Clinical trial NCT03226067
Conditions: Primary Biliary Cirrhosis
Sponsor: Calliditas Therapeutics AB
Start date: 2017-06-26; Completion date: 2019-04-11
Enrollment: 111 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of GKT13783 in patients with Primary Biliary Cholangitis (PBC) who are taking a stable dose of ursodeoxycholic acid (UDCA) treatment, and have persistently high levels of a liver enzyme called Alkaline Phosphatase (ALP).

Detailed description:
Primary biliary cholangitis (PBC) is a disease of the liver. It is caused a sustained attack by the body's immune system on the bile ducts (canals) inside the liver. This continuous assault leads to their gradual destruction and eventual disappearance. This results in obstruction to the flow of bile which gets worse with disease progression. Once the bile duct injury has been established, the disease progresses due to ongoing obstruction of bile flow, inflammation and scarring of the liver tissue(fibrosis). The liver eventually fails.

This research is looking into whether the study drug is better than a dummy drug when given to patients with PBC. This trial will monitor the patients taking part with regular blood tests and ultrasound liver scans before, during, and at the end of the trial. These measures will allow for the ongoing assessment of liver function, and liver stiffness. It is hoped that in patients in whom the study drug is beneficial, the liver function or stiffness may progress at a slower pace, or may even improve during or at the end of the trial. Liver injury, inflammation and fibrosis Participants will be randomly assigned to 1 of 3 treatment groups (active drug once daily, active drug twice daily or placebo). This is a double blinded study so neither the participants nor the staff responsible for their care will know which group they have been assigned to. During the treatment period, participants will take 4 capsules orally at home in the morning and 4 capsules in the evening for 24 weeks.

Participants will be in the trial for 32 weeks in total (about 8 months) and will attend approximately 8 clinic visits.

Arms: arm 1: GKT137831 400mg twice daily

Patients will self-administer 4 capsules in the morning and 4 capsules in the evening. arm 2: GKT137831 400mg once daily

Patients will self-administer 4 capsules in the morning and 4 capsules in the evening. The capsules in the evening will be placebos. arm 3: Patients will self-administer 4 capsules in the morning and 4 capsules in the evening. All capsules will be placebos.
Interventions: intervention 1: GKT137831 intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily. intervention 2: Matching capsules.

Protocol documents:
Prot_002.pdf: 
 
 
 
Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
CONFIDENTIAL 
Page 1 of 113 
CLINICAL STUDY PROTOCOL 
 
A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Assess the Efficacy 
and Safety of Oral GKT137831 in Patients with Primary Biliary Cholangitis Receiving 
Ursodeoxycholic Acid and with Persistently Elevated Alkaline Phosphatase 
 
Protocol Number: 
GSN000300 
Test Product:  
GKT137831 
Indication:  
Primary Biliary Cholangitis 
Study/IND Sponsor:  
Genkyotex 
Development Phase:  
Phase 2 
IND No.: 
132135 
EudraCT No.: 
2016-004599-23 
Sponsor Program Official: 
Philippe Wiesel, MD 
Chief Medical Officer 
Genkyotex SA 
218 avenue Marie Curie  
Forum 2 – Archamps Techonopole  
74166 Saint Julien en Genevois  
Cedex – France 
Medical Monitoring: 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP 
United Kingdom 
Original Protocol Version No.:  
Final 1.0 dated 23 February 2017 
Amendment 1: 
Final 2.0 dated 10 May 2017 
Amendment 2: 
Final 3.0 dated 09 November 2017 
Amendment 3: 
Final 4.0 dated 24 July 2018 
The confidential information in this document is provided to you as an Investigator, potential Investigator, 
or consultant for review by you, your staff, and an Independent Ethics Committee and/or Institutional 
Review Board as applicable. It is understood that the information will not be disclosed to others without 
written authorization from Genkyotex except to the extent necessary to obtain informed consent from 
those persons to whom the Investigational Medicinal Product may be administered. 






Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: 
A 
Double-Blind, 
Randomized, 
Placebo-Controlled 
Clinical Trial to Assess the Efficacy and Safety of Oral 
GKT137831 in Patients with Primary Biliary Cholangitis 
Receiving Ursodeoxycholic Acid and with Persistently 
Elevated Alkaline Phosphatase 
PROTOCOL NUMBER: 
GSN000300 
PROTOCOL VERSION AND DATE: 
Final 4.0; Amendment 3; 24 July 2018 
 
INVESTIGATOR STATEMENT: 
I agree to conduct the above-entitled study in accordance with the terms and conditions of this 
protocol, ICH GCP guidelines, the provisions of the Declaration of Helsinki and with all applicable 
regulatory requirements. All information pertaining to the study shall be treated in a confidential 
manner. 
I agree to conduct the study in person or to supervise the trial. 
I agree to ensure that all who assist me in the conduct of the study are aware of their obligations. 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name: 
Title: 
Site Address:___________________________ 
                     ___________________________ 
                     ___________________________ 
                     ___________________________ 
 
 
 
 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
V 
LIST OF TABLES 
VIII 
LIST OF FIGURES 
VIII 
LIST OF ABBREVIATIONS 
IX 
PROTOCOL SUMMARY 
XII 
1 
ROLES AND RESPONSIBILITIES 
18 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
21 
2.1 
Background Information 
21 
2.1.1 
Primary Biliary Cholangitis 
21 
2.1.2 
GKT137831 
22 
2.1.3 
Choice of Endpoints 
24 
2.1.4 
Summary of Non-Clinical Studies with GKT137831 
26 
2.1.5 
Summary of Clinical Studies with GKT137831 
28 
2.2 
Rationale 
30 
2.3 
Potential Risks and Benefits 
32 
3 
OBJECTIVES AND ENDPOINTS 
34 
4 
STUDY DESIGN 
37 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
39 
5.1 
Population 
39 
5.2 
Inclusion Criteria 
39 
5.3 
Exclusion Criteria 
40 
5.4 
Contraception 
41 
5.5 
Strategies for Recruitment, Retention and to Improve Adherence to 
Protocol 
42 
5.6 
Treatment Assignment Procedures 
42 
5.6.1 
Randomization Procedures 
42 
5.6.2 
Blinding Procedures 
42 
5.6.3 
Emergency Breaking of Assigned Treatment Code 
43 
5.6.4 
Reasons for Withdrawal 
43 
5.6.5 
Handling of Withdrawals 
44 
5.6.6 
Termination of Study 
44 
6 
TREATMENT OF SUBJECTS 
46 
6.1 
Identity of Study Treatment(s) 
46 
6.1.1 
Description and Formulation 
46 
6.1.2 
Packaging and Labeling 
46 
6.1.3 
Storage and Stability 
46 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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6.2 
Administration of Study Treatment(s) 
47 
6.3 
Criteria for Study Treatment Modification or Discontinuation 
48 
6.3.1 
In case of Confirmed or Suspected Drug Induced Liver Injury 
49 
6.3.2 
In case of Anemia 
49 
6.3.3 
In case of Drug Induced Hypothyroidism 
50 
6.4 
Accountability Procedures for the Study Treatment(s) 
50 
6.5 
Subject Compliance 
50 
6.6 
Concomitant Medications/Treatments 
51 
6.6.1 
Required Concomitant Medications 
51 
6.6.2 
Prohibited Medications 
51 
7 
STUDY SCHEDULE 
53 
7.1 
Screening 
53 
7.2 
Enrollment/Baseline 
54 
7.3 
Treatment Period 
55 
7.4 
Final Study Visit (Follow-Up) 
58 
7.5 
Early Termination Visit 
58 
7.6 
Unscheduled Visit 
59 
8 
STUDY PROCEDURES/EVALUATIONS 
60 
8.1 
Clinical Evaluations 
60 
8.1.1 
Demographics and Medical History 
60 
8.1.2 
Physical Examination 
60 
8.1.3 
Vital Signs 
60 
8.1.4 
Electrocardiogram 
61 
8.1.5 
Transient Elastography (FibroScan® or Similar Technology) 
61 
8.1.6 
Subject Reported Outcomes 
61 
8.2 
Laboratory Evaluations 
62 
8.2.1 
Clinical Laboratory Evaluations 
62 
8.2.2 
Pharmacokinetics 
62 
8.2.3 
Pharmacogenetics 
63 
8.2.4 
Pharmacodynamics 
64 
9 
ASSESSMENT OF SAFETY 
65 
9.1 
Safety Parameters 
65 
9.2 
Adverse Events 
65 
9.2.1 
Definition of Adverse Event 
65 
9.2.2 
Eliciting Adverse Events 
66 
9.2.3 
Recording Adverse Events 
67 
9.2.4 
Follow-up of Adverse Events 
67 
9.3 
Serious Adverse Events 
68 
9.3.1 
Definition of Serious Adverse Event 
68 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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9.3.2 
Reporting of Serious Adverse Events 
69 
9.4 
Regulatory Reporting of Serious, Unexpected, Adverse Reactions 
(SUSARs) 
70 
9.5 
Drug-Induced Liver Injury 
71 
9.6 
Pregnancy 
71 
9.7 
Safety Monitoring Board 
71 
10 
STATISTICAL CONSIDERATIONS 
73 
10.1 
Study Hypotheses 
73 
10.2 
Sample Size Considerations 
73 
10.3 
Planned Interim Analyses 
73 
10.4 
Analysis Methods 
74 
10.4.1 
Analysis Populations 
74 
10.4.2 
Definition of Analysis Endpoints: Primary, Secondary, Tertiary, Exploratory, Safety 
and Pharmacokinetics 
75 
10.4.3 
Statistical Methodology 
77 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
82 
12 
QUALITY CONTROL AND QUALITY ASSURANCE 
83 
12.1 
Conduct of the Study 
83 
12.2 
Study Monitoring 
83 
13 
ETHICS 
84 
13.1 
Ethical Standard 
84 
13.2 
Institutional Review Board/Independent Ethics Committee 
84 
13.3 
Informed Consent Process 
84 
13.3.1 
Exclusion of Women, Minorities, and Children 
85 
13.4 
Subject Confidentiality 
85 
13.5 
Treatment Plan in the Event of Study Discontinuation 
85 
13.6 
Future Use of Stored Samples 
85 
13.7 
Insurance 
86 
14 
DATA HANDLING AND RECORD KEEPING 
87 
14.1 
Data Capture Methods 
87 
14.2 
Study Site Responsibilities 
87 
14.3 
Data Management Responsibilities 
87 
14.4 
Study Records Retention 
88 
14.5 
Protocol Deviations 
88 
15 
PUBLICATION POLICY 
89 
16 
REFERENCES 
90 
APPENDICES 
96 
APPENDIX A: 
SCHEDULE OF EVENTS 
97 
APPENDIX B: 
SCHEDULE OF BLOOD SAMPLING 
100 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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APPENDIX C: 
DECLARATION OF HELSINKI 2013 
101 
APPENDIX D: 
PRURITUS VAS 
106 
APPENDIX E: 
PBC-40 QUESTIONNAIRE 
107 
APPENDIX F: 
CLOSE OBSERVATION PROCEDURES 
112 
 
LIST OF TABLES 
Table 1 Predicted Typical Parent and Metabolite Exposures based on Parent and 
Metabolite Mouse and Human Population PK Models ..................................................... 31 
Table 2 Safety Margins of Predicted Human Exposure Compared with Exposures at 
the NOAEL in Dog Safety Study GSN000157.................................................................. 32 
Table 3 Description of Investigational Medicinal Products ............................................................ 46 
Table 4 Quantity of IMP Bottles Dispensed at Each Visit .............................................................. 47 
Table 5 Investigational Medicinal Product Self-Administration ...................................................... 48 
Table 6 Pruritus VAS Assessment [66]......................................................................................... 61 
Table 7 Pharmacokinetic Time Points .......................................................................................... 63 
 
LIST OF FIGURES 
Figure 1: Study Design Flowchart .................................................................................................. 38 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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LIST OF ABBREVIATIONS 
ADME 
Absorption, Distribution, Metabolism And Excretion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALD 
Alcoholic Liver Disease 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMA 
Anti-Mitochondrial Antibody(ies) 
ANA 
Anti-Nuclear Antibody(ies) 
ANCOVA 
Analysis of Covariance 
APRI 
AST to Platelet Ratio Index 
AST 
Aspartate Aminotransferase 
AUC 
Area Under The Curve 
BID 
Twice Daily 
BSEP 
Bile Salt Export Pump 
CFR 
Code of Federal Regulations 
CK-18 
Cytokeratin-18 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CV% 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DILI 
Drug-Induced Liver Injury 
DKD 
Diabetic Kidney Disease 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ELF 
Enhanced Liver Fibrosis 
EMA 
European Medicines Agency 
EudraCT 
European Union Drug Regulatory Agency Clinical Trial 
FDA 
Food And Drug Administration 
FIB-4 
Fibrosis-4 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HDPE 
High-Density Polyethylene 
hsCRP 
High Sensitivity C-Reactive Protein 
HTD 
Highest Tolerated Dose 
IB 
Investigator’s Brochure 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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ICF 
Informed Consent Form 
ICH 
International Conference On Harmonization 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IIV 
Inter-Individual Variability 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IPF 
Idiopathic Pulmonary Fibrosis 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IU 
International Units 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IWRS 
Interactive Web-Based Randomization System 
LREs 
Liver Related Events 
MAR 
Missing at Random 
MARS 
Molecular Adsorbent Recirculation System 
MCP-1 
Monocytic Chemoattractant Protein-1 
MELD 
Model For End Stage Liver 
MNAR 
Missing Not at Random 
MSAP 
Modeling and Simulation Analysis Plan 
NADPH 
Nicotinamide Adenine Dinucleotide Phosphate 
NASH 
Nonalcoholic Steatohepatitis 
NOAEL 
No Observed Adverse Effect Level 
OCA 
Obeticholic Acid 
OD 
Once Daily 
PBC 
Primary Biliary Cholangitis 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
QTcF 
Corrected QT Interval (Fredericia’s Formula) 
RBC 
Red Blood Cell 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SMB 
Safety Monitoring Board 
SOP 
Standard Operating Procedure 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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SSc 
Systemic Sclerosis 
t½ 
Half-life 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time To Maximum Plasma Concentration 
TSH 
Thyroid-Stimulating Hormone 
UDCA 
Ursodeoxycholic Acid 
ULN 
Upper Limit Of Normal 
US 
United States 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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PROTOCOL SUMMARY 
Title: 
A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to 
Assess the Efficacy and Safety of Oral GKT137831 in Patients 
with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid 
and with Persistently Elevated Alkaline Phosphatase 
Study Overview: 
This will be a double-blind, randomized, placebo-controlled, 
multicenter, parallel group phase 2 trial assessing a 24-week 
period of treatment with oral GKT137831 administered in addition 
to standard of care medication (ursodeoxycholic acid; UDCA) in 
subjects with primary biliary cholangitis (PBC). 
Subjects will be assessed for their eligibility during the screening 
period (Visit 1), which will last up to 4 weeks, until the 
baseline/Day 1 visit (Visit 2). 
Eligible subjects will be randomized to oral GKT137831 (400 mg 
once daily (OD) or 400 mg twice daily (BID) or placebo, according 
to a 1:1:1 randomization ratio, stratified at study entry by disease 
severity defined as baseline serum gamma glutamyl transferase 
(GGT) < 2.5 x the upper normal limit (ULN) or ≥ 2.5 x the ULN.  
Subjects will self-administer orally 400 mg of GKT137831 OD or 
400 mg of GKT137831 BID or matching placebo for a total of 24 
weeks. 
Baseline assessments will be performed at baseline/Day 1 (Visit 
2). The 24-week treatment period will include assessments after 
2 weeks of treatment (Visit 3), after 6 weeks of treatment (Visit 4), 
after 12 weeks of treatment (Visit 5), after 18 weeks of treatment 
(Visit 6) and after 24 weeks of treatment (End of Treatment/Visit 
7). Subjects will be followed up for 28 days after the end of 
treatment (Week 28/Visit 8), totaling 6 post-baseline visits. 
Subjects who discontinue treatment before Week 24 will have an 
early termination visit (premature end of treatment visit). 
Pharmacokinetic samples will be taken at Week 2, Week 12 and 
Week 18. 
Subjects will be taking a stable dose of UDCA at enrollment and 
will continue their UDCA treatment at a stable dose (no changes 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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at all) during the treatment period.  
An Independent Safety Monitoring Board (SMB) will oversee the 
conduct of the study to ensure the safety of participating subjects. 
An interim analysis will be conducted when 80-90% of the 
planned number of subjects to be randomized in the study have 
completed their Week 6 visit. 
Objectives: 
 
