471-6. 
16. 
Miura, K. and H. Ohnishi, Role of gut microbiota and Toll-like receptors in nonalcoholic 
fatty liver disease. World J Gastroenterol, 2014. 20(23): p. 7381-7391. 
17. 
Machado, M.V. and H. Cortez-Pinto, Gut microbiota and nonalcoholic fatty liver disease. 
Ann Hepatol, 2012. 11(4): p. 440-9. 
18. 
Park, J.S., J.H. Seo, and H.S. Youn, Gut microbiota and clinical disease: obesity and 
nonalcoholic Fatty liver disease. Pediatr Gastroenterol Hepatol Nutr, 2013. 16(1): p. 22-
7. 
19. 
Brun, P., et al., Increased intestinal permeability in obese mice: new evidence in the 
pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol, 
2007. 292(2): p. G518-25. 
20. 
Ley, R.E., et al., Microbial ecology: human gut microbes associated with obesity. Nature, 
2006. 444(7122): p. 1022-3. 
21. 
Paik, Y.H., et al., Toll-like receptor 4 mediates inflammatory signaling by bacterial 
lipopolysaccharide in human hepatic stellate cells. Hepatology, 2003. 37(5): p. 1043-55. 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 52 of 60
22. 
Amaia Oregui, C.C., Eric Norris, Shengzhong Cui, Ed Wu, Mark G. Clemens, A TLR4 
antagonist decreases hepatic inflammatorion in response to endotoxin in fatty livers, in 
AASLD. 2012: Boston, MA. 
23. 
Day, S.A., et al., Opioid-like compound exerts anti-fibrotic activity via decreased hepatic 
stellate cell activation and inflammation. Biochem Pharmacol, 2011. 81(8): p. 996-1003. 
24. 
Loomba, R., et al., Placebo in nonalcoholic steatohepatitis: insight into natural history 
and implications for future clinical trials. Clin Gastroenterol Hepatol, 2008. 6(11): p. 
1243-8. 
25. 
Sanyal, A.J., et al., Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N 
Engl J Med, 2010. 362(18): p. 1675-85. 
26. 
Lindor, K.D., et al., Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: 
results of a randomized trial. Hepatology, 2004. 39(3): p. 770-8. 
27. 
Abdelmalek, M.F., et al., Betaine for nonalcoholic fatty liver disease: results of a 
randomized placebo-controlled trial. Hepatology, 2009. 50(6): p. 1818-26. 
28. 
Kleiner, D.E., et al., Design and validation of a histological scoring system for 
nonalcoholic fatty liver disease. Hepatology, 2005. 41(6): p. 1313-21. 
29. 
Steele, R.G.D., Torrie, J.H., Analysis of variance: I. The one-way classification, in 
Principles and Procedures of Statistics. , edited by Steele, R.G.D., Torrie, J.H. New 
York: McGraw-Hill Book Company, Inc, 1980. 
30. 
Agresti, A., Categorical Data Analysis. . New York: John Wiley & Sons, Inc. , 1990. 
 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 53 of 60
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
Protocol Number  JKB-121-001 
Protocol Version: 4.0 (Amendment 1) 
Protocol Final Date: 2, March 2016 
Title: A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II trial of JKB-
121 in Treating Subjects with Nonalcoholic Steatohepatitis (NASH) 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol. I 
will also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with good clinical practices and the applicable laws and 
regulations. I will accept the Sponsor or designee overseeing of the study. I will abide by the 
publication plan set forth in my agreement with the Sponsor. I will promptly submit the protocol to 
applicable ethical review board(s). I confirm that if I or any of my staff are members of the ethical 
review board, we will abstain from voting on this protocol. 
Investigator Name: 
 
 
Name of Facility: 
 
 
 
 
Address of Facility: 
 
 
 
Telephone: 
 
 
Investigator Signature: 
 
 
Investigator Title: 
 
 
Date: 
 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 54 of 60
APPENDIX I 
 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by 
the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, 
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA 
General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General Assembly, 
Washington DC, USA, October 2002 (Note of Clarification added) 55th WMA General 
Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 59th WMA General 
Assembly, Seoul, Republic of Korea, October 2008 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013  
 
Preamble  
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  The Declaration is intended to be 
read as a whole and each of its constituent paragraphs should be applied with 
consideration of all other relevant paragraphs.  
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
 
General Principles  
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.”  
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty.  
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects.  
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality.  
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights.  


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 55 of 60
8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects.  
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research 
subjects must always rest with the physician or other health care professionals and 
never with the research subjects, even though they have given consent.  
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment.  
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional.  
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research.  
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects.  
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured.  
 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and 
burdens. Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research subjects.  
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. Measures to minimize the risks must be 
implemented. The risks must be continuously monitored, assessed and documented by 
the researcher.  
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be 
satisfactorily managed.   
When the risks are found to outweigh the potential benefits or when there is conclusive proof 
of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study.  


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 56 of 60
Vulnerable Groups and Individuals  
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. All vulnerable groups and 
individuals should receive specifically considered protection.  
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research.  
 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.  
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts of 
interest, incentives for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the research 
study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions.  
 
Research Ethics Committees  
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects 
set forth in this Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by 
the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
 
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 57 of 60
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information.  
 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in 
a research study unless he or she freely agrees.  
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-
written consent must be formally documented and witnessed. 
 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study.  
 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship.  
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorized representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden.  
29. When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must 
seek that assent in addition to the consent of the legally authorized representative. The 
potential subject’s dissent should be respected.  
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 58 of 60
that prevents giving informed consent is a necessary characteristic of the research  
group. In such circumstances the physician must seek informed consent from the legally 
authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative.  
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship.  
32. For medical research using identifiable human material or data, such as research on 
material or data contained in bio banks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee.  
 
Use of Placebo  
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or  
 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not 
be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention.  
 
Extreme care must be taken to avoid abuse of this option.  
 
Post-Trial Provisions  
34. In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be disclosed to 
participants during the informed consent process.  
 
Research Registration and Publication and Dissemination of Results  
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject.  
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 59 of 60
a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration 
should not be accepted for publication.  
 
Unproven Interventions in Clinical Practice  
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorized representative, 
may use an unproven intervention if in the physician's judgment it offers hope of saving 
life, re-establishing health or alleviating suffering. This intervention should 
subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made 
publicly available.  
 
 


JKB121                                                                                                                                    March 2, 2016 
TaiwanJ Pharmaceuticals                                  NASH Protocol                                                  Version 4.0 
Manal F. Abdelmalek, MD, MPH                          CONFIDENTAL 
 
 Page 60 of 60
APPENDIX II 
Histological Scoring System for Nonalcoholic Fatty Liver Disease 
Components of NAFLD Activity Score (NAS) and Fibrosis Staging 
 
NAS Components (see scoring interpretation) 
Item 
Score 
Extent 
Definition and Comment 
Steatosis 
0 
<5% 
Refers to amount of surface area involved by 
steatosis as evaluated on low to medium 
power examination; minimal steatosis (<5%) 
receives a score of 0 to avoid giving excess 
weight to biopsies with very little fatty change 
1 
5-33% 
 
2 
>33-66% 
 
3 
>66% 
 
Lobular 
Inflammation 
0 
No foci 
Acidophil bodies are not included in this 
assessment, nor is portal inflammation 
1 
<2 foci/200x 
 
2 
2-4 foci/200x 
 
3 
>4 foci/200x 
 
Hepatocyte 
Ballooning 
0 
None 
 
1 
Few balloon cells 
The term "few" means rare but definite 
ballooned hepatocytes as well as cases that 
are diagnostically borderline 
2 
Many cells/prominent 
ballooning 
Most cases with prominent ballooning also 
had Mallory's hyalin, but Mallory's hyaline is 
not scored separately for the NAS 
Fibrosis Stage (Evaluated separately from NAS) 
Fibrosis 
0 
None 
 
1 
Perisinusoidal or 
periportal 
 
1A 
Mild, zone 3, 
perisinusoidal 
"delicate" fibrosis 
1B 
Moderate, zone 3, 
perisinusoidal 
"dense" fibrosis 
1C 
Portal/periportal 
This category is included to accommodate 
cases with portal and/or periportal fibrosis 
without accompanying 
pericellular/perisinusoidal fibrosis 
2 
Perisinusoidal and 
portal/periportal 
 
3 
Bridging fibrosis 
 
4 
Cirrhosis 
 
Total NAS score represents the sum of scores for steatosis, lobular inflammation, and ballooning, 
and ranges from 0-8. Diagnosis of NASH (or, alternatively, fatty liver not diagnostic of NASH) 
should be made first, then NAS is used to grade activity. In the reference study, NAS scores of 0-2 
occurred in cases largely considered not diagnostic of NASH, scores of 3-4 were evenly divided 
among those considered not diagnostic, borderline, or positive for NASH. Scores of 5-8 occurred in 
cases that were largely considered diagnostic of NASH 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, 
PARALLEL-GROUP, PHASE II TRIAL OF JKB-121 FOR THE 
TREATMENT OF NONALCOHOLIC STEATOHEPATITIS (NASH) 
 
 
Protocol Number: 
JKB-121-001 
Duke IRB Protocol Number:  
Pro00062677 
FDA IND Number: 
124,082 
Study Medication:  
JKB-121 
Sponsor: 
Investigator Initiated Study 
Current Protocol: 
V4.0 / March 2, 2016 
 
 
 
 
SAP: 
V1.0 / March 31, 2017 
 
NCT02442687 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 2 of 20 
 
Protocol: A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II 
trial of JKB-121 for the Treatment of Nonalcoholic Steatohepatitis (NASH) 
 
Protocol Number: 
JKB-121-001 
Current Protocol: 
V4.0 / March 2, 2016 
SAP: 
V1.0 / March 31, 2017 
 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
 
 
 
 
 
Miriam Zangmeister, MS 
Project Statistician 
Medpace 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Rong Zhou, PhD 
Program Statistician 
Medpace 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Manal F. Abdelmalek, MD, MPH 
Principle Investigator 
Duke University 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Edwin Wu, PhD 
Strategic Advisor 
TaiwanJ Pharmaceuticals 
 