Primary: 
To evaluate the efficacy of oral GKT137831 in comparison with 
placebo, in subjects with PBC receiving UDCA and with 
persistently elevated Alkaline Phosphatase (ALP). 
Secondary: 
 
To evaluate the safety of oral GKT137831 in comparison with 
placebo, in subjects with PBC. 
 
To estimate the population pharmacokinetics (PK) of 
GKT137831 and explore any potential Pharmacokinetics-
Pharmacodynamics (PK-PD) relationships in this subject 
population. 
 
To explore any relationship between genetic parameters and 
therapeutic responses in a subset of subjects. 
Primary Efficacy Endpoint: 
The percent change from baseline to Week 24 (Visit 7) in serum 
GGT. 
Secondary Efficacy 
Endpoints: 
 
Absolute and percent change in serum GGT from baseline to 
each assessment. 
 
Absolute change in Enhanced Liver Fibrosis (ELF) score from 
baseline to Weeks 12 and 24. 
 
Absolute and percent change in serum ALP from baseline to 
each assessment.  
 
Absolute and percent change in serum levels of high-
sensitivity C-reactive protein (hsCRP) and fibrinogen, from 
baseline to each assessment. 
 
Absolute 
and 
percent 
change 
in 
serum 
Alanine 
Aminotransferase (ALT), Aspartate Aminotransferase (AST), 
conjugated and total bilirubin, from baseline to each 
assessment. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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 
Absolute and percent change in the Fibrosis-4 (FIB-4) and 
AST to Platelet Ratio Index (APRI) scores, from baseline to 
each assessment (FIB-4: age (years) x AST (IU/L)/(platelet 
count (109/L) x (ALT (IU/L)1⁄2, APRI: AST (IU/L)/ upper normal 
limit AST)x100/platelet count (109/L). 
 
Absolute and percent change in liver stiffness as assessed by 
transient elastography (FibroScan® or similar technology), 
from baseline to Week 24, in patients with values at baseline 
and Week 24. 
 
Absolute and percent change in serum levels of collagen 
fragments indicative of collagen formation and degradation, 
from baseline to Weeks 12 and 24. 
 
Absolute and percent change in Quality of Life (QoL), Fatigue 
and Pruritus scores based on the PBC-40 and Pruritus Visual 
Analogue Score (VAS), from baseline to Weeks 12 and 24. 
Eligibility Criteria 
Eligibility assessments will be conducted at Screening (Visit 1). 
When confirming eligibility at baseline/Day 1 (Visit 2), not every 
eligibility assessment needs to be repeated i.e., confirmatory 
laboratory and diagnostic tests. Subjects with adverse events 
(AE) at baseline may need to be withdrawn in accordance with 
the eligibility and withdrawal criteria. 
Inclusion Criteria: 
1. Male or female aged 18 to 80 years, inclusive. 
2. Willing and able to give written informed consent and to 
comply with the requirements of the study. 
3. PBC diagnosis as demonstrated by the presence of ≥ 2 of the 
following 3 diagnostic factors: 
o History of elevated ALP levels (> ULN) for at least 6 
months 
o Positive anti-mitochondrial antibody (AMA) titer or if AMA 
negative or in low titer (< 1:80) PBC-specific antibodies 
(anti-GP210 and/or anti-SP100 and/or antibodies against 
the major M2 components [PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex]) 
o Liver biopsy consistent with PBC (based on historic liver 
biopsy), including non-suppurative, destructive cholangitis 
affecting mainly the interlobular and septal bile ducts. 
4. Serum ALP ≥ 1.5 x ULN.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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5. Serum GGT ≥ 1.5 x ULN. 
6. UDCA treatment for at least 6 months and stable dose for at 
least 3 months prior to Visit 1. 
7. Subjects being treated for pruritus with colestyramine must be 
on a stable dose of colestyramine for at least 8 weeks prior to 
baseline/Day 1 (Visit 2). Subjects must be willing and able to 
take colestyramine at least 2 hours before or after study 
medication. 
8. Female subjects of childbearing potential must use a highly 
effective method of contraception to prevent pregnancy for 4 
weeks before randomization and must agree to continue strict 
contraception for 90 days after last administration of 
investigational medicinal product (IMP). Male participants with 
female partners of childbearing potential must be willing to 
use a condom and require their partner to use an additional 
form of adequate contraception as approved by the 
Investigator. This requirement begins at the time of informed 
consent and ends 90 days after the last administration of 
IMP. Male study participants must also not donate sperm 
from baseline until 90 days after the last administration of 
IMP. 
 
Exclusion Criteria: 
1. A positive pregnancy test or breast-feeding for female 
subjects. 
2. Any hepatic decompensation, defined as a past or current 
history of hepatic encephalopathy, gastrointestinal tract 
bleeding due to esophageal varices, or ascites. 
3. International normalized ratio (INR) > 1.2 unless subject is on 
anticoagulant therapy. 
4. ALT > 3 x ULN. 
5. Total bilirubin > 1 x ULN. 
6. Planned or current plasmapheresis or other extra-corporeal 
treatments (e.g., molecular adsorbent recirculation system 
(MARS)) for treatment-refractory pruritus. 
7. History of liver transplantation, current placement on a liver 
transplant list or current Model for End Stage Liver Disease 
(MELD) score ≥ 15. 
8. Cirrhosis with complications, including history or presence of: 
spontaneous bacterial peritonitis, hepatocellular carcinoma.  
9. Hepatorenal syndrome (type I or II) or Screening serum 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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creatinine > ULN. 
10. Competing etiology for liver disease (e.g., hepatitis C, active 
hepatitis B, non-alcoholic steatohepatitis (NASH), alcoholic 
liver disease (ALD), autoimmune hepatitis, primary sclerosing 
cholangitis, Gilbert’s Syndrome). 
11. Subjects receiving prohibited medications within 3 months of 
Screening (Visit 1) according to the list (a, b and c) provided 
in Section 6.6.2. 
12. Treatment with any investigational agent within 4 weeks of 
Visit 1 or 5 half-lives of the investigational medicinal product 
(whichever is longer). 
13. A history of long QT syndrome. 
14. Evidence of any of the following cardiac conduction 
abnormalities during the screening period: 
 
A QTc Fredericia interval > 450 milliseconds for 
males and > 470 milliseconds for females. 
 
A second or third degree atrioventricular block not 
successfully treated with a pacemaker. 
15. A history of severe cardiovascular disease defined as any of 
the following within the 12 weeks preceding initiation of study 
treatment: 
 
Acute myocardial infarction or unstable angina 
pectoris. 
 
A coronary revascularization procedure. 
 
Congestive heart failure New York Health Association 
(NYHA) Class III or IV. 
 
Stroke, including a transient ischemic attack. 
16. History of cancer in the preceding 5 years, except adequately 
treated non-melanoma skin cancer, carcinoma in situ of the 
cervix, in situ prostate cancer, in situ breast ductal carcinoma, 
or superficial bladder cancer stage 0). 
17. The occurrence of any acute infection requiring systemic 
antibiotic therapy within the 2 weeks prior the Screening Visit 
(Visit 1), or human immunodeficiency virus (HIV) infection. 
18. A history of bone marrow disorder including aplastic anemia, 
or marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 


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mmol/L). 
19. A known hypersensitivity to GKT137831 or to any of the 
excipients. 
20. Any condition which, in the opinion of the Investigator, 
constitutes a risk or contraindication for the participation of 
the subject in the study, or which could interfere with the 
study objectives, conduct, or evaluation. 
Phase: 
Phase 2 
Number of Sites: 
Approximately 50-60 investigational sites will be initiated in North 
America, Europe, and Israel. 
Study Duration: 
Planned start: Q2 2017 
Planned end: Q2 2019 
Subject Participation 
Duration: 
The total duration of double-blind treatment will be 24 weeks from 
baseline/Day 1 (Visit 2) to Week 24 (End of Treatment/Visit 7). A 
Screening visit (Visit 1) will be done within 4 weeks before 
baseline/Day 1. A follow up visit (Visit 8) will be carried out within 
4 weeks after the end of treatment (i.e., Week 28). 
Description of Agent or 
Intervention: 
Capsules of GKT137831 or matching placebo to be taken orally: 
400 mg OD or 400 mg BID for 24 weeks. 
Estimated Time to 
Complete Enrollment: 
7-8 months 


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1 
ROLES AND RESPONSIBILITIES 
Sponsor 
Genkyotex SA 
218 avenue Marie Curie  
Forum 2 – Archamps Techonopole  
74166 Saint Julien en Genevois  
Cedex – France 
Sponsor Program Official 
Philippe Wiesel, MD 
Chief Medical Officer 
Genkyotex SA 
218 avenue Marie Curie  
Forum 2 – Archamps Techonopole  
74166 Saint Julien en Genevois  
Cedex – France 
Tel. No.: +33 (0) 6 73 63 67 21 
Medical Monitor  
Peter Adura 
Director, Medical Services, Medical Services 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP  
United Kingdom 
Tel. No.: +44 (0) 1403 755611 
Clinical Research Organization 
 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP  
United Kingdom 
Tel. No.: +44 (0)1403 75 50 50 
Statistical and Data Management 
Center 
Jean-Luc Beffy 
Cmed Clinical Services – Data and Analytics 
Department 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP,  
United Kingdom 
Tel. No.: +44 (0)1403 758269 
Clinical Trial Management And 
Monitoring 
Brandon Fletcher 
Cmed Inc. 
4000 Aerial Center Parkway, Suite 102 
Morrisville, NC 27560, United States 
Tel. No.:+1 (919) 600 4897 
 


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Serious Adverse Event Reporting  
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP,  
United Kingdom 
Email: sae@cmedresearch.com 
24 Hour Phone: +44 (0)1403 75 8462 
US Toll-Free Phone: +1 866 966 8429 
Fax: +44 (0)1403 33 0459 
US Toll-Free Fax: +1 866 966 2970 
Interactive Web-based Randomization 
System (IWRS)/Unblinding 
Almac 
25 Fretz Road 
Souderton, PA 18964 
Phone: +1 267-697-9932 
Central Laboratory (USA) 
Clinical Reference Laboratory, Inc. 
8433 Quivira Road 
Lenexa, KS 66215 
Central Laboratory (Europe) 
Clinical Reference Laboratory 
New Market Road 
Fordham, Cambridgeshire, CB7 5WW 
United Kingdom 
Phone: +44 1638 724 500 
Central Laboratory (Israel) 
AML-Israel Ltd 
37 Havatzelet hasharon St 
Herzliyah Petuah 
Israel 46641 
Phone: 972-9-9561268 
Fibrosis Biomarker Assays 
Nordic Bioscience Biomarkers & Research 
Herlev Hovedgade 207 
DK-2730 Herlev 
Denmark 
Phone: +45 4452 5252 
Analysis of PK Samples 
York Bioanalytical Solutions (YBS) 
Cedar House 
Northminster Business Park 
Upper Poppleton 
York 
YO26 6QR 
United Kingdom 
Phone: +44 (0)1904 686 060 
PK/PD Analysis 
ICON 
2 Globeside  
Globeside Business Park 
Marlow SL7 1HZ UK 
Phone: +44 (0)1628 496404 


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DNA Extraction and Storage 
Imagene 
Plateforme de Biotechnologie Industrielle 
Genopole Campus 1 - Batiment Genavenir 6 
4 rue Henri Desbrueres 
91030 Evry 
France 
Phone: +33 (0) 1 60 77 85 00 
Fax: +33 (0) 1 60 77 84 44 
Optional Metabolomic Analysis 
Metabolon  
617 Davis Drive, Suite 400 
Durham, NC 27713 
Phone: +1 919 572 1711 
 
 
 
 


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2 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
2.1 
Background Information 
2.1.1 Primary Biliary Cholangitis 
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a liver disease 
caused by auto-immune (T-cell-mediated) attack on the small to medium intra-lobular bile ducts [1, 
2]. A continuous assault on the bile duct epithelial cells leads to their gradual destruction and 
eventual disappearance (i.e., ductopenia). Once immune-mediated bile duct injury has been 
established, the disease progresses due to chronic cholestasis, secondary inflammation and fibrosis, 
and may lead to liver cirrhosis and liver failure [3, 4]. The reasons for the auto-immune attack are not 
well understood but may involve environmental triggers in genetically susceptible individuals. 
The reported prevalence of PBC ranges from 20-400 cases per million of the population with some 
geographical differences [5, 6]. PBC is more common in women than men (9:1 ratio) and mostly 
diagnosed between the ages of 30 and 60 years [7, 8].  
Up to 60% of patients with PBC are asymptomatic at diagnosis and are detected through 
coincidental finding of abnormalities in liver biochemistry tests. The most common symptoms, where 
present, are fatigue and pruritus. Physical examination is often normal but, where present, common 
findings are: skin hyperpigmentation, jaundice, excoriations, xanthomata, xanthelasmas and, rarely, 
hepatosplenomegaly [9, 10]. 
Common laboratory test abnormalities in patients with PBC include: elevated ALP, anti-mitochondrial 
antibodies (AMA), anti-nuclear antibodies (ANA), and hyperlipidemia. Other findings may include 
elevations in serum aminotransferases and bilirubin. Complications of PBC include cirrhosis, 
hepatocellular carcinoma, metabolic bone disease, and malabsorption [11, 12]. 
PBC is often associated (co-diagnosed) with other auto-immune disorders including: Sjogren 
syndrome, auto-immune thyroid disease (Hashimoto’s thyroiditis) and rheumatoid arthritis.  
Management of patients with PBC consists of treatment of the underlying disease and management 
of its symptoms and complications, including: pruritus, xanthomata, hypercholesterolemia, vitamin 
deficiencies, anemia, malabsorption, osteoporosis, etc. 
PBC is a progressive disease in most patients. It eventually becomes irreversible, and therefore 
untreatable. The only widely accepted treatment is UDCA. It is the only treatment recommended in 
guidelines issued by the American Association for the Study of Liver Diseases and the European 
Association for the Study of the Liver.  