Date 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 3 of 20 
 
TABLE OF CONTENTS 
1 
SUMMARY OF CHANGES ........................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................... 5 
3 
STUDY OBJECTIVES .................................................................................................................... 5 
3.1 
Primary Objective .................................................................................................................. 5 
3.2 
Secondary Objectives ............................................................................................................. 5 
3.3 
Exploratory Objective ............................................................................................................ 5 
4 
STUDY OVERVIEW ...................................................................................................................... 6 
4.1 
Study Design .......................................................................................................................... 6 
4.2 
Randomization and Treatments .............................................................................................. 6 
5 
EFFICACY ENDPOINTS ............................................................................................................... 7 
5.1 
Primary Efficacy Endpoint ..................................................................................................... 7 
5.2 
Secondary Efficacy Endpoints ............................................................................................... 7 
5.3 
Other Efficacy Endpoints ....................................................................................................... 8 
6 
STATISTICAL METHODOLOGY ................................................................................................ 8 
6.1 
Sample Size Determination .................................................................................................... 8 
6.2 
Baseline, Endpoint, and Other Statistical Considerations ...................................................... 9 
6.3 
Analysis Populations ............................................................................................................ 10 
6.3.1 
Full Analysis Set Population ................................................................................... 10 
6.3.2 
Modified Intent-to-Treat Analysis Population ........................................................ 10 
6.3.3 
Safety Population .................................................................................................... 10 
6.3.4 
Per Protocol Population ........................................................................................... 10 
6.3.5 
PK Substudy Population.......................................................................................... 11 
6.4 
Subject Disposition .............................................................................................................. 11 
6.5 
Demographic and Baseline Characteristics .......................................................................... 11 
6.6 
Medical History .................................................................................................................... 11 
6.7 
Prior and Concomitant Medications ..................................................................................... 11 
6.8 
Study Medication Exposure and Compliance ...................................................................... 12 
6.9 
Efficacy Analysis ................................................................................................................. 13 
6.9.1 
Primary Efficacy Endpoint ...................................................................................... 13 
6.9.2 
Secondary Endpoints ............................................................................................... 14 
6.9.2.1 
ALT Remission .................................................................................................. 14 
6.9.2.2 
Liver Function .................................................................................................... 16 
6.9.2.3 
Other Endpoints .................................................................................................. 16 
6.10 Pharmacokinetic Analysis .................................................................................................... 16 
6.10.1 Sample Collections for Pharmacokinetic Analysis ................................................. 16 
6.10.2 Pharmacokinetic Variables ...................................................................................... 17 
6.10.3 Pharmacokinetic Summary and Analysis ................................................................ 18 
6.11 Safety Analyses .................................................................................................................... 18 
6.11.1 Adverse Events ........................................................................................................ 18 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 4 of 20 
 
6.11.2 Clinical Laboratory Evaluations .............................................................................. 19 
6.11.3 Vital Signs and ECG ............................................................................................... 20 
6.11.4 Other Safety Parameters .......................................................................................... 20 
7 
GENERAL INFORMATION ........................................................................................................ 20 
7.1 
Statistical Software............................................................................................................... 20 
 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 5 of 20 
 
1 
SUMMARY OF CHANGES 
SAP Version History 
Version Date 
Description of Changes 
1.0 
March 31, 2017 
Original Document 
2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a description of the statistical and 
pharmacokinetic (PK) methods and procedures to be implemented for the analyses of data 
from TaiwanJ Pharmaceuticals Protocol JKB-121-001.  Any deviations from this analysis 
plan will be substantiated by sound statistical/PK rationale and will be documented in the 
final clinical study report. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily 
and 10 mg twice daily) in reducing liver fat compared to placebo. 
3.2 
Secondary Objectives 
The secondary objectives are: 
 Determine the pharmacokinetic profile of JKB-121 in nonalcoholic steatohepatitis 
(NASH) 
 Assess the impact of treatment with JKB-121 on metabolic markers 
 Assess the impact of treatment on liver enzymes (serum alanine aminotransferase 
[ALT]) over 24 weeks. 
 Establish the recommended dose for future NASH treatment studies. 
 To evaluate changes of NASH related biomarkers such as adiponectin, leptin, ghrelin, 
tumor necrosis factor alpha (TNF-alpha), TGF-beta, hyaluronic acid and matrix 
metallopeptidase 2 (MMP-2). 
3.3 
Exploratory Objective 
Investigate the impact of treatment of potentially relevant inflammatory and metabolic 
biomarkers associated with NASH. 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 6 of 20 
 
4 
STUDY OVERVIEW 
4.1 
Study Design 
This is a randomized, double-blind, placebo controlled, parallel-group, phase II trial of 
JKB-121 in treating subjects with biopsy-proven NASH. 
Subjects will be randomized at study entry to placebo twice daily, 5 mg twice daily, or 10 mg 
twice daily of JKB-121 orally to improve NASH with regard to biochemical and MRI/MRS 
features of NASH in a 1:1:1 ratio. 
 Treatment Group 1: placebo twice a day orally 
 Treatment Group 2: 5mg of JKB-121 twice a day orally 
 Treatment Group 3: 10 mg of JKB-121 twice a day orally 
The maximum time on study drug for each subject is 24 weeks with an additional 4 weeks of 
follow-up. 
This allocation is shown diagrammatically below: 
 
4.2 
Randomization and Treatments 
Patients will be randomized in the order in which they are enrolled into this double-blind 
study by using a computer-generated randomization schedule. TaiwanJ Pharmaceuticals 
prepared the schedule prior to the start of the study. This number will designate which 
allocated treatment a patient will receive. The randomization schedule will be a ratio of 1:1:1 
to one of the following three treatment groups: 
 JKB-121 5 mg tablet twice daily orally 
 JKB-121 10 mg tablet twice daily orally 
 Placebo as tablet twice daily orally 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 7 of 20 
 