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Although there is currently no treatment for the autoimmune injury to biliary endothelial cells, in 
recent years, novel therapies targeting cholestasis have improved outcomes for many patients with 
PBC. UDCA and more recently obeticholic acid (OCA) have been licensed by the Food and Drug 
Administration (FDA) and European Medicines Agency (EMA), for treatment of PBC  
UDCA is a synthetic secondary bile acid, given orally at a dose of 10-15 mg/kg/day as first line 
treatment for PBC. The following mechanisms of action may be involved in the beneficial therapeutic 
effects of UDCA in PBC and other cholestatic disorders: (a) increase in the hydrophilicity of 
circulating bile acids; (b) stimulation of hepatocellular and ductular secretions; (c) protection against 
cellular injury caused by bile acids and cytokines; (d) some degree of immunomodulation and anti-
inflammatory effects. Currently, treatment with UDCA represents the global standard of care [2, 3], 
and can delay histologic progression [4–6] and improve long-term survival [7, 8]. However, UDCA is 
not a uniformly effective drug, there is little benefit to symptoms, and approximately 40% of PBC 
patients have a sub-optimal response to UDCA [13, 14]. Patients with an inadequate response to 
UDCA (assessed biochemically), or those not tolerating UDCA, progress to cirrhosis and liver failure 
leading to liver transplant or death. Therefore, there is an unmet medical need in PBC patients with 
inadequate response to UDCA. 
OCA is another synthetic secondary bile acid which has only recently been approved by the FDA 
and EMA for treatment of PBC [15, 16]. OCA is indicated for the treatment of PBC in combination 
with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to 
tolerate UDCA. OCA is not yet in wide clinical use. It has a similar mechanism of action as UDCA 
but has been shown to achieve further reductions in ALP levels in patients with inadequate response 
to UDCA. This additional anti-cholestatic effect was associated with a reduction in hepatocellular 
damage, as shown by decreases in AST and ALT levels. However, OCA treatment achieved only 
small reductions in these markers of hepatocellular injury which failed to normalize to below the 
upper limit of the normal reference range [17]. Over time, this sustained hepatocellular injury likely 
contributes to progressive liver fibrosis and failure. Separately, OCA worsens the severity of pruritus, 
a key symptom of PBC which significantly impacts patients’ quality of life. The currently available 
therapies mainly target cholestasis. However, there is a need for well-tolerated therapies able to 
address additional components of the disease, including autoimmune injury to biliary endothelial 
cells, bile acid-mediated hepatocellular injury, and fibrogenesis [18, 19].  
2.1.2 GKT137831 
GKT137831 is a small organic molecule of low molecular weight, a member of the pyrazolopyridine 
dione chemical class. It is a selective inhibitor of NOX 1 and 4 isoforms of the Nicotinamide Adenine 
Dinucleotide Phosphate (NADPH) oxidase family of enzymes, and is the first drug in this class of 
NOX inhibitors to enter the clinic.  
The NADPH oxidase family (NOX) is a set of transmembrane proteins [20]. NOX enzymes require 
the stable assembly of transmembrane and cytosolic subunits. Upon assembly of a full enzymatic 
complex and activation by its substrates NADPH and molecular oxygen, NOX enzymes transport 
electrons through the cell membrane to produce reactive oxygen species (ROS). In turn, ROS 


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modulate multiple signaling pathways by oxidizing regulatory cysteine residues in target proteins. 
ROS can also cause other types of post-translational modification of proteins, and can target lipids 
and nucleic acids.  
When exaggerated in duration and/or magnitude, NOX activation participates in the pathogenesis of 
a broad range of human diseases.  In particular, the NOX1 and NOX4 isoforms have been shown to 
play a key role in a broad range of inflammatory and fibrotic disorders [21-25]. Importantly, recent 
studies have revealed that liver tissue expression of NOX1 and/or NOX4 is consistently elevated in 
patients with fibrotic liver diseases [26, 27]. 
GKT137831 is thus being investigated in several inflammatory and fibrotic disorders, including PBC, 
Nonalcoholic Steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), Diabetic Kidney Disease 
(DKD), Systemic Sclerosis (SSc). It is also under investigation in the development of the fibrotic 
tumor stroma. 
In in vitro studies in isolated cells, GKT137831 was shown to attenuate signaling evoked by a 
number of ligands known to induce and/or drive the fibrogenic process in multiple fibrogenic 
pathways, including TGF-β1, PDGF, TLR4, hedgehog and angiotensin II [26]. As a result, 
GKT137831 markedly reduced the induction of markers of myofibroblast activation, including αSMA, 
fibronectin, and pro-collagen I [28, 29]. 
These direct anti-fibrogenic effects translate into anti-fibrotic activity in multiple in vivo models of liver 
fibrosis. Specifically, GKT137831 attenuated the development of liver fibrosis induced by 
experimental cholestasis (in the bile duct ligation and MDR2-/-, mouse models). GKT137831 also 
prevented liver fibrosis in models of NASH (in the STAM and fast food diet models [29]). GKT137831 
also prevented liver fibrosis in models of NASH (in the STAM and fast food diet models [27, 30]) and 
in toxic hepatitis (in CCL4-induced liver injury [28]). Reduced in vivo fibrogenesis was associated 
with a marked reduction in markers of myofibroblast activation. 
In addition, GKT137831 has shown potent anti-inflammatory effects in a number of biological 
settings, including metabolic and cholestatic liver injury. Specifically, GKT137831 prevented the 
induction of adhesion molecules, cytokines, and chemokines in CCL4-induced liver injury and fast 
food diet-induced NASH [27]. These effects on innate immunity resulted in a profound reduction of 
macrophage infiltration. Available data suggests that these anti-inflammatory effects are mediated 
through reduced activation of multiple pathways, including TLR4 and NF-B [21]. In these studies, 
reduced liver inflammation was associated with a reduction in plasma levels of liver transaminases. 
GKT137831 was evaluated in patients with type 2 diabetes and kidney disease. Because this patient 
population has a high prevalence of the metabolic syndrome and non-alcoholic fatty liver disease, 
the trial assessed markers of liver injury and inflammation. GKT137831 achieved statistically 
significant reductions in GGT and hsCRP. 
These extensive pre-clinical studies and initial clinical results suggest that GKT137831 has the 
potential to alleviate hepatocellular injury and prevent progressive liver fibrosis. 


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2.1.3 Choice of Endpoints 
The main objective of the trial is to evaluate the effect of GKT137831 on liver injury and 
inflammation, and on fibrogenesis. While plasma ALP is a reasonably well-validated surrogate 
endpoint of outcomes for anti-cholestatic drugs, there are no validated surrogate endpoints for anti-
inflammatory and anti-fibrotic drugs. Accordingly, the primary and secondary efficacy endpoints have 
been selected to provide proof of concept for the therapeutic value of GKT137831, and to 
characterize its initial efficacy profile. 
2.1.3.1 
Primary Efficacy Endpoint 
GGT was selected as the primary efficacy endpoint because it is consistently elevated in PBC 
patients, correlates with disease severity, can respond quickly to therapeutic interventions, and is 
likely to be modulated by GKT137831 through anti-inflammatory and redox mechanisms. In 
cholestatic disease, elevated GGT reflects inflammatory and cholestatic injury to bile ducts and 
hepatic parenchymal structures. GGT is expressed in biliary epithelial cells and hepatocytes, and is 
elevated in multiple biliary and non-biliary liver disorders, including PBC, PSC, NASH, ALD, and 
hepatitis B and C. GGT correlates with the severity of liver fibrosis across a broad range of fibrotic 
liver disorders [31-37]. As a result, GGT has been included in the FibroSure/FibroTest score, a non-
invasive marker of liver fibrosis [38]. Importantly, GGT responds rapidly (i.e. within weeks) to the 
administration of UDCA, OCA, fibrates, or a modified FGF-19 [17, 39]. 
GGT is involved in hepatic redox homeostasis and is a marker of oxidative stress [40-42]. So, in 
addition to cholestatic and inflammatory injury, oxidative stress can also participate in the induction 
of GGT expression in PBC patients. Accordingly, GKT137831 has the potential to reduce GGT 
levels through anti-inflammatory and redox mechanisms in cholangiocytes and hepatocytes. While 
not directly relevant to PBC, the statistically significant reduction in GGT achieved with GKT137831 
in patients with DKD supports this assumption. Of note, GGT levels predict renal and all-cause 
mortality in DKD patients [43, 44].  
In summary, while GGT is not a validated surrogate endpoint of outcome in PBC, it is a clinically 
relevant efficacy endpoint that is well suited to demonstrate the pharmacodynamic activity of 
GKT137831, and together with supportive secondary endpoints, inform dose-response relationships. 
2.1.3.2 
Secondary Efficacy Endpoints Related to Fibrosis 
The evaluation of the anti-fibrotic activity of GKT137831 is an important objective of the trial. Patients 
with inadequate response to UDCA undergo accelerated liver fibrosis [45]. It is therefore critical to 
develop novel therapies able to directly target fibrogenesis. GKT137831 has shown profound anti-
fibrotic activity in multiple models of fibrotic liver diseases. It was not only effective in models of 
NASH, where hepatic stellate cells are the main source of activated myofibroblasts, it was also 
effective in cholestatic models such as MDR2-/- mice where portal fibroblasts are the source of 
activated myofibroblasts. 


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The effect of GKT137831 on liver fibrosis will be explored through the evaluation of direct non-
invasive markers of fibrogenesis. These markers include the ELF score and a panel of collagen 
fragments. In addition, liver stiffness will be evaluated by transient elastography (performed at 
centers where FibroScan™ or similar equipment is available). Finally, indirect markers of fibrosis, 
such as FIB-4 and APRI, will be also assessed [46]. 
A growing body of evidence supports the use of the ELF score to evaluate anti-fibrotic therapies. 
The ELF score is a direct marker of fibrogenesis; its components (HA, TIMP-1, and PIIINP) have a 
direct role in the fibrogenic process [47-56]. The ELF score correlates well with the presence and 
severity of liver fibrosis in several fibrotic liver diseases, including hepatitis C, hepatitis B, NASH, 
PBC, autoimmune hepatitis, alcohol liver disease and others [57-62]. Furthermore, the ELF score 
accurately predicts disease progression in PBC, NASH, and hepatitis C, as shown by the correlation 
between the baseline ELF score and the occurrence of liver-related events (LREs) during follow up. 
Initial clinical results suggest the ELF test has the ability to detect the effect of therapeutic 
interventions in several fibrotic liver diseases, including PBC [19, 46, 57, 58]. In PBC patients, event-
free survival was significantly lower in those with high baseline ELF. Each 1- point increase in ELF 
was associated with a 3-fold increase in future complications [57]. Similar data was obtained in 
patients with primary sclerosing cholangitis, where patients stratified by the ELF score tertiles 
exhibited significantly different transplant-free survival (P < 0.001), with higher scores associated 
with shorter survival, further confirmed in the validation set stratified by ELF Test tertiles (P= 0.003). 
In addition, the ELF Test distinguished between mild and severe disease as defined by clinical 
outcome (transplantation or death) with an area under the curve (AUC) of 0.81. 
The ELF test has received the CE and has been extensively validated and reference values have 
been published [57, 63, 64]. Accordingly, treatment guidelines issues by NICE and EASL–EASD–
EASO recommend the use of the ELF test to detect the presence of liver fibrosis and to monitor 
therapeutic responses.  
Despite these encouraging developments, further work is required to validate the ELF score as 
surrogate endpoint of outcome in PBC. In particular, it is still unclear that ELF score reductions 
achieved by specific therapeutic interventions do predict improvements in clinical outcomes. 
Importantly however, available data suggest that the ELF score will be elevated in the target patient 
population. In a comparable patient population, the ELF score suggested that most patients had 
moderate-to-severe liver fibrosis [Hirschfield, 2016]. This data is consistent with results obtained in a 
similar patient population in the OCA phase 3 trial [17]. In this trial, all patients had some degree of 
liver fibrosis, and over 50% of patients had at least septal fibrosis (OCA, FDA medical review). 
Therefore, the ELF score is well suited for the evaluation of anti-fibrotic effects in this trial. 
 