Treatment allocation will be stratified by known diagnosis of diabetes status. Nondiabetic 
status will be defined as HbA1c ≤ 6.0 and absence of any medications to treatment diabetes. 
Diabetic status will be defined as HbA1c > 6.0 and/or requiring medication for treatment of 
diabetes mellitus. 
Subjects who are withdrawn from the study will not be replaced. 
Until formal conclusion of the study, subjects, investigators and all site study personnel will 
be remain blinded as to treatment allocation, except in the event of a medical emergency 
which necessitates unblinding. 
5 
EFFICACY ENDPOINTS  
5.1 
Primary Efficacy Endpoint 
Mean and absolute changes from baseline in the percentage fat content of the liver measured 
by magnetic resonance imaging (MRI) at week 24. 
5.2 
Secondary Efficacy Endpoints 
 Mean and absolute changes from baseline in the percentage fat content of the liver 
measured by magnetic resonance imaging (MRI) at week 12. 
 Time to remission (TTR) defined as the time in weeks from randomization to liver 
function remission as defined as two consecutive ALT values within normal range 
(<20 U/L for women and <30 U/L for men). The time of the first of the two 
consecutive ALT values within normal range will be used as the TTR. 
 Percentage of subjects reaching liver function remission as defined as two 
consecutive ALT values within normal range (<20 U/L for women and <30 U/L for 
men). 
 Percentage of subjects at each scheduled visit whose ALT level is within normal 
range (<20 U/L for women and <30 U/L for men). 
 Percentage of subjects whose ALT level is within normal range (<20 U/L for women 
and <30 U/L for men) at any time within the following time intervals which will be 
derived using actual study days: 
o Baseline to Week 12 
o Week 12 to Week 24 
 Percentage of subjects achieving a 20% reduction in ALT from baseline at any time 
during the study period. 
 Change from baseline in serum ALT at each scheduled visit. 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 8 of 20 
 
 Serum aspartate aminotransferase (AST), ALT, and gamma-glutamyl transpeptidase 
(GGT) at each scheduled visit and the corresponding changes from baseline. 
All endpoints which define the normal range as <20 U/L for women and <30 U/L for men 
will be repeated with the normal range defined as <40 U/L. 
5.3 
Other Efficacy Endpoints 
 Metabolic Marker Endpoints 
o Body mass index (BMI) at each scheduled visit and the corresponding 
changes from baseline. 
o HbA1c and the homeostatic model assessment of insulin resistance (HOMA-
IR) at each scheduled visit and the corresponding changes from baseline. 
o Serum lipid profile (total cholesterol, triglycerides, low density lipoprotein 
[LDL], and high density lipoprotein [HDL]) at each scheduled visit and the 
corresponding changes from baseline. 
 Biomarker Endpoints 
o Biomarkers such as adiponectin, leptin, ghrelin, TNF-alpha, TGF-beta, 
hyaluronic acid and MMP-2 at each scheduled visit and the corresponding 
changes from baseline. 
 Exploratory Outcome Measures 
o Mean serum concentrations of lipopolysaccharide (LPS), c-reactive protein 
(CRP), cytokeratin (CK)-18 fragments, proinsulin c-peptide, glucagon-like 
polypeptide (GLP-1) and adiponectin. 
o Relative levels of inflammatory cytokines, interferon gamma (IFN-γ), and 
TNF-alpha 
o Relative levels of regulatory T cells in the peripheral blood mononuclear cells 
(PBMC) samples including CD4, CD8, CD 25, Fox P3, NKT, and CD62 T 
cells. 
6 
STATISTICAL METHODOLOGY 
6.1 
Sample Size Determination 
An approximate total of 60 subjects will be enrolled. Subjects will be randomized into three 
treatment groups in a ratio of Group 1 (5 mg twice daily): Group 2 (10 mg twice daily): 
Group 3 (placebo twice daily) = 1:1:1. No empirical power calculation is performed. The 
sample size is based on the best medical judgment. 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 9 of 20 
 
The power to detect a difference between placebo and active treatment with respect to change 
from baseline in liver fat content and serum ALT has been determined for a sample size of 20 
patients per arm to assess safety and potential efficacy. Fat quantification by MRI is very 
sensitive with as small as a 5% detectable change in fat quantification. 
Further, since the endpoint is the change from baseline, plausible estimates of the degree of 
correlation between pre-and post-baseline measurements will be incorporated into the 
variance estimates. Given the wide range of results observed in the literature, several “what-
if” scenarios were examined. As such, the current sample size was considered sufficient for 
the exploratory objectives of the study for the given range of plausible treatment effects and 
variance estimates. Due to the exploratory objects of the protocol, no adjustment for the two 
co-primary endpoints was made. Additionally, there will be no adjustments for multiple 
comparisons between the 3 treatment groups. 
Assuming the observed difference between two treatment groups is 20%, then the 95% 
confidence interval for the true mean is given by (2.5%, 37.5%) with 20 subjects in each 
group. 
Fat Liver Content Change from Baseline: 
The current sample size of 20 subjects per group should yield approximately 85% power to 
detect a treatment effect of at least ~ 5% with respect to the difference in the mean change 
from baseline between one of the JKB-121 treatment groups and placebo 
ALT change from Baseline: 
The current sample size of 20 subjects per group should yield approximately 73% power to 
detect a treatment effect of at least 30 U/L assuming a SE of 50 U/L (α= 0.05; two tailed; 
unpaired t-test). The SD of 50 U/L for the change from baseline endpoint was derived 
assuming SDs of 40 for the pre-and post-baseline measurements with a correlation of 0.25. 
Sample size and power estimates have not been adjusted for multiple comparisons or 
multiple endpoints, dropouts or stratifications. 
The analysis of each primary endpoint will be based on a linear model that incorporates the 
baseline measures as a covariate, the stratification factor and randomization treatment group. 
Pairwise comparisons of each active treatment group to control will be conducted vial linear 
contrasts. 
6.2 
Baseline, Endpoint, and Other Statistical Considerations 
The clinical statistical analyses will be performed by Medpace. 
Baseline will be the measurement at Day 1. If missing, the last valid measurement on or prior 
to the first date administration of study medication will be used as baseline. 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 10 of 20 
 