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2.1.3.3 
Secondary Efficacy Endpoints Related to Hepatocellular Injury 
Markers of hepatocellular injury such as AST or ALT are only modestly elevated in PBC patients, 
and have shown inconsistent responses to OCA. Accordingly, they were not selected as primary 
efficacy endpoints. Nevertheless, these markers, together with CK-18 and total and conjugated 
bilirubin will provide supportive information about drug effects on hepatocellular injury. In preclinical 
models of cholestatic and metabolic liver diseases, GKT137831 achieved marked reductions in liver 
function tests and reduced hepatocyte apoptosis. 
2.1.3.4 
Secondary Efficacy Endpoints Related to Immunological 
Processes and Inflammation 
GKT137831 has shown consistent anti-inflammatory effects in preclinical studies. In patients with 
type 2 diabetes, GKT137831 achieved a significant reduction in hsCRP (an acute phase protein 
produced in the liver), and tended to reduce plasma levels of serum amyloid protein A and IL-6. 
Accordingly, changes in hsCRP, fibrinogen, and IL-6 will be evaluated to assess the anti-
inflammatory effect of GKT137831. 
The role of NOX enzymes in the underlying immunological process is unknown. Nevertheless, it is 
suggested that NOX1 and NOX4 play a role in some of the immunological pathways underlying 
PBC. Accordingly, changes in serum IgM, IL-4, IL-12, IL-17A, and interferon γ will be assessed. 
2.1.4 Summary of Non-Clinical Studies with GKT137831 
A broad range of in vitro and in vivo pharmacology studies have been conducted to support the use 
of GKT137831 in several indications. Detailed summaries for all studies are given in the current 
Investigator’s brochure (IB). GKT137831 selectively inhibits human isolated NOX4 (IC50 0.147 µM) 
and NOX1 (IC50 0.214 µM) but is considerably less active at inhibiting isolated human NOX2 (IC50 
3.44 µM), NOX3 (IC50 3.44 µM) and NOX5 (IC50 0.457 µM). This selectivity against NOX2 means 
GKT137831 does not compromise phagocyte function. Moreover, GKT137831 was inactive against 
the non-NADPH oxidase flavoprotein xanthine oxidase, and inhibited glucose oxidase with an IC50 of 
5.7µM, indicating selective inhibition of ROS generation via the NADPH oxidase pathway. 
Meanwhile, GKT137831 reduced DPPH with an IC50 of 20µM, suggesting GKT137831 is a weak 
electron donor, and may therefore possess weak antioxidant activity. Investigation of potential 
effects against a broad range of receptors and enzymes confirmed that GKT137831 demonstrated 
no significant off-target activity, except for significant inhibition of human recombinant 15-
lipoxygenase-2. However, a review of available literature did not detect a safety concern. 
Similarly, a literature review on the effect of gene deletion of NOX isoforms indicated that no basal 
phenotype has been associated with NOX1 or NOX4 gene deletion in mice. Specifically, there are 
no reported defects in fertility, embryonic development, life span, animal behavior or breeding. 
These observations did not identify potential safety concerns related to inhibition of NOX1 and/or 
NOX4. 


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Overall, there are no observations from the available literature to indicate safety concerns 
associated with chronic pharmacological inhibition of NOX1, NOX4 and NOX5. 
Safety pharmacology studies demonstrated that there were no effects on general activity, behavior 
or respiratory parameters at doses up to 1000 mg/kg of GKT137831 when administered orally. 
Minimal effects on hERG currents were recorded with a reduction of ~20% at 300 µM with 
GKT137831 or major active metabolite GKT138184. In addition, GKT137831 was found to be a 
weak inhibitor (IC50 = 78.8 µM) of the cardiac IKs channel, while the metabolite, GKT138184 has no 
activity on this channel at 100 µM. GKT137831 and GKT138184 have no significant inhibitory activity 
on the IKr cardiac ion channel at 300 µM and no activity on INa and ICa channels at 100 µM. 
Overall, review of the electrocardiogram (ECG) data from the safety pharmacology and toxicology 
studies did not provide sufficient information that GKT137831 could prolong QTc or QTCF in a way 
that indicated a definite risk to humans. 
The non-clinical PK and absorption, distribution, metabolism and excretion (ADME) of GKT137831 
have been investigated in vivo in the mouse, hamster, rat and dog, and in animal and human in vitro 
preparations. GKT137831 is a rapidly and extensively orally absorbed compound. In rats and dogs it 
has moderately low clearance and a volume of distribution approximately similar to that of 
extracellular fluid and elimination predominates in feces rather than urine.   
Significant amounts of the major phase 1 active metabolite GKT138184 have been quantified in 
animal plasma after oral dosing. The phase 1 metabolism of GKT137831 is likely to be mediated 
mainly by CYP3A4, and GKT137831 showed the potential to inhibit and induce CYP3A4 in vitro. A 
human drug interaction study indicated that GKT137831 is a weak inhibitor of CYP3A4 although the 
modest increase in the exposure of midazolam and its metabolites upon repeat dosing of 
GKT137831 may be due to a combination of mechanisms. Initial in vitro studies indicated that 
GKT137831 was a potent inhibitor of Bile Salt Export Pump (BSEP). Because BSEP inhibitors have 
the potential to cause cholestatic liver injury, the effects of GKT137831 on bile acid levels were 
investigated in the clinical drug interaction study. GKT137831 administered for 10 days at 300 mg 
BID had no effect on bile acid concentration. Furthermore, GKT137831 did not cause hepatocellular 
injury in toxicology studies. Because of these discrepant in vitro and in vivo results, the in vitro BSEP 
assay was repeated and did not confirm the initial data. It is therefore likely that GKT137831 is not a 
potent inhibitor of BSEP. Other in vitro transporter studies indicate that there is no requirement for 
additional testing prior to further phase 2 studies. 
GKT137831 has undergone a comprehensive toxicology testing programme which has 
demonstrated that there is no genotoxicity liability with either the parent or the active metabolites. In 
chronic studies in both rat and dog the potential toxicity of GKT137831 following up to 6 months of 
daily oral dosing was explored. The no observed adverse effect level (NOAEL) in rats was 
established at 1000 mg/kg/day, the highest dose tested and findings included minimal or slight 
decreases in red blood cells and slight increases in platelets, modest increases in total plasma 
bilirubin and a small increase above control in the incidence of foamy macrophages in the lung 
which was of minimal severity grading. No such difference between treated and control animals was 


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observed in animals subjected to a 5-week treatment free period after 6 months of dosing and these 
effects were thus not considered of toxicological significance. 
The dog was the most sensitive species and the NOAEL was established at 150 mg/kg/day in the 26 
week study. Treatment related effects in the dog studies were confined to ECG changes, effects on 
thyroid hormones, and effects on hematology parameters/bone marrow. Changes in liver function 
tests observed were generally considered to be of minimal severity and reversible and led to no liver 
pathologies and are consequently not considered to be of toxicological relevance. In the 28 Day 
study, QTc(F) prolongation was observed in high dose dogs (1000 mg/kg) and there was a single 
animal with an AV-block. The QTc prolongation was observed at both measurement times (Day 1 
and Day 23) but the increase at the Day 23 reading was limited and seemed to affect only 2/6 
treated high dose animals. Although there were no such ECG alterations observed in the 13 Week 
study, measurements in high dose dogs taken at Week 1 and 4 of the 26 Week study (animals still 
on 500 mg/kg/day) showed QTc (VdeW) increases of up to 20 msec. There were no QTc 
prolongation observed after the dose reduction to 300 mg/kg/day at week 13 and 26. The absence of 
any clear treatment-related ECG alterations at both the NOAEL of 150 mg/kg/day and the HTD 
(Highest Tolerated Dose) of 300 mg/kg/day in the 26 Week dog study and in already conducted 
clinical trials suggest that any such liability will not compromise subject safety in early stage clinical 
studies. Effects on bone marrow were seen at 500 mg/kg/day, the highest dose tested in the 26 
week study and in one animal resulted in a severe non regenerative anemia which lead to 
euthanasia. Effects were restricted to the erythroid lineage and were preceded by a marked 
reduction in reticulocytes indicating the potential to monitor any potential effect in the clinic. 
Reproductive toxicology studies have been performed in rats and rabbits. No treatment-related 
embryo-fetal findings in any dose group were seen in rats at doses of up to 1000 mg/kg/day. The 
NOAEL for maternal toxicity was established at 1000 mg/kg/day and for embryo-fetal toxicity was 
300 mg/kg/day. In rabbits, GKT137831-related maternal mortality and severe effects on food 
consumption and body weight were seen at 1000 mg/kg/day, but there was no evidence of embryo-
fetal toxicity at any dose level. The NOAEL for maternal and embryo-fetal toxicity was considered to 
be 300 mg/kg/day. 
Overall, this body of non-clinical data suggests that NOX1/4 inhibition with GKT137831 may 
represent an attractive therapeutic strategy for a broad range of fibrotic disorders. 
2.1.5 Summary of Clinical Studies with GKT137831 
2.1.5.1 
Healthy Volunteers Program 
A total of four phase 1 studies have been completed in healthy male subjects.  The program was 
designed to examine the safety and pharmacokinetics of single and multiple ascending doses of 
GKT137831, the potential for drug interactions using the CYP3A4 probe substrate midazolam, as 
well as the relative bioavailability of micronized and unmicronized GKT137831 and the potential 
interactions with food. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
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Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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In the phase 1 program, a total of 105 male subjects were exposed to GKT137831, and ranged with 
age from 18 to 49 years. Doses of GKT137831 ranged between 10 mg and 1800 mg and for up 10 
successive days in the repeating dose study. The overall safety results indicate good systemic and 
local tolerability of single or repeated doses of GKT137831. 
Overall subjects exposed to GKT137831 had a low incidence of AEs.  Most reported AEs were mild 
in intensity, self-limiting and considered to be unrelated to GKT137831. The most frequently reported 
AEs were occurrences of nonspecific headache related events. Other reported AEs were mainly mild 
common infections unrelated to GKT137831. There were no deaths or serious adverse events 
(SAEs) reported during the course of these studies. There were no changes in vital signs, ECG, 
hematology, clinical chemistry or urinalysis associated with GKT137831. Thyroid hormones were 
specifically investigated in a multiple ascending dose study. All mean values remained within the 
normal range, and changes compared to baseline showed no trend over time suggestive of a 
relationship with GKT137831.  
The pharmacokinetics of GKT137831 were consistent in all phase 1 studies. Exposure to 
GKT137831, measured by mean AUC and Cmax, whether after single or repeat administration, 
increased in a broadly dose proportional manner or less than dose proportional manner. No 
increased exposure was seen upon single administration of doses higher than 900 mg. After a single 
dose of 300 mg in either the fasted state or with a non-high fat meal, the mean AUC0-t ranged from 
24,100 to 38,000 ng.h/mL.  Administration of micronized or unmicronized drug substance did not 
appear to have any notable impact on plasma exposure. Administration with food appeared to 
reduce inter-subject variability in exposure, and administration with a high-fat meal increased the 
mean AUC of GKT137831 by approximately 25%. No reduction in mean exposure was seen upon 
repeat dosing either at daily doses of 100-900 mg or twice-daily doses of 300-400 mg. A slight 
accumulation in AUC0-t was measured between the first and last doses upon twice daily dosing, 
consistent with the increased dosing frequency. 
2.1.5.2 
Phase 2 Program 
A multicenter double blind randomized phase 2 study has been conducted to evaluate the efficacy 
and safety of GKT137831 in the treatment of DKD and persistent albuminuria. A total 136 subjects 
were randomized in the study. In the GKT137831 arm, 68 subjects received 100 mg BID for 6 weeks 
followed by 200 mg BID for a further 6 weeks, representing over 15.22 subject years in GKT137831 
exposure. 
The trial did not meet its primary endpoint. At the end of the treatment period, no difference could be 
detected between GKT137831 and placebo in the changes of albuminuria level from baseline. 
GKT137831 did not appear to affect other measures of renal function and injury, including serum 
creatinine, eGFR, and urine MCP-1. Reasons for the lack of efficacy on the primary endpoint may 
include the short treatment period and/or under-dosing during the first half of the trial (see Section 
2.2). 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Nevertheless, the trial met several predefined secondary endpoints, indicating that GKT137831 is 
pharmacodynamically active in humans. Specifically, subjects receiving GKT137831 had a 
statistically significant reduction in GGT and hsCRP levels, two markers which predict mortality in 
patients with DKD. Furthermore, subjects receiving GKT137831 also showed a robust trend for 
lower levels of serum amyloid protein A, plasminogen activator inhibitor type 1, and triglyceride 
levels, compared to subjects receiving placebo. These changes are potentially related to a systemic 
anti-inflammatory effect, and/or reduced severity of non-alcoholic fatty liver disease in these subjects 
with type 2 diabetes and excess body weight. Trends toward reduced neuropathic pain and erectile 
dysfunction were observed but did not reach statistical significance. 
In this phase 2 study, GKT137831 was well tolerated. The reporting rate of AEs was low with fewer 
than 50% of subjects reporting AEs during the course of the study. In GKT137831-treated subjects, 
most Treatment-Emergent Adverse Events (TEAEs) were self-limiting, mild in severity, not 
treatment-related and resolved rapidly. The most commonly reported AEs were events related to 
respiratory tract infections. Other reported events were single occurrences experienced by 1 or 2 
GKT137831 subjects. There was no evidence of dose-related increase in the occurrence of TEAEs. 
The only notable safety finding was a statistically significant, albeit slight and non-clinically significant 
(~2.5 mm Hg) increase in diastolic blood pressure (DBP). A trend for a marginal (~3 mm Hg) 
increase in systolic blood pressure (SBP) was also observed, but did not reach statistical 
significance. Finally safety signals related to findings made in previous toxicology studies were not 
confirmed. In particular, there were no safety signals related to thyroid function, liver function, bone 
marrow function, or cardiac conduction. No bone marrow toxicity, cardiac toxicity, liver toxicity, or 
renal toxicity was observed. 
Upon review of all available safety data, the evaluation of GKT137831 at doses up to 200 mg BID in 
68 subjects with DKD indicated a good tolerability and safety profile of GKT137831 compared with 
placebo.  
2.2 
Rationale 
The proposed doses of 400 mg OD and 400 mg BID were selected to achieve target plasma 
exposure levels in a majority of study subjects. The plasma exposure target was defined according 
to the exposure achieved in mice by the maximally effective dose. There is considerable experience 
with GKT137831 in animal models of inflammatory and fibrotic disorders. Over 35 peer-reviewed 
manuscripts have been published to date, with an average impact factor >9. In these studies, and as 
presented in the IB, dose of 20 to 30 mg/kg achieved maximal efficacy. This was particularly well 
demonstrated in the OVE26 and Akita models of DKD, or in a model of acute CCL4-induced liver 
injury. However, in some instances, trends for higher efficacy were observed at higher doses. For 
instance, 60 mg/kg tended to be more effective than 5 and 20 mg/kg in the STAM models of non-
alcoholic steatohepatitis, and in the MDR2-/- model of cholestatic liver injury and fibrosis. In the bile 
duct ligation model, 60 mg/kg was as effective as 120 mg/kg. Altogether, this data indicates that the 
maximally effective doses range from 20 to 60 mg/kg in murine models. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Table 1 highlights the modelled steady state exposure levels for the proposed clinical doses. These 
exposure estimates were based on a population PK model developed based on the PK data 
obtained in the completed phase 2 trial, and compared against single dose exposure levels in mice. 
Table 1 
Predicted Typical Parent and Metabolite Exposures based on Parent and 
Metabolite Mouse and Human Population PK Models 
Species 
 
Mouse 
Human 
Dose 
20 mg/kg 
60 mg/kg 
400 mg OD 
400 mg BID 
AUC24 
(ng.hr/mL) 
25,766 
77,299 
53,091* 
28,423-98,231 
103,967* 
56,589-187,098 
 
 
 
 
* Median (10th-90th) 
 