Unless specified otherwise, the order of the columns in descriptive summaries will be 
placebo, JKB-121 5 mg, JKB-121 10 mg, and total. 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
used to summarize the continuous efficacy and safety data by treatment group. The count and 
frequency will be used to tabulate the categorical measurements. 
Scheduled visits will be used according to their visit label. Unscheduled visits will be used if 
the scheduled visit is unavailable and the unscheduled visit is within the visit window. The 
window is defined as the halfway point between the previous (or subsequent) scheduled visit 
and the expected day of the visit.  
Data will be used as it is reported. Last observation carried forward (LOCF) or multiple 
imputation may be used when specified. 
6.3 
Analysis Populations 
6.3.1 
Full Analysis Set Population 
The Full Analysis Set Population includes all subjects who received at least one dose of 
study medication. Only subjects with clear documentation that no study medication was 
received may be excluded. The Full Analysis Set Population will be the primary population 
for the efficacy analyses. In the event of allocation errors, subjects will be analyzed for 
efficacy according to the treatment to which they were randomized. 
6.3.2 
Modified Intent-to-Treat Analysis Population 
The Modified Intent-to-Treat (mITT) Population will consist of all patients who receive at 
least one dose of study medication, have a valid baseline and at least 1 post-baseline MRI or 
ALT assessment. In the event of allocation errors, subjects will be analyzed for efficacy 
according to the treatment to which they were randomized. 
6.3.3 
Safety Population 
The Safety Population includes all subjects who received at least one dose of study 
medication. Only subjects with clear documentation that no study medication was received 
may be excluded. In the event of treatment allocation errors, subjects will be analyzed for 
safety according to the treatment group they received. 
6.3.4 
Per Protocol Population 
The Per Protocol Population includes all subjects who complete 24 weeks of study treatment 
and have MRI and ALT measured at baseline and at week 24 and no major protocol 
violations, determined prior to break of the treatment blind. 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 11 of 20 
 
6.3.5 
PK Substudy Population 
The PK Substudy Population will consist of all patients who receive at least one dose of 
JKB-121, have no significant deviation in dosing that will affect PK evaluation, and have 
sufficient evaluable plasma PK concentrations to calculate PK parameters. 
6.4 
Subject Disposition 
Subject disposition information will be summarized by randomized treatment group and 
total. Number and percentage of subjects who are randomized, who are in each analysis 
population, who complete the study, and who withdraw early from the study will be 
presented. The primary reasons for early withdrawals will also be tabulated. The number of 
randomized patients within each treatment group will be used as the denominator for the 
percentage calculations.  
6.5 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively by treatment 
group and total for the Safety Population and mITT Population. 
Demographic and baseline characteristics include, but are not limited to, age at informed 
consent, gender, race, ethnicity, body weight, body mass index (BMI), and baseline efficacy 
measures (percentage fat content of the liver measured by MRI, ALT, AST, GGT). 
Randomization stratum (diabetic status) will also be summarized. Continuous variables will 
be summarized by descriptive statistics. Categorical variables will be summarized by the 
number and percentage of patients in corresponding categories. The baseline is defined in 
Section 6.2, Baseline, Endpoint, and Other Statistical Considerations. 
6.6 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The numbers and percentages of subjects in each treatment group and in total 
having medical/surgical history will be summarized by system organ class and preferred term 
for the Safety Population. All medical history will be listed. 
Liver histology scoring (steatosis grade, ballooning, lobular inflammation, fibrosis stage, and 
NAS score) will be summarized with numbers and percentages of subjects in each treatment 
group. 
6.7 
Prior and Concomitant Medications 
Medication start and stop dates that are recorded on the Prior & Concomitant Medications 
case report form will be used to determine whether the medications are prior or concomitant 
to the study treatment. Concomitant medications are defined as those used on or after the first 
dose of study treatment. Prior medications are defined as those used prior to and stopped 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 12 of 20 
 
before the first dose of study treatment. All prior and concomitant medication verbatim terms 
will be coded using the World Health Organization Drug Dictionary. The numbers and 
percentages of subjects taking concomitant medications in each treatment group and in total 
will be summarized by anatomic and therapeutic chemical term and preferred term for the 
Safety Population. All prior and concomitant medications will be listed. 
6.8 
Study Medication Exposure and Compliance 
Subjects’ exposure to randomized study medication will be summarized with descriptive 
statistics for the Safety Population.  
Days of exposure is defined as: 
date of last dose of study drug – date of first dose + 1 
If a subject has been instructed to stop dosing for any portion of the study, for example due to 
AE, then the days of interruption will be subtracted from the days of exposure. The days of 
interruption is defined as: 
last date of interruption – first date of interruption + 1 
If the last dose of study drug is missing, the date of completion/early termination will be 
used. In addition, a contingency table will be provided to display the number and percentage 
of subjects in each treatment group with exposure in the following categories: 1-56 days (1-8 
weeks), 57-112 days (8-16 weeks), 113-168 days (16-24 weeks), 169-196 days (24-28 
weeks), and ≥197 days (>28 weeks). 
Summary statistics will be presented for percent compliance to study medication by 
treatment group and total. The count and percentage of subjects will also tabulated by groups 
with overall compliance < 80%, 80% to 120%, and > 120%.  
The percent compliance to study medication will be calculated as: 
100 × 
total number of tablets dispensed – total number of tablets returned 
days of exposure × 2 – days of interruption 
If a subject has been instructed to take half dose (1 tablet per day) for any portion of the 
study, for example due to AE, then the percent compliance will be calculated as: 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 13 of 20 
 
100 × 
total number of tablets dispensed – total number of tablets returned 
days of regular exposure × 2 + days of half dose exposure – days of interruption 
6.9 
Efficacy Analysis 
6.9.1 
Primary Efficacy Endpoint 
The change from baseline at Week 24 of the percentage fat content of the liver measured by 
MRI will be analyzed by analysis of covariance (ANCOVA) in the Full Analysis Set 
Population with treatment group and diabetes stratum as factors and baseline MRI value as a 
covariate. The comparisons will be (1) between the response of the JKB-121 5 mg group and 
the response of the Placebo group and (2) between the response of the JKB-121 10 mg group 
and the response of the Placebo group. The least-squares means, standard errors, and 95% 
confidence intervals for each treatment group and for each comparison will be provided. The 
two-sided p-values testing for significance within treatment group change from baseline and 
comparisons between treatment groups will be presented. No multiple comparisons 
techniques will be applied. The sample SAS code can be found below: 
*********************************************************************** 
Note:  
  TREATMENT = 0, (placebo), 1 (JKB-121 5 mg), 2 (JKB-121 10 mg) 
  DIABSTAT = nondiabetic, diabetic 
  BASE: baseline percentage fat content of the liver measured by MRI 
  CHG: change from baseline to Week 24 in the percentage fat content of  
       the liver measured by MRI 
**********************************************************************; 
proc glm data=MRI; 
  class TREATMENT DIABSTAT; 
  model CHG = TREATMENT DIABSTAT BASE / ss1 ss3; 
  means TREATMENT; 
  lsmeans TREATMENT / cov stderr pdiff cl; 
  estimate "JKB-121 5 mg : Placebo" TREATMENT -1 1 0; 
  estimate "JKB-121 10 mg : Placebo" TREATMENT -1 0 1; 
run; 
The data and model residuals will be inspected for normality and homogeneity of variance, 
and a logarithmic transformation will be applied if necessary. 
To handle missing results such as due to early termination, multiple imputation will be 
performed. The detailed steps are specified below. 
Step 1: Prepare the data for multiple imputation. Since there is only one intermediate 
visit (Week 12) for MRI collection, the missing pattern would be monotone if 
endpoint values are not available. 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 14 of 20 
 
Step 2: PROC MI would be used to impute the missing MRI values. The treatment, 
diabetes stratum, and MRI values at baseline and all available post-baseline visits 
would be included. The SAS code can be found as below: 
PROC MI data=MRI out=MI_OUT nimpute=1000 seed=12345 minimum=0; 
  var TREATMENT DIABSTAT BASE WEEK12 WEEK24; 
  mcmc initial=em prior=jeffreys nbiter=200 niter=500 chain=single; 
run; 
Step 3: Endpoint would be calculated by averaging the values of Week 12 and Week 
24. For each imputation, the ANCOVA model specified above would be performed to 
compare the change from baseline to Week 24 endpoint between JKB-121 5 mg 
group the placebo group, and between JKB-121 10 mg group and the placebo group.  
Step 4: The procedure PROC MIANALYZE would be used with estimated statistics 
(“least-squares means”) and associated standard error from each simulation for 
overall testing results. The overall least-squares means, standard errors, 95% 
confidence intervals, and p-values would be reported. 
The same analysis will be repeated for the mITT and Per Protocol Populations. Multiple 
imputation will not be performed for the Per Protocol Population; only subjects with both 
baseline and endpoint will be included in the analysis. 
The percentage of fat content of the liver measured by MRI at Baseline and Week 24 will be 
summarized descriptively, as well as the change from baseline.  
The same descriptive statistics and ANCOVA model as the primary efficacy endpoint will be 
applied to the percentage of fat content of the liver measured by MRI at Baseline and Week 
12. 
6.9.2 
Secondary Endpoints 
6.9.2.1 
ALT Remission 
All TTR and responder analyses described below will be repeated for both ALT normal 
range definitions: 
 <20 U/L for women and <30 U/L for men 
 <40 U/L 
Time to Remission  
TTR defined as the time in weeks from randomization to liver function remission, defined as 
two consecutive ALT values within normal range during the treatment period (i.e. excluding 
Week 28 follow-up visit), will be assessed by survival analysis. The time to the first of the 
two consecutive ALT values within normal range will be used for the TTR. The time in 
weeks will be calculated as (sample date – first dose date + 1)/7. For those reaching 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 15 of 20 
 