 
These exposure estimates indicate that more than 90% of subjects allocated to the 400 mg OD dose 
are predicted to have plasma exposure levels above the average exposure achieved in mice by the 
20 mg/kg dose (i.e. the less conservative target exposure level). A majority of subjects allocated to 
the 400 mg BID dose are predicted to have plasma exposure levels above the average exposure 
achieved in mice by the 60 mg/kg dose (i.e. the more conservative target exposure levels). In 
addition, the 2 proposed doses should achieve plasma concentrations above 5xIC50 (200 ng/mL) for 
the full dosing interval. As shown in the rat quantitative whole-body autoradiography study, high 
levels of radiolabeled drug-related material were observed in liver tissue where it achieves 
concentrations that are 3-5 times higher than in other organs, such as kidney or lung. This tissue 
distribution pattern and elimination route matches the target organ in PBC patients. Based on 
recently reported trials, which applied very similar eligibility criteria, the subjects enrolled in this trial 
will mainly have mild PBC. Nevertheless, the impact of potential hepatic drug accumulation will be 
assessed by careful monitoring of liver function tests and drug concentration in plasma.  
The proposed dosing regimens are supported by the available non-clinical and clinical data. Doses 
up to 1800 mg were tested in the single ascending dose phase 1 study. Subsequently, doses of up 
to 900 mg/day were tested in the multiple ascending dose study. In these studies conducted in 
healthy subjects, GKT137831 was well tolerated. No dose limiting toxicities and no safety signals 
were detected. 
In the completed phase 2 trial in DKD patients, 100 mg BID was evaluated over the first 6 weeks, 
and 200 mg BID was evaluated over the following 6 weeks. The safety profile of GKT13783 was 
again very favorable. Subjects receiving GKT137831 reported a lower incidence of AEs compared to 
subjects receiving placebo. This reduction (in the range of 40% for TEAEs) was especially marked 
for moderate to severe TEAEs. In addition, a low number of serious adverse events were reported in 
subjects receiving GKT137831 (3 SAEs) or placebo (7 SAEs). No safety signals were identified in 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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subjects receiving GKT137831, except for a marginal yet statistically significant increase in DBP. 
GKT137831 has not been shown to increase blood pressure in toxicology studies or in healthy 
subjects. Therefore, these findings may be due to chance, or specific to patients with DKD. 
Meanwhile, the toxicology signals identified in rat and dog toxicology studies were not observed in 
human. In particular, GKT137831 did not cause consistent changes in ECG parameters, liver 
function tests, thyroid function tests, and hematology parameters. Overall, these results indicated 
that GKT137831 is very well tolerated when administered orally for up to 12 weeks at doses up to 
400 mg/day. In our opinion, the combined safety data obtained in human subjects support the 
evaluation of GKT137831 at higher doses and for longer treatment durations.  
Specifically, the combined non-clinical and clinical data support the two doses proposed for this trial. 
The 400 mg OD dose corresponds to the daily dose evaluated during the second 6-week period in 
the completed phase 2 study. As indicated above, this dosing regimen was very well tolerated in the 
study population, which consisted of type 2 diabetics presenting with multiple diabetic complications 
and concomitant medications. Considering the very good safety profile of GKT137831 in this 
susceptible population, the 400 mg BID was selected to explore a higher dose range while 
maintaining adequate safety margins based on animal data. Specifically, the dose of 400 mg BID is 
estimated to provide a safety margin of 2.1 and 3.2 for AUC and Cmax, respectively (see Table 2).  
Table 2 
Safety Margins of Predicted Human Exposure Compared with Exposures at the 
NOAEL in Dog Safety Study GSN000157 
PK parameter 
[GKT137831 + 
GKT138184] 
Exposure at toxicology 
NOAEL (26 week 
dog)a 
Predicted human exposure 
at 400 mg b.i.d.b [safety 
margin] 
Predicted human exposure at 
400 mg q.d.b [safety margin] 
AUC (µg.h/mL) 
220 
104 [2.1] 
53 [4.1] 
Cmax (µg/mL) 
44 
14 [3.1] 
14 [3.1] 
a: combined [GKT137831 + GKT138184] value in non-acidified plasma at Week 26 in study GSN000157 at NOAEL 
dose (150 mg/kg/day). 
b: predicted median [GKT137831 + GKT138184] exposures based on 1000 simulations of GKT137831 and 
GKT138184 in human population PK models. 
We anticipate a low enrollment rate for this trial, with a total enrollment period of around 7-8 months. 
Considering the number of treatment arms, the exposure of subjects to the top dose will accrue at a 
slow pace (an average of approximately 3-5 subjects will be randomized to the 400 mg BID dose 
every month). We expect even slower incremental exposure during the early stages of the trial 
conduct due to the progressive activation of investigational centers. Careful monitoring of study 
subjects, as well as periodical review of safety data by the trial Safety Monitoring Board will ensure 
the safety of participating subjects. Of note, study subjects will be monitored more frequently in the 
early phase of the trial, with visit intervals of 2 weeks, 4 weeks, and subsequently 6 weeks. 
2.3 
Potential Risks and Benefits 
As summarized above, GKT137831 has been extensively investigated in pre-clinical studies as well 
as in four studies in healthy volunteers and one study in subjects with Type 2 diabetes. GKT137831 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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was well tolerated when administered for up to 12 weeks at a dose of up to 200 mg BID. No safety 
signal or dose-limiting toxicities were identified in these studies. In particular, safety signals identified 
in toxicology studies were not detected. Specifically, there was no detectable drug effect on thyroid 
function, bone marrow function, liver function tests, or cardiac conduction. The careful extension of 
the treatment duration (i.e. 24 weeks) and dose increase to 400 mg BID are supported by the 
favorable safety data obtained in previous clinical studies. As a general precaution, however, 
appropriate safety endpoints have been built into this study for frequent monitoring (see Section 3). 
In addition, a SMB will carefully review the emerging study data on a regular basis in order to detect 
any safety signals early and take appropriate action according to the SMB charter.  
Nevertheless, specific risks related to the subject population exist. GKT137831 caused minor 
elevations of total bilirubin in dog toxicology studies. These changes were transient and reversible, 
and were not associated with biochemical or pathological evidence of hepatocellular injury. The 
underlying cause for these changes has not been identified, and may involve competition for, or 
inhibition of, UGT enzymes which are responsible for the glucuronide conjugation. In phase 1 and 
phase 2 trials, GKT137831 did not cause elevations in total bilirubin. Nevertheless, this study will 
evaluate a higher dose over a longer treatment period, and drug accumulation in liver tissue is 
anticipated in PBC patients. Accordingly, the incidence of drug-induced liver injury (DILI) will be 
carefully monitored as outlined in Section 6.3.1. 
In addition, a case of non-regenerative anemia was observed in the 26 week dog toxicology study. 
Accordingly, hematological parameters were carefully monitored in subsequent phase 1 and phase 2 
studies. No safety signal related hematological parameters were detected in these trials. 
Nevertheless, hematological parameters will be carefully monitored as described in Section 6.3.2. 
While NOX1/4 inhibition represents an attractive therapeutic strategy in patients with PBC, actual 
therapeutic benefits in PBC patients remain to be demonstrated. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVE 
ENDPOINT (OUTCOME MEASURE) 
To evaluate the efficacy of oral 
GKT137831 
in 
comparison 
with placebo, in subjects with 
PBC receiving UDCA and with 
persistently 
elevated 
serum 
ALP. 
Primary efficacy endpoint: 
 
The percent change from baseline to Week 24 (Visit 7) in 
serum GGT. 
 
Secondary efficacy endpoints: 
 
Absolute and percent change in serum GGT from baseline to 
each assessment. 
 
Absolute change in ELF score from baseline to Weeks 12 and 
24. 
 
Absolute and percent change in serum ALP from baseline to 
each assessment.  
 
Absolute and percent change in serum levels of hsCRP, and 
fibrinogen, from baseline to each assessment. 
 
Absolute and percent change in serum ALT, AST, conjugated 
and total bilirubin, from baseline to each assessment. 
 
Absolute and percent change in the FIB-4 and APRI scores, 
from baseline to each assessment (FIB-4: age (years) x AST 
(IU/L)/(platelet count (109/L) x (ALT (IU/L)1⁄2, APRI: AST (IU/L)/ 
upper normal limit AST)x100/platelet count (109/L). 
 
Absolute and percent change in liver stiffness as assessed by 
transient elastography (FibroScan® or similar technology), from 
baseline to Week 24, in subjects with values at baseline and 
Week 24. 
 
Absolute and percent change in serum levels of collagen 
fragments indicative of collagen formation and degradation, 
from baseline to Weeks 12 and 24. 
Absolute and percent change in Quality of Life (QoL), Fatigue and 
Pruritus scores based on the PBC-40 and Pruritus Visual 
Analogue Score (VAS), from baseline to Weeks 12 and 24. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Tertiary efficacy endpoints: 
 
Absolute and percent change in total bile acid levels from 
baseline to Week 12 and 24. 
 
Proportion of subjects achieving a 15, 20, 30 and 40% 
reduction in serum ALP from baseline to each assessment. 
 
Proportion of subjects who meet the definition of PBC 
responder criteria applying the Paris I, Toronto I, Toronto II, 
Toronto III, Toronto IV, Mayo II, and Barcelona disease 
prognostic risk criteria at Weeks 12 and 24. 
Exploratory Endpoints: 
 
Optionally, absolute and percent change in serum C4 and 
FGF19 from baseline to Weeks 12 and 24. 
 
Optionally, absolute and percent change in serum interleukin 
(IL)-6 and cytokeratin-18 (CK-18), from baseline to Weeks 12 
and 24. 
 
Optionally, absolute and percent change in serum IgM, IL-4, IL-
12, IL-17A, and interferon γ, from baseline to Weeks 12 and 24. 
 
Optionally, assessment of metabolomics signatures. 
 
Optionally, assessment of additional biomarkers of interest. 
SECONDARY OBJECTIVES: 
To evaluate the safety of oral 
GKT137831 in comparison 
with placebo, in subjects with 
PBC. 
 
Subjects with AEs from starting IMP to 28 days after the last 
administration.  
 
Clinical laboratory evaluations at Screening, baseline/Day 1 
and Weeks 2, 6, 12, 18, 24 and 28. 
 
Urinalysis at Screening and Weeks 12, 24 and 28.  
 
Thyroid stimulating hormone (TSH) measured at baseline/Day 
1 and Weeks 12 and 24. 
 
Pulse rate, SBP and DBP at Screening, baseline/Day 1 and 
Weeks 2, 6, 12, 18, 24 and 28. 
 
Body weight at baseline/Day 1 and at Week 24. 
 
12-lead ECG during Screening and at Weeks 2, 12, and 24. 
To estimate the population 
pharmacokinetics (PK) of 
GKT137831 and explore any 
potential PK-PD relationships 
 
Plasma concentrations of GKT137831 and its main phase 1 
metabolite, GKT138184.  
The plasma concentrations will be subjected to population PK 
analysis to estimate population PK parameters such as clearance 
and volume of distribution and associated inter-individual variability 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
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Author: Cmed Clinical Services 
 
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in this subject population. 
(IIV), and to determine predictors of IIV. 
PK-PD analysis will be carried out using the primary endpoint and 
selected secondary endpoints in order to explore any potential PK-
PD relationships.  
Exploratory Endpoint: 
 
Additional biomarkers of interest will be measured in plasma or 
serum. The identity of these exploratory markers will be defined 
in response to findings described in the literature or obtained in 
this study. These markers will not have diagnostic or prognostic 
value and will not have an established normal range according 
to the World Health Organization (WHO). 
To explore any relationship 
between genetic parameters 
and therapeutic responses in a 
subset of subjects. 
 
Genetic and pharmacogenetic research may be conducted on 
the DNA samples collected at baseline/Day 1 from subjects 
who sign an optional, additional informed consent. In particular, 
the impact of polymorphisms in the NOX1 and/or NOX4 genes 
on pharmacodynamic and therapeutic responses may be 
assessed. 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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4 
STUDY DESIGN 
This will be a double-blind, randomized, placebo-controlled, multicenter, parallel group phase 2 trial 
assessing a 24-week period of treatment with oral GKT137831 administered in addition to standard 
of care medication (UDCA) in subjects with PBC. 
Subjects will be assessed for their eligibility during the screening period (Visit 1), which will last up to 
4 weeks, until the baseline/Day 1 visit (Visit 2). 
Eligible subjects will be randomized to oral GKT137831 (400 mg OD or 400 mg BID) or placebo, 
according to a 1:1:1 randomization ratio, stratified at study entry by disease severity defined as 
baseline serum GGT < 2.5 x the ULN or ≥ 2.5 x ULN.  
Subjects will self-administer orally 400 mg OD or 400 mg BID of GKT137831 or matching placebo 
for a total of 24 weeks. 
Baseline assessments will be performed at baseline/Day 1 (Visit 2). The 24-week treatment period 
will include assessments after 2 weeks of treatment (Visit 3), after 6 weeks of treatment (Visit 4), 
after 12 weeks of treatment (Visit 5), after 18 weeks of treatment (Visit 6) and after 24 weeks of 
treatment (End of Treatment/Visit 7). Subjects will be followed up for 28 days after the end of 
treatment (Week 28/Visit 8), totaling 6 post-baseline visits. Subjects who discontinue treatment 
before Week 24 will have an Early Termination visit (premature end of treatment). 
Pharmacokinetic samples will be taken at Week 2, Week 12 and Week 18 (see Section 8.2.2 for the 
sampling time points). 
Subjects will be taking a stable dose of UDCA at enrollment and will continue their UDCA treatment 
at a stable dose (no changes at all) during the treatment period.  
A Safety Monitoring Board will oversee the conduct of the study to ensure the safety of participating 
subjects (see Section 9.7 for more details). An interim analysis will be conducted when 80-90% of 
the planned number of subjects to be randomized in the study have completed their Week 6 visit 
(see Section 10.3). 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Figure 1: 
Study Design Flowchart 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Population 
Subjects with primary biliary cholangitis receiving a stable dose of UDCA and with persistently 
elevated ALP, who meet all of the inclusion criteria listed in Section 5.2 and none of the exclusion 
criteria listed in Section 5.3, may be included in this study. Approximately 100 subjects will be 
randomized. 
5.2 
Inclusion Criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
1. Male or female aged 18 to 80 years, inclusive. 
2. Willing and able to give written informed consent and to comply with the requirements of the 
study. 
3. PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors: 
a) 
History of elevated ALP levels (>ULN) for at least 6 months 
b) 
Positive AMA titer or if AMA negative or in low titer (<1:80) PBC specific antibodies (anti-
GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-
oxo-glutaric acid dehydrogenase complex]) 
c) 
Liver biopsy consistent with PBC (based on historic liver biopsy), including non-
suppurative, destructive cholangitis affecting mainly the interlobular and septal bile ducts. 
4. Serum ALP ≥1.5 x ULN. 
5. Serum GGT ≥1.5 x ULN. 
6. UDCA treatment for at least 6 months and stable dose for at least 3 months prior to Visit 1. 
7. Subjects being treated for pruritus with colestyramine must be on a stable dose of colestyramine 
for at least 8 weeks prior to baseline/Day 1 (Visit 2). Subjects must be willing and able to take 
colestyramine at least 2 hours before or after study medication. 
8. Female subjects of childbearing potential must use a highly effective method of contraception to 
prevent pregnancy for 4 weeks before randomization and must agree to continue strict 
contraception for 90 days after last administration of IMP (see Section 5.4). Male participants 
with female partners of childbearing potential must be willing to use a condom and require their 
partner to use an additional form of adequate contraception as approved by the Investigator. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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This requirement begins at the time of informed consent and ends 90 days after the last 
administration of IMP. Male study participants must also not donate sperm from baseline until 90 
days after the last administration of IMP. 
5.3 
Exclusion Criteria 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: 
1. A positive pregnancy test or breast-feeding for female subjects. 
2. Any hepatic decompensation, defined as a past or current history of hepatic encephalopathy, 
gastrointestinal tract bleeding due to esophageal varices, or ascites. 
3. INR > 1.2 unless subject is on anticoagulant therapy. 
4. ALT > 3 x ULN. 
5. Total bilirubin > 1 x ULN. 
6. Planned or current plasmapheresis or other extra-corporeal treatments (e.g., MARS) for 
treatment-refractory pruritus. 
7. History of liver transplantation, current placement on a liver transplant list or current MELD score 
≥ 15. 
8. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, 
hepatocellular carcinoma.  
9. Hepatorenal syndrome (type I or II) or Screening serum creatinine > ULN.  
10. Competing etiology for liver disease (e.g., hepatitis C, active hepatitis B, NASH, ALD, 
autoimmune hepatitis, primary sclerosing cholangitis, Gilbert’s Syndrome). 
11. Subjects receiving prohibited medications within 3 months of Screening (Visit 1) according to the 
list (a, b and c) provided in Section 6.6.2. 
12. Treatment with any investigational agent within 4 weeks of Screening (Visit 1) or 5 half-lives of 
the IMP (whichever is longer). 
13. A history of long QT syndrome. 
14. Evidence of any of the following cardiac conduction abnormalities during the screening period: 
 
A QTc Fredericia interval > 450 milliseconds for males and > 470 milliseconds for 
females. 
 
A second or third degree atrioventricular block not successfully treated with a 
pacemaker. 
15. A history of severe cardiovascular disease defined as any of the following within the 12 weeks 
preceding initiation of study treatment: 
 
Acute myocardial infarction or unstable angina pectoris. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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 
A coronary revascularization procedure. 
 
Congestive heart failure New York Health Association (NYHA) Class III or IV. 
 
Stroke, including a transient ischemic attack. 
16. History of cancer in the preceding 5 years, except adequately treated non-melanoma skin 
cancer, carcinoma in situ of the cervix, in situ prostate cancer, in situ breast ductal carcinoma, or 
superficial bladder cancer stage 0). 
17. The occurrence of any acute infection requiring systemic antibiotic therapy within 2 weeks prior 
to Screening (Visit 1), or HIV infection. 
18. A history of bone marrow disorder including aplastic anemia, or marked anemia defined as 
hemoglobin < 10.0 g/dL (or 6.2 mmol/L). 
19. A known hypersensitivity to GKT137831 or to any of the excipients. 
20. Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for 
the participation of the subject in the study, or which could interfere with the study objectives, 
conduct, or evaluation. 
5.4 
Contraception  
Female subjects of childbearing potential must use a highly effective method of contraception to 
prevent pregnancy for 4 weeks before randomization and must agree to continue strict contraception 
for 90 days after the last administration of IMP.  
For the purposes of this trial, women of child bearing potential (WOCBP) are defined as “All female 
subjects after puberty unless they are post-menopausal (defined as amenorrhea for 12 months with 
documented date of last monthly period) or are surgically sterile (i.e., bilateral tubal occlusion).” For 
female subjects aged <55 who are considered post-menopausal and who are not on concomitant 
estrogen replacement therapy, confirmation of postmenopausal status will be required with follicle 
stimulating hormone (FSH) test results in the postmenopausal range for age at Screening (Visit 1).  
Highly effective contraception is defined as methods which can achieve a failure rate of less than 1% 
per year when used consistently and correctly. Such methods include: combined (estrogen + 
progestogen) hormonal contraception (oral/intravaginal/transdermal); progestogen-only hormonal 
contraception (oral/injectable/implantable); intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS); vasectomized partner (provided that partner is the sole sexual partner of the WOCBP 
study subject and that the vasectomized partner has received medical assessment of the surgical 
success); or sexual abstinence (defined as refraining from heterosexual intercourse from 4 weeks 
before randomization until 90 days after the last administration of IMP and only if this is the preferred 
and usual lifestyle of the subject). 
WOCBP must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine 
pregnancy test at baseline/Day 1 (Visit 2) before dosing.   


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Male participants with female partners of childbearing potential must be willing to use a condom and 
require their partner to use an additional form of adequate contraception as approved by the 
Investigator, such as an established form of hormonal contraceptive, a diaphragm or cervical/vault 
cap, IUD, or sponge with spermicide. This requirement begins at the time of informed consent and 
ends 90 days after last administration of IMP. Male study participants must also not donate sperm 
from baseline until 90 days after last administration of IMP. 
5.5 
Strategies for Recruitment, Retention and to Improve Adherence to 
Protocol 
Sites will be selected based on their access to the PBC population. Several strategies may be 
implemented as enhancements to support subject identification and recruitment, including 
advertising through patient advocacy groups/networks, on Orphanet and other health-related social 
networks and early engagement with Key Opinion Leaders in each country to provide PBC expertise 
as well as physicians actively treating patients in the selected countries to encourage potential 
referrals. 
Genkyotex’s designated Clinical Research Organization (CRO), Cmed, will provide ongoing 
management of enrollment by regular review of site performance. Upon indication a site may benefit 
from further support, the site and the Clinical Research Associate (CRA) will partner to re-examine 
the current recruitment strategy. 
5.6 
Treatment Assignment Procedures 
5.6.1 Randomization Procedures 
This will be a double-blind, randomized, placebo-controlled, multicenter, parallel group phase 2 trial. 
Approximately 100 subjects will be randomized and allocated to placebo or one of the 2 active 
treatment arms, according to a 1:1:1 randomization ratio, stratified at study entry by disease severity 
defined as baseline serum GGT < 2.5 x ULN or ≥ 2.5 x ULN). Accordingly, approximately 33-34 
subjects will be allocated to each of the 3 treatment arms.   
A master reproducible randomization list will be produced by or under the responsibility of Cmed 
accounting for block size and stratification. The IWRS will assign a unique randomization number in 
ascending, sequential order (with associated treatment arm) to the subject, based on the pre-
determined randomization schedule. The system will assign the pre-determined blocks of 
randomization numbers for each stratification level to ensure similarly balanced treatment groups. 
Assignment will be in sequential order within blocks and stratification level. The investigator will enter 
the randomization number in the electronic case report form (eCRF). 
5.6.2 Blinding Procedures 
This is a double-blind study: the Sponsor, subjects, investigator staff, persons performing the 
assessments and data reviewers and statisticians will remain blinded to the identity of the study 
treatments.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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The identity of the study treatments will be concealed by the use of IMPs which are all identical in 
packaging, labeling, schedule of administration, appearance and odor. 
Randomization data will be kept strictly confidential, and will be accessible only to authorized 
personnel (e.g., unblinded pharmacist or authorized designee), until unblinding of the trial as 
described in the statistical analysis plan (SAP). 
Unblinding will only occur for the following reasons: 
 
 Subject emergencies (see Section 5.6.3) 
 
Scheduled and unscheduled safety reviews by the SMB (see Section 9.7) 
 
At the time of the interim analysis (see Section 10.3) 
 
At the conclusion of the study. 
5.6.3 Emergency Breaking of Assigned Treatment Code 
If an emergency unblinding becomes necessary, the Investigator should notify the Sponsor/Medical 
Monitor prior to unblinding, if possible, unless identification of the IMP is required for emergency 
therapeutic measures. The result of the code break should not be revealed to the Sponsor/Medical 
Monitor. Unblinding will be performed through the IWRS. The Investigator will access the IWRS to 
access the subject’s treatment code. The Investigator may always, for urgent safety reasons, break 
the blind at any time during the conduct of the study. If the blind is broken, the date, time and reason 
must be recorded in the subject’s eCRF and any associated AE report.  
The unblinded treatment code must not be recorded in the eCRF. 
5.6.4 Reasons for Withdrawal 
Subjects will be informed that they have the right to withdraw from the study at any time, without 
prejudice to their medical care, and that they are not obliged to state their reasons. Any withdrawal 
must be fully documented in the eCRF, and should be followed up by the Investigator. 
The Investigator may withdraw a subject at any time if this is considered to be in the subject’s best 
interest. 
A subject MUST be withdrawn for the following reasons: 
 
Pregnancy or breast feeding. 
 
A change in UDCA dose during the treatment period. 
 
Confirmed or suspected DILI, as defined in Section 6.3.1. 
 
Confirmed or suspected liver decompensation, defined as hepatic encephalopathy, 
gastrointestinal tract bleeding due to esophageal varices, or ascites. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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 
Confirmed Grade ≥ 2 severity anemia without documented alternative cause, as defined in 
Section 6.3.2. 
 
Grade 3 severity AE recurring or not resolving after a pre-defined interruption and resumption of 
IMP (see Section 6.3). 
 
Any Grade 4 severity AE. 
 
Subject’s withdrawal of consent. 
The subject MAY be also discontinued for the following reasons: 
 
Protocol violations, including non-compliance and loss to follow-up. 
 
Safety reasons. 
 
Administrative reasons. 
 
Other: the subject was withdrawn for a reason other than those listed above, such as termination 
of the study by the Sponsor (see Section 5.6.6). 
A subject will be considered to have completed the study when he/she completes the final 
assessment visit of the follow-up period, i.e., Week 28 (Visit 8).   
5.6.5 Handling of Withdrawals 
If the IMP is prematurely discontinued (i.e., before Week 24), the primary reason for discontinuation 
must be recorded in the appropriate section of the eCRF and all efforts must be made to complete 
and report the observations as thoroughly as possible. A premature end of treatment evaluation 
should be performed following the subject’s withdrawal as described in Section 7.5, and recorded in 
the early termination eCRF page.  A final follow-up visit should be performed within 4 weeks 
following the early termination visit, as described in Section 7.4.  
If a subject fails to return for follow-up, attempts should be made to contact the subject to ensure the 
reason for not returning is not an AE. Likewise, if a subject decides to discontinue from the study, an 
attempt should be made to establish that the true reason is not an AE (bearing in mind subjects are 
not obliged to state their reasons). For subjects considered lost to follow-up, the eCRF must be 
completed up to the last visit performed. 
Ongoing AEs should be followed up in accordance with the procedures described in Section 9.2.4. 
Subjects who discontinue early will not be replaced. 
5.6.6 Termination of Study 
This study may be terminated at any time by the Sponsor because of safety concerns, ethical 
issues; plans to modify, suspend or discontinue the development of the IMP or serious and/or 
continued non-compliance with the protocol. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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If the study is suspended or terminated, the Sponsor will promptly inform the Investigator, and will 
also inform the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action. The relevant Institutional Review Board/Independent Ethics Committee (IRB/IEC) will 
also be informed promptly and provided the reason(s) for the termination or suspension by the 
Sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). 
The Sponsor may at any time, at its sole discretion, discontinue a study center for various reasons, 
including, without limitation, the following: 
 
Failure of the Investigator to enroll subjects into the study at a reasonable rate. 
 
Failure of the Investigator to comply with applicable laws and/or pertinent regulations. 
 
Submission of knowingly false information from the research facility to the Sponsor, CRA, or 
regulatory authorities. 
 
Insufficient adherence to protocol requirements. 
The Sponsor will issue a written notice to the Investigator, which will contain the reasons for taking 
such action. If the study center is terminated for non-compliance, the Sponsor will notify the 
appropriate regulatory authorities. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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6 
TREATMENT OF SUBJECTS 
6.1 
Identity of Study Treatment(s) 
6.1.1 Description and Formulation 
The description of IMP provided to each study center pharmacy is shown in Table 3. 
Table 3 
Description of Investigational Medicinal Products 
Drug code 
GKT137831 
Placebo 
Formulation 
Micronized API formulated with 
excipients in capsules 
Matching capsules containing only the 
excipients 
Strength 
100 mg 
- 
Route 
Oral 
Oral 
GKT137831 capsules will contain 100 mg GKT137831 powder formulated with the following 
excipients per capsule: microcrystalline cellulose, Aerosil® (silicon dioxide), magnesium stearate and 
hard gelatin. 
6.1.2 Packaging and Labeling 
The IMP will be packed and labeled in accordance with applicable local regulatory requirements and 
applicable International Conference for Harmonization (ICH) Good Manufacturing Practice (GMP) 
and ICH Good Clinical Practice (GCP) guidelines, and to protect the blinded nature of this clinical 
study. The multi-language tear-off label will be adapted to the size of the IMP package and 
translated into the appropriate languages. 
Child resistant 150 mL high-density polyethylene (HDPE) bottles with a tamper evident seal 
containing 70 capsules of either 100 mg GKT137831 capsules or matching placebo will be provided 
to the responsible pharmacist at the study center, who will dispense the bottles of IMP in cardboard 
packs for each subject, at each dispensing visit, in accordance with the Pharmacy Manual which will 
be developed according to ICH GCP guidelines and applicable local laws. 
6.1.3 Storage and Stability 
The IMP must be stored in a cool, dry, area at room temperature (between 15°C and 25°C). At the 
site IMP must be securely locked and stored with restricted access. Temperature should be 
controlled during shipment and during storage at study centers. The IMP must not be frozen or 
stored above 27°C.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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6.2 
Administration of Study Treatment(s) 
At each dispensing visit, each subject will be given individual packs containing 2, 4 or 6 (depending 
on the visit) IMP bottles (70 capsules of 100 mg GKT137831 and/or matching placebo per bottle), in 
accordance with Table 4 and the Pharmacy Manual. Each subject will be given a sufficient supply of 
IMP to last until the next study visit, with some overage (up to 3 days). 
Table 4 
Quantity of IMP Bottles Dispensed at Each Visit 
Visits 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Week 
Baseline/ 
Day 1 
2 
6 
12 
18 
24 (End of 
Treatment) 
IMP Bottles 
P 
A 
P 
A 
P 
A 
P 
A 
P 
A 
No dispensing 
Treatment arm 
Placebo 
2 
_ 
4 
_ 
6 
_ 
6 
_ 
6 
_ 
No dispensing 
400 mg OD 
1 
1 
2 
2 
3 
3 
3 
3 
3 
3 
No dispensing 
400 mg BID 
_ 
2 
_ 
4 
_ 
6 
_ 
6 
_ 
6 
No dispensing 
P = Placebo; A = Active (GKT137831) 
The IMP will be orally self-administered BID, once in the morning and once in the evening (aiming 
for a period of at least 10 hours between doses) with meals or up to 30 minutes after eating a meal. 
On the day of the visit, study subjects should not self-administer the IMP as usual but instead should 
bring the IMP bottles to the clinic (used and unused, see Section 6.5) where he/she will be instructed 
to self-administer the morning dose after the required pre-dose blood samplings have been 
performed, fasted. The subject must fast overnight from 10 p.m. 
The dose of test product will be 400 mg OD or 400 mg BID for 24 weeks. 
Each day during the treatment period, subjects will self-administer 4 capsules in the morning and 4 
capsules in the evening. 
All subjects will be provided with: 
 
2 bottles at baseline/Day 1 (Visit 2) and will self-administer: 
o 
When allocated to GKT137831 400 mg OD: 4 capsules of GKT137831 100 mg from one 
bottle in the morning and 4 capsules of placebo from the other bottle in the evening. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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o 
When allocated to GKT137831 400 mg BID: 4 capsules of GKT137831 100 mg from 
one bottle in the morning and 4 capsules of GKT137831 100 mg from the other bottle in 
the evening.  
o 
When allocated to placebo: 4 capsules of placebo from one bottle in the morning and 4 
capsules of placebo from the other bottle in the evening  
 
4 bottles at Week 2 (Visit 3) and will self-administer the IMP as described above. 
 