remission, the Hodges-Lehmann estimator of the “location shift” between each dose group 
and placebo will be presented. The asymptotic (Moses) 95% confidence limits for the 
location shift will also be presented. The cumulative portion of the time-to-remission of each 
treatment group will be determined by Kaplan-Meier estimates. The time-to-remission will 
be analyzed using Cox proportional hazards model with treatment and diabetes stratum as 
explanatory variables. The following SAS code was used for the analyses of proportional 
hazards models: 
proc phreg; 
  Model TIME*CENSOR(0) = TREATMENT DIABSTAT / risklimits; 
run; 
Subjects who discontinue from the study before remission and subjects who complete the 
study without reaching remission will be assigned a TTR equal to the larger of the following 
two quantities: 
 (Maximum TTR in days observed for all subjects in the study + 1 day) / 7; 
 (Time to censoring (last ALT assessment during the treatment period) + 2 days) / 7. 
Responder Analysis 
The number and percentage of responders will be provided by treatment group. A subject 
who had as two consecutive ALT values within normal range during the treatment period 
will be defined as a responder. Subjects who are not responders and early withdraw will be 
considered as non-responders. Cochran-Mantel-Haenszel statistics will be provided adjusting 
for diabetes stratum.  
*********************************************************************** 
Note:  
  TREATMENT = 0, (placebo), 1 (JKB-121 5 mg), 2 (JKB-121 10 mg) 
  DIABSTAT = nondiabetic, diabetic 
  RESPONDER: Y/N responder 
  COUNT: number of subjects 
**********************************************************************; 
proc freq data=ALT; 
   tables DIABSTAT*TREATMENT*RESPONDER / cmh; 
   weight COUNT; 
run; 
Sensitivity analyses will be conducted using subjects who complete the study. 
Similar summaries and analyses will be provided for: 
 Subjects whose ALT level at each scheduled visit during the treatment period is 
within normal range. 
 Subjects whose ALT level is within normal range at any time within the following 
time intervals which will be derived using actual study days: 
a. Baseline to Week 12 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 16 of 20 
 
b. Week 12 to Week 24 
 Subjects achieving a 20% reduction from baseline at any time during the treatment 
period. 
6.9.2.2 
Liver Function 
The same descriptive statistics, ANCOVA model, and multiple imputation as the primary 
efficacy endpoint will be applied to serum aspartate aminotransferase (AST), ALT, and 
gamma-glutamyl transpeptidase (GGT) at each scheduled visit for the Full Analysis Set 
Population and the mITT Population.  
As a sensitivity analysis, the change from baseline in AST, ALT, and GGT will be analyzed 
using a mixed-model repeated-measures (MMRM) ANCOVA model for the Full Analysis 
Set Population, implemented using SAS® Proc Mixed. The factors in the model will be 
diabetes stratum, treatment group, baseline value, visit, and the treatment group by visit 
interactions. An unstructured covariance matrix will be used (TYPE=UN). No imputation 
will be performed. The sample SAS code can be found below: 
*********************************************************************** 
Note:  
  USUBJID = unique subject identifier 
  TREATMENT = 0, (placebo), 1 (JKB-121 5 mg), 2 (JKB-121 10 mg) 
  DIABSTAT = nondiabetic, diabetic 
  VISIT = visit 
  BASE = baseline value 
  CHG = change from baseline to the specified visit 
**********************************************************************; 
proc mixed;  
  class USUBJID DIABSTAT TREATMENT BASE VISIT;  
  model CHG = DIABSTAT TREATMENT BASE VISIT TREATMENT*VISIT;  
  Repeated VISIT / TYPE=UN sub=USUBJID;  
  lsmeans VISIT*TREATMENT / cl pdiff slice=VISIT;  
run;  
6.9.2.3 
Other Endpoints 
The same descriptive statistics and ANCOVA model as the primary efficacy endpoint will be 
applied to metabolic marker endpoints, biomarker endpoints, and other secondary outcome 
measures will be summarized and analyzed in the same manner as the primary efficacy 
endpoint. LOCF will be used in place of multiple imputation. 
6.10 
Pharmacokinetic Analysis 
6.10.1 
Sample Collections for Pharmacokinetic Analysis 
Six mL of blood will be collected from fasting (at least 8 hours) subjects on Day 1 prior to 
dosing, and during Visits 4, 6, and 8 for measurements of the plasma concentrations of 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 17 of 20 
 
JKB-121. In a subset of volunteers who consent to participate in PK Substudy, blood samples 
will be collected on Day 1 pre-dose and at each sampling point post-dose for PK evaluation. 
From volunteered subjects for intensive PK studies: Blood samples will be obtained on Day 1 
prior to 12 hour dosing (predose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, 
and 24 (next day) hours post dose administration in three volunteered subjects from each 
treatment group (5 mg and 10 mg bid). Additional pre-dose blood sample for trough PK level 
at Day 1, weeks 8, 16, and 24 will be collected for assessment of steady state PK analysis as 
well as biomarker study. 
6.10.2 
Pharmacokinetic Variables 
The following noncompartmental PK parameters will be calculated from plasma samples 
prior to the 12 hour dosing collected for the PK Substudy Population if data allows: 
 Area under concentration-time (AUC) curve from time 0 to infinity (AUCinf) 
 AUC curve from time 0 to time of last quantifiable concentration (AUClast) 
 AUC curve from time 0 to 12 hours (AUC12h) 
 Minimum post-dose concentration (Cmin) 
 Maximum post-dose concentration (Cmax) 
 Time of Cmax (Tmax) 
 Apparent first-order terminal elimination rate constant calculated by linear regression 
of the terminal linear portion of the log concentration vs. time curve (Kel) 
 Terminal phase elimination half-life (t½) 
 Clearance (CL/F) 
 Volume of Distribution (Vz/F) 
 Percent AUC Extrapolated (AUC%extrap) 
Parameters Kel, t½, and AUCinf will not be presented for those subjects who do not exhibit a 
terminal elimination phase in their concentration versus time profiles. In order to estimate the 
constant Kel, linear regression of concentration in logarithm scale vs. time will be performed 
using at least 3 data points. Uniform weighting will be selected to perform the regression 
analysis to estimate Kel. The constant Kel will not be assigned if the terminal elimination 
phase is not linear (as appears in a semi-logarithmic scale), the terminal elimination rate 
constant indicates a positive slope (Kel < 0), if the Tmax is one of the 3 last data points, or 
the regression coefficient (R2) is less than 0.8. 
The actual time relative to dosing will be used in the PK parameter calculation. The Linear 
Up/Log Down method will be used in the computation of all AUC values. The AUClast will 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 18 of 20 
 
be calculated from 0 hour to the last time point with quantifiable concentration. The AUCinf 
will be calculated as AUClast + Clast/Kel, where Clast is the last quantifiable plasma 
concentration. 
If one or more non-quantifiable (NQ) values occur in a profile before the first measurable 
concentration, they will be assigned a value of zero. If a single NQ value occurs between 
measurable concentrations in a profile, the NQ should generally be omitted (set to missing). 
NQs which occur after the last measurable concentration will be omitted (set to missing). 
6.10.3 
Pharmacokinetic Summary and Analysis 
PK concentration data will be summarized for each time point using descriptive statistics 
from the Safety Population and PK Substudy Population (i.e., Mean, SD, Minimum, 
Maximum, Median, %CV, Geometric Mean, Geometric %CV) by treatment group. Plots of 
mean concentrations of plasma concentrations (with standard deviation bars) versus nominal 
time will be generated for each treatment. Individual plasma concentration versus actual time 
plots will also be provided. 
The PK parameters will be summarized by treatment group using the PK Substudy 
Population. Geometric mean and geometric coefficient of variation (CV%) will be added to 
the descriptive statistics for Cmin, Cmax, and all AUCs.  
Trough (pre-dose) concentrations at Week 8, Week 16, and Week 24 will be summarized by 
treatment group for the Safety Population. If any trough concentration is NQ, it will be set to 
zero prior to summarization. Plots of mean trough concentrations (with standard deviation 
bars) by visit will be generated for each treatment. 
The relationship between PK and efficacy may be explored as needed. 
6.11 
Safety Analyses 
All safety analyses will be conducted on the Safety Population. The evaluation of safety will 
be based primarily on the frequency of adverse events (AEs), clinical laboratory assessments 
(chemistry, hematology, and urinalysis), 12-lead electrocardiograms (ECG), physical 
examinations, weight, waist circumference, and vital signs (heart rate, blood pressures, 
respiratory rate, and temperature). Other safety data will be summarized as appropriate. 
6.11.1 
Adverse Events 
For the purposes of this study, any sign (including a clinically significant laboratory result) or 
medical diagnosis noted by medical personnel, or symptom reported by the subject, 
regardless of relationship to investigational drug, that is treatment-emergent is considered to 
be an AE. All adverse events reported by the subject or observed by study site personnel 
from time of informed consent until completion of the study or premature withdrawal must 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 19 of 20 
 
be recorded in the subject’s CRF as per the CRF instructions. All AEs will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events (TEAEs) are defined as those AEs that have a start date 
on or after the first dose of study medication, or occur prior to the first dose and worsen in 
severity or relationship to study medication after the first dose. AEs beginning >7 days after 
last dose will not be considered treatment emergent. An overview of AEs will be provided by 
treatment group and in total for the following information: 
 All TEAEs, 
 Maximum severity of TEAEs, 
 Study drug-related TEAEs, 
 Maximum severity of drug-related TEAEs, 
 All serious adverse events (SAEs), 
 All treatment-emergent SAEs, 
 Drug-related SAEs, 
 Death due to AEs, 
 Withdrawals due to AEs, and 
 Withdrawals due to study drug-related AEs. 
The numbers and percentages of subjects with TEAEs will be summarized for each treatment 
group and in total by MedDRA system organ class and preferred term. Similar summaries 
will be provided by maximum severity. Drug-related TEAEs will be summarized in the same 
manner. Listings of SAEs and AEs leading to study medication discontinuation will be 
provided. 
6.11.2 
Clinical Laboratory Evaluations 
Summary statistics will be provided for safety laboratory tests at baseline and all scheduled 
post-baseline visits for chemistry, hematology, and urinalysis assessments by treatment group 
and in total. The change from baseline to post-baseline visits will also be presented.  
The number and frequency of subjects with laboratory abnormalities (worst value post first 
dose for each subject) will be summarized by treatment group and in total. Shift tables from 
baseline to worst value post first dose will be presented for ALT and AST (>1xULN to 
≤2xULN, >2xULN to ≤3xULN, >3xULN) and CK (>1xULN to ≤5xULN, >5xULN to 
≤10xULN, >10xULN). 


TaiwanJ Pharmaceuticals 
JKB-121-001 Statistical Analysis Plan 
Page 20 of 20 
 
6.11.3 
Vital Signs and ECG 
Height, weight, waist circumference, and vital signs will be summarized at baseline and each 
scheduled post-baseline visit. The change from baseline will also be presented. 
The overall ECG interpretation will be summarized by scheduled visit with counts and 
percentages by treatment group and in total.  
6.11.4 
Other Safety Parameters 
All other safety parameters such as lifestyle, hospital anxiety and depression scale, 
Columbia-Suicide Severity Rating Scale, physical examination, and pregnancy tests will be 
listed. 
7 
GENERAL INFORMATION 
The mock-ups for SAS-generated tables/figures/listings will be prepared in a separate 
document and finalized before database lock for the study. 
7.1 
Statistical Software 
The creation of analysis datasets and all statistical analyses will be done using SAS® version 
9.3.  The PK parameters will be determined using Phoenix™ WinNonlin® version 6.3 or 
higher. The Medpace standard operating procedures will be followed for the validation of all 
SAS programs and outputs.