6 bottles at Week 6 (Visit 4), Week 12 (Visit 5) and Week 18 (Visit 6) and will self-administer the 
IMP as described above. 
Bottles will be blinded but will contain distinct identification to specify from which bottles the subject 
should take the capsules. 
Table 5 
Investigational Medicinal Product Self-Administration 
 
IMP Bottle 
4 capsules by intake 
(oral) 
Morning placebo 
Morning 100 mg 
Evening placebo 
Evening 100 mg 
Placebo 
X 
 
X 
 
400 mg OD 
 
X 
X 
 
400 mg BID 
 
X 
 
X 
 
6.3 
Criteria for Study Treatment Modification or Discontinuation 
AEs will be graded according to the CTCAE grading system. If an AE is not listed in the CTCAE, the 
Investigator will use a similar 4-point scale (Grade 1 = mild, 2 = moderate, 3 = severe and 4 = life 
threatening), as described in 9.2.1.1. 
In case of a Grade 1 or 2 severity AE, the subject will be treated as deemed appropriate by the 
Investigator, and treatment with the IMP should be continued as scheduled. 
In case of a Grade 3 severity AE, administration of the IMP must be interrupted until the severity of 
the event has resolved to ≤ Grade 2 and then resumed at 100% of the initial dose and schedule. 
Treatment withheld due to a Grade 3 severity AE will not be made up later. If a Grade 3 severity AE 
does not resolve to ≤ Grade 2 within 24 hours of IMP interruption, or if a Grade 3 severity AE recurs 
after resumption of IMP, the subject must be permanently discontinued from treatment (see Section 
5.6.4). 
In case of any Grade 4 severity AE, administration of the IMP must be permanently discontinued. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Withdrawals will be handled as described in Section 5.6.5. 
6.3.1 In case of Confirmed or Suspected Drug Induced Liver Injury 
In case of any of the following events: 
 
Grade ≥ 2 severity liver-related AE, or 
 
Grade ≥ 3 severity ALT or AST (i.e. ≥ 5x ULN), or 
 
Grade ≥ 2 severity total bilirubin (i.e. ≥ 1.5x ULN), or 
 
Grade ≥ 2 severity INR (i.e. ≥ 1.5x ULN)  
The investigator will instruct the subject to interrupt IMP administration and to return to the study 
center within 2-3 days to perform a re-test and to undergo additional investigations (i.e. close 
monitoring as described in Appendix F) to assess for potential DILI. In case of confirmed or 
suspected DILI as assessed by the investigator, IMP administration must be permanently 
discontinued, in particular in the following cases: 
 
Re-test ALT and/or AST values ≥ 3 x baseline and greater than the ULN associated with new 
onset total bilirubin ≥ 2 x ULN or INR ≥ 1.5. 
If subjects live in a remote area, they can be tested locally and the results communicated to the 
investigator site promptly. 
In case of non-confirmed DILI, IMP administration will be resumed in accordance with the protocol 
and subject will remain under close monitoring as deemed necessary by the investigator. 
Any confirmed or suspected DILI event will be closely monitored by the investigator and reported to 
Sponsor following the same procedure as for SAEs, as described in Section 9.5. 
Withdrawals will be handled as described in Section 5.6.5. 
6.3.2 In case of Anemia 
In case of grade ≥ 2 severity anemia, the Investigator will instruct the subject to interrupt IMP 
administration and to return to the study center within 7 days to perform a re-test of absolute 
reticulocyte count. 
If the re-test value is below 50% of baseline, and/or if an alternative cause for the anemia cannot be 
documented, treatment will not be resumed. IMP administration will be resumed only if the re-test 
value for the absolute reticulocyte count is ≥ 50% of the baseline value and an alternative cause for 
the anemia can be documented. The subject will continue to be closely monitored until 
normalization, i.e. return to baseline values. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Withdrawals will be handled as described in Section 5.6.5. 
6.3.3 In case of Drug Induced Hypothyroidism 
In case of TSH ≥ 10 mIU/L, the Investigator will instruct the subject to interrupt IMP administration 
and to return to the study center within 2-3 days to perform a re-test of TSH and measure free T4. 
If the re-test value is ≥ 10 mIU/L and the subject presents with signs and symptoms consistent with 
hypothyroidism or if overt biological hypothyroidism is confirmed (i.e. TSH ≥ 10 mIU/L and reduced 
free T4), treatment will not be resumed. If drug induced hypothyroidism is not confirmed, IMP 
administration will be resumed as per protocol. The subject will continue to be closely monitored until 
normalization, i.e. return to baseline values. 
Withdrawals will be handled as described in Section 5.6.5. 
6.4 
Accountability Procedures for the Study Treatment(s) 
Records will be maintained of the delivery of IMP to the study centers, the inventory at the study 
centers, the allocation to, use of, and return by each subject to the study center, and the return to the 
Sponsor. 
These records will include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the IMP and to the study subjects. No subject diary is planned. 
The Investigator will be responsible for ensuring the records adequately document that the subjects 
are provided the doses specified in the protocol and all IMP received from the Sponsor is reconciled. 
6.5 
Subject Compliance 
The assigned IMP, dosage, timing and mode of administration may not be changed, except as 
described in Section 6.3. Any departures from the intended regimen must be recorded in the eCRF. 
IMP accountability and subject compliance will be documented throughout the study using study-
specific IMP dispensing and return record forms. 
Subjects will be asked to return all used IMP, including empty and partially used containers. IMP will 
be dispensed at baseline/Day 1 (Visit 2), Week 2 (Visit 3), Week 6 (Visit 4), Week 12 (Visit 5) and 
Week 18 (Visit 6). At Week 2 (Visit 3), Week 6 (Visit 4), Week 12 (Visit 5), Week 18 (Visit 6) and 
Week 24 (Visit 7), the unused IMP dispensed to the subject at the previous visit will be returned to 
the Investigator. The Investigator will determine compliance by capsule count per bottle and batch 
number. Subjects exhibiting non-compliance as assessed by capsule counts will be counseled on 
the importance of good compliance to the study dosing regimen. Drug non-compliance is defined as 
taking less than 80% or more than 120% of IMP during the double-blind treatment period. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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6.6 
Concomitant Medications/Treatments 
6.6.1 Required Concomitant Medications 
Subjects must be taking UDCA for at least 6 months and be on a stable dose (defined as no 
changes) for at least 3 months prior to the first Screening visit (Visit 1). All efforts should be made to 
keep the dose of UDCA stable during the treatment period. Changes in UDCA dose during the 
treatment period will lead to the early discontinuation of the study subject. 
6.6.2 Prohibited Medications 
Note: these are not exhaustive lists. The FDA and other agencies maintain current lists, which can 
be referred to via their websites. Furthermore, these lists will evolve as new drugs come to market 
and more is learned about the pharmacology of GKT137831 and other medications. Therefore, they 
should be regarded as a minimum set of excluded and pre-cautioned concomitant medications. 
The following medications are prohibited within 3 months of Screening (Visit 1) and during the 
double-blind treatment period: 
a) OCA, budesonide and other systemic corticosteroids, colchicine, mycophenolate mofetil, 
azathioprine, sulfasalazine, leflunomide, cyclophosphamide, fenofibrates and other fibrates, 
valproate, isoniazid, and nitrofurantoin. 
b) Any biologic agent within 12 weeks or 5 half-lives prior to Screening (Visit 1), whichever is 
longer. In the case of rituximab, use within 168 days (24 weeks) of Screening or no recovery 
(level < 20% of pre-rituximab levels or below lower level of normal, whichever is lower) of 
CD19-positive B lymphocytes if the last dose of rituximab has been more than 24 weeks 
prior to Screening.  
c) Patients taking the following medications which are OAT1 and OAT3 substrates are not 
allowed on the study because of the underlying conditions these medications are used to 
treat: methotrexate, probenecid, aminohippurate, cephradine, cidofovir, adefovir, oseltamivir, 
acyclovir, ganciclovir, benzylpenicillin, cefaclor, ceftizoxime, bumetanide, famotidine, 
conjugated equine estrogens*, liothyronine, ouabain, caspofungin, liotrix, romidepsin, 
fluvastatin, paclitaxel, docetaxel, cobimetinib, selexipag, ambrisentan, grazoprevir, 
technetium tc 99m mebrofenin, and parachlorophenol. Should these drugs become 
necessary during the treatment period, the treating physician should make all efforts to use 
alternative drugs. However, where it is not feasible or desirable to change to an alternative, 
the subject must be monitored closely for occurrence of adverse events possibly related to 
drug accumulation as well as clinical effects of increased exposure, and consideration must 
be given to reducing the dose. 
*Only equine estrogen derivatives are prohibited. Synthetic estradiol is allowed. 
In addition, the following medications are prohibited during the double-blind treatment period: 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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d) Systemically administered potent CYP3A4 inhibitors: itraconazole, lopinavir/ritonavir, 
telaprevir, clarithromycin, ritonavir, ketoconazole, indinavir, conivaptan, and voriconazole.  
e) Sensitive CYP3A4 substrates which have a narrow therapeutic range: alfentanyl, astemizole, 
cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
systemic sirolimus, systemic tacrolimus, terfenadine. However, should fentanyl or alfentanyl 
use become necessary during the study, and where it is not feasible or desirable to change 
to an alternative, use of fentanyl or alfentanyl is permitted provided the dose is carefully 
titrated. 
f) 
UGT 
inhibitors 
and 
inducers: 
atazanavir, 
rifabutin, 
carbamazepine, 
phenytoin, 
oxcarbazepine, nevirapine, methsuximide and phenobarbital.  
g) Pruritus medication: rifampicin, naltrexone. Anti-histamines are permitted, if the dose is 
stable for at least 8 weeks before Screening (Visit 1) and throughout the study. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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7 
STUDY SCHEDULE 
The schedule of assessments table is provided in Appendix A. A schedule of blood sampling, 
including required volumes, is provided in Appendix B. All PD samples are to be collected pre-dose 
and in fasting condition. Transient elastography must be performed in the morning in fasting 
condition. 
7.1 
Screening 
Visit 1 (Week -4 to -1) 
The following assessments and procedures will be performed at Screening: 
 
Signed informed consent. 
 
Determination of eligibility. 
 
Demographics and medical history. 
 
Height and oral or tympanic temperature. 
 
Serum pregnancy test for female subjects of childbearing potential. 
 
Blood sample for viral serology (HIV antibodies 1 and 2, hepatitis B surface antigen and hepatitis 
C virus antibodies). 
 
Blood samples for the determination of anti-mitochondrial antibodies (anti-AMA, anti-GP210, 
anti-SP100, antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex]). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Urinalysis (dipstick). 
 
Pulse rate, SBP and DBP. 
 
12-lead ECG. 
 
Complete physical examination. 
 
Prior and concomitant medication recording. 
 
Recording of AEs. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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7.2 
Enrollment/Baseline 
Visit 2 (Day 1) 
The following assessments and procedures will be performed at baseline: 
 
Confirmation of eligibility (not every eligibility assessment needs to be repeated; i.e., 
confirmatory laboratory and diagnostic tests. Subjects with AEs at baseline may need to be 
withdrawn in accordance with the eligibility and withdrawal criteria). 
 
Body weight. 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Optional collection of blood sample for DNA (only for subjects who have signed the additional, 
specific consent form). 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen, IL-6, CK-18). 
 
Blood samples for markers of fibrosis (ELF score, collagen fragments). 
 
Blood samples for optional assessments of immunological markers (IgM, IL-4, IL-12, IL-17A, 
IFNγ). 
 
Blood samples for mandatory and optional assessments of bile acid metabolism (serum, C4, 
total bile acids, FGF-19). 
 
Blood samples for optional additional biomarkers. 
 
Blood samples for optional metabolomic studies. 
 
Transient elastography (FibroScan® or similar technology). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Thyroid function tests. 
 
PBC-40 QoL questionnaire and pruritus VAS. 
 
Pulse rate, SBP and DBP. 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording. 
 
Randomization. 
 
Dispense IMP. 
 
Supervise subject during first self-administration of IMP. 
 
Recording of AEs. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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7.3 
Treatment Period 
Visit 3 (Week 2 ± 3 Days) 
The following assessments and procedures will be performed after 2 weeks of treatment ± 3 days: 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Thyroid function tests. 
 
Pulse rate, SBP and DBP. 
 
12-lead ECG: post-dose, 12-lead ECG is to be performed around Tmax, (i.e. 1 to 4 hours post 
dose). 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording. 
 
Dispense IMP. 
 
Blood samples for PK: one pre-dose and two post-dose samples. See Table 7 for time points. 
 
Recording of AEs. 
 
Record subject’s compliance with treatment regimen. 
 
Visit 4 (Week 6 ± 3 Days)  
The following assessments and procedures will be performed after 6 weeks of treatment ± 3 days: 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Thyroid function tests. 
 
Pulse rate, SBP and DBP. 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording 
 
Dispense IMP. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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 
Recording of AEs. 
 
Record subject’s compliance with treatment regimen. 
 
Visit 5 (Week 12 ± 3 Days)  
The following assessments and procedures will be performed after 12 weeks of treatment ± 3 days: 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen, IL-6, CK-18). 
 
Blood samples for markers of fibrosis (ELF score, collagen fragments). 
 
Blood samples for optional assessments of immunological markers (IgM, IL-4, IL-12, IL-17A, 
IFNγ). 
 
Blood samples for mandatory and optional assessments of bile acid metabolism (serum, C4, 
total bile acids, FGF-19). 
 
Blood samples for optional additional biomarkers. 
 
Blood samples for optional metabolomic studies. 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Thyroid function tests. 
 
Urinalysis (dipstick). 
 
PBC-40 QoL questionnaire and pruritus VAS. 
 
Pulse rate, SBP and DBP. 
 
12-lead ECG: post-dose, 12-lead ECG is to be performed around Tmax, (i.e. 1 to 4 hours post 
dose). 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording. 
 
Dispense IMP. 
 
Blood samples for PK: one pre-dose and two post-dose samples. See Table 7 for time points. 
 
Recording of AEs 
 
Record subject’s compliance with treatment regimen. 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Visit 6 (Week 18 ± 3 Days) 
The following assessments and procedures will be performed after 18 weeks of treatment ± 3 days: 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Thyroid function tests. 
 
Pulse rate, SBP and DBP. 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording. 
 
Dispense IMP. 
 
Blood sample for PK: one post-dose sample. See Table 7 for time point. 
 
Recording of AEs. 
 
Record subject’s compliance with treatment regimen. 
 
Visit 7 (Week 24 ± 3 Days): End of Treatment Visit 
The following assessments and procedures will be performed after 24 weeks of treatment (end of 
treatment) and recorded in the Week 24/End of Treatment eCRF: 
 
Body weight. 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen, IL-6, CK-18). 
 
Blood samples for markers of fibrosis (ELF score, collagen fragments). 
 
Blood samples for optional assessments of immunological markers (IgM, IL-4, IL-12, IL-17A, 
IFNγ). 
 
Blood samples for mandatory and optional assessments of bile acid metabolism (serum, C4, 
total bile acids, FGF-19). 
 
Blood samples for optional additional biomarkers. 
 
Blood samples for optional metabolomic studies. 
 
Transient elastography (FibroScan® or similar technology). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
CONFIDENTIAL 
Page 58 of 113 
 
Thyroid function tests. 
 
Urinalysis (dipstick). 
 
PBC-40 QoL questionnaire and pruritus VAS. 
 
Pulse rate, SBP and DBP. 
 
12-lead ECG. 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording. 
 
Recording of AEs. 
 
Record subject’s compliance with treatment regimen. 
7.4 
Final Study Visit (Follow-Up) 
Visit 8 (Week 28 ± 3 Days)  
The following assessments and procedures will be performed 4 weeks after the end of treatment ± 3 
days: 
 
Urine pregnancy test for female subjects of childbearing potential. 
 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen). 
 
Blood samples for optional additional biomarkers. 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Urinalysis (dipstick). 
 
Pulse rate, SBP and DBP. 
 
Complete physical examination. 
 
Concomitant medication recording. 
 
Recording of AEs. 
7.5 
Early Termination Visit 
If a subject discontinues treatment earlier than Week 24, the following assessments and procedures 
should be performed and recorded in the Early Termination eCRF. The subject should return to the 
clinic within 4 weeks after the Early Termination visit for a Final Study visit as detailed in Section 7.4. 
 
Body weight. 
 
Urine pregnancy test for female subjects of childbearing potential. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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 
Blood samples for markers of inflammation and liver injury (hsCRP, fibrinogen, IL-6, CK-18). 
 
Blood samples for markers of fibrosis (ELF score, collagen fragments). 
 
Blood samples for optional assessments of immunological markers (IgM, IL-4, IL-12, IL-17A, 
IFNγ). 
 
Blood samples for mandatory and optional assessments of bile acid metabolism (serum, C4, 
total bile acids, FGF-19). 
 
Blood samples for optional additional biomarkers. 
 
Blood samples for optional metabolomic studies. 
 
Transient elastography (FibroScan® or similar technology). 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and 
INR. 
 
Thyroid function tests. 
 
Urinalysis (dipstick). 
 
PBC-40 QoL questionnaire and pruritus VAS. 
 
Pulse rate, SBP and DBP. 
 
12-lead ECG. 
 
Symptoms-directed physical examination. 
 
Concomitant medication recording. 
 
Recording of AEs. 
 
Record subject’s compliance with treatment regimen until discontinuation of treatment. 
7.6 
Unscheduled Visit  
All unscheduled study visits, procedures, examinations, clinical laboratory evaluations etc., will be 
noted in the subject’s medical record including: 
 
Reason for visit/procedure. 
 
Follow-up. 
 
Recording of AEs and use of concomitant measures. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Page 60 of 113 
8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
8.1.1 Demographics and Medical History 
Demographic and baseline characteristic data will be collected on all subjects at Screening (Visit 1).  
Relevant medical history/baseline medical conditions will be recorded. 
Prior and concomitant medications history will be recorded (prescription medications, over-the-
counter and herbal remedies). Assessment of eligibility at Visits 1 and 2 should include a review of 
permitted and prohibited medications (see Section 6.6). 
8.1.2 Physical Examination 
Height will be recorded at Screening (Visit 1). Body weight will be recorded at baseline/Day 1 (Visit 
2) and Week 24 (Visit 7). 
A complete physical examination will be performed at Screening (Visit 1) and the Week 28 follow-up 
(Visit 8) and will include: general appearance, skin, head and neck, eyes-ears-nose-throat, lymph 
node palpation, lungs, chest, abdomen, extremities, and neurological function. 
A symptom-directed physical examination will be performed at all other visits. This examination will 
always be associated with the occurrence of an AE. 
In the absence of any AE, the physical examination will be reported “normal” for all items in the 
eCRF. 
8.1.3 Vital Signs 
Vitals signs measurements will include: 
 
Oral or tympanic temperature, at Screening (Visit 1). 
 
Pulse rate at all visits. 
 
Blood pressure: SBP and DBP, at all visits. 
Supine blood pressure and pulse rate will be measured using an automatic device after the subject 
has rested comfortably for 5 minutes.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Page 61 of 113 
8.1.4 Electrocardiogram 
A 12-lead ECG will be performed during Screening (Visit 1) and at Weeks 2, 12, and 24 (Visits 3, 5, 
and 7, respectively). The measurement will be performed around Tmax (i.e. 1 to 4 hours post dose). 
ECG recordings will be reviewed locally by the Investigator or by a designated cardiologist. ECG 
parameters including heart rate, QRS axis, PR interval, QRS duration and QT will be recorded. 
8.1.5 Transient Elastography (FibroScan® or Similar Technology) 
Transient elastography (FibroScan® or similar technology) will be performed at selected centers at 
baseline/Day 1 (Visit 2) and Week 24 (Visit 7). Absolute and percent change in liver stiffness will be 
recorded. If transient elastography is not performed, this will not be a major protocol deviation. 
8.1.6 Subject Reported Outcomes 
PBC-40 
All subjects will complete the PBC-40 questionnaire (see Appendix E) at baseline/Day 1 (Visit 2), 
Week 12 (Visit 5) and Week 24 (Visit 7).  
The PBC-40 is a subject-derived, disease specific QoL measure developed and validated for use in 
PBC. It is designed for self-completion and takes approximately 45 minutes to complete.   
Pruritus VAS 
Pruritus will be self-assessed by the subject using a Pruritus VAS (see Appendix D) at baseline/Day 
1 (Visit 2), Week 12 (Visit 5) and Week 24 (Visit 7). To capture the intensity of itching within the 24 
hours preceding these visits, subjects are to be asked to write a number from 0 to 10 below the 
horizontal scale, with no decimal. Subjects should not mark a cross on the actual horizontal line, nor 
should the line be measured to obtain a value. 
Table 6 
Pruritus VAS Assessment [66] 
VAS Score (Scale is 0 to 10) 
Meaning 
0  
No pruritus 
>0 but <4 
Mild pruritus 
>4 but <7 
Moderate pruritus 
>7 but <9 
Severe pruritus 
>9 
Very severe pruritus 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Page 62 of 113 
 
8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
The following safety laboratory investigations will be conducted at time points indicated in “Schedule 
of Assessments” (Appendix A).   
The following clinical safety laboratory tests will be performed at each visit: 
 
Hematology: hematocrit, hemoglobin, absolute and relative reticulocyte counts, red blood cell 
(RBC) count, white blood cell (WBC) count, differential WBC count, platelet count, absolute 
neutrophil count, mean cell volume and INR. 
 
Biochemistry: glucose, total protein, albumin, creatinine, urea, creatine kinase, total cholesterol, 
triglycerides, sodium, potassium, chloride, ALP, AST, ALT, conjugated and total bilirubin and 
GGT.  
 
TSH levels will be tested at each visit, except Visits 1 and 8. Free T4 will be also measured if 
TSH levels are ≥ 10 mIU/L. 
Urinalysis (to be performed at Visits 1, 5, 7 and 8): quantitative test for pH and protein; qualitative 
tests for glucose, ketones, bilirubin, blood; microscopic examination of the sediment. 
Viral serology will be performed at Screening (Visit 1): HIV antibodies (1 and 2), hepatitis B surface 
antigen and hepatitis C virus antibodies. 
Determination of AMA will be performed at Screening (Visit 1): AMA titer, or if AMA is negative or in 
low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against 
the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]). 
Female subjects of child-bearing potential must have a negative serum pregnancy test documented 
at Screening (Visit 1). A negative urine pregnancy test must be done prior to study intervention at 
baseline/Day 1 (Visit 2) and all subsequent visits and the results must be available prior to 
dispensing of IMP. 
8.2.2 Pharmacokinetics 
For the PK assessments, venous blood samples of 2 mL each taken by venipuncture at the time 
points listed in Table 7. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Table 7 
Pharmacokinetic Time Points 
Visit 
Pre-dose time point 
Post-dose time points 
Week 2 ± 3 Days  
(Visit 3) 
One 2 mL sample taken before subject 
takes the morning dose 
 
One 2 mL sample taken 1-2 hours 
after morning dose 
 
One 2 mL sample taken before 
subject leaves clinic but no earlier 
than 2 hours after first post-dose 
sample 
Week 12 ± 3 Days  
(Visit 5) 
One 2 mL sample taken before subject 
takes the morning dose 
 
One 2 mL sample taken 1-2 hours 
after morning dose 
 
One 2 mL sample taken before 
subject leaves clinic but no earlier 
than 2 hours after first post-dose 
sample 
Week 18 ± 3 Days  
(Visit 6) 
N/A 
One 2 mL sample taken before subject 
leaves clinic at 3-4 hours after morning 
dose 
Plasma samples will be analyzed for the determination of concentrations of GKT137831 and its main 
active metabolite, GKT138184, using a validated bioanalytical method.  
Detailed information about the blood sample collection, processing, handling, storage, and shipping 
is provided in the Laboratory Manual. 
8.2.3 Pharmacogenetics 
Genetic and pharmacogenetic research may be conducted on the DNA samples collected during the 
study from subjects who sign an optional, additional informed consent. A 5 mL venous blood sample 
will be collected into a suitable tube at baseline/Day 1 (Visit 2) pre-dose for genotyping purposes. 
Sample labels will include: 
 
Study Number. 
 
Genotyping. 
 
Subject ID number. 
 
Collection date (dd/mm/yyyy). 
 
Visit 2 pre-dose. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Detailed information about the blood sample collection, processing, handling, storage, and shipping 
is provided in the Laboratory Manual. 
8.2.4 Pharmacodynamics 
All PD samples are to be collected pre-dose and in fasting condition. These sample collections are 
not optional for the subject, meaning that blood samples must be collected for all subjects and 
defined time points. The actual testing analysis of the collected samples is optional. 
Venous blood samples (4 mL at each sampling time point) will be collected for markers of 
inflammation and liver injury (hsCRP, fibrinogen) at baseline/Day 1 (Visit 2), and Weeks 2, 6, 12, 18, 
24 and 28 (Visits 3 – 8). 
Venous blood samples (4 mL at each sampling time point) will be collected for optional analysis of 
markers of inflammation and liver injury (IL-6, CK-18) at baseline/Day 1 (Visit 2), Weeks 12 and 24 
(Visits 5 and 7). 
Venous blood samples (4 mL at each sampling time point) will be collected for markers of fibrosis 
(ELF score and collagen fragments) at baseline/Day 1 (Visit 2), at Weeks 12 and 24 (Visits 5 and 7). 
Venous blood samples (1.5 mL at each sampling time point) will be collected for optional analysis of 
metabolomics, in fasting condition at baseline/Day 1 (Visit 2), and at Weeks 12 and 24 (Visits 5 and 
7). 
Venous blood samples (4 mL at each sampling time point) will be collected for mandatory and 
optional analysis of markers of cholestasis (Serum C4, total bile acids, and FGF 19) at baseline/Day 
1 (Visit 2), Weeks 12 and 24 (Visits 5 and 7). 
Venous blood samples (3 mL at each sampling time point) will be collected for optional analysis of 
immunological markers (IgM, IL4, IL12, IL1-7A, interferon γ) at baseline/Day 1 (Visit 2), Weeks 12 
and 24 (Visits 5 and 7). 
Venous blood samples (3 mL at each sampling time point) will be collected for optional analysis of 
biomarkers of interest. These samples will be collected at baseline/Day 1 (Visit 2), Weeks 12, 24 and 
28 (Visits 5, 7 and 8). The identity of these exploratory markers will be defined in response to 
findings described in the literature or obtained in this study. These markers will not have diagnostic 
or prognostic value and will not have an established normal range according to WHO. 
Detailed information about the blood sample collection, processing, handling, storage, and shipping 
is provided in the Laboratory Manual. 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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9 
ASSESSMENT OF SAFETY 
9.1 
Safety Parameters 
The safety of GKT137831 will be assessed through the recording, reporting and analyzing of 
baseline medical conditions, AEs, general physical examination, laboratory tests, 12-lead ECGs, and 
vital signs data. The timing and frequency of safety assessments are described in Section 8.  
9.2 
Adverse Events 
9.2.1 Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or disease that emerges or worsens relative to baseline during a clinical study 
with an IMP, regardless of causal relationship and even if no IMP has been administered. 
Unchanged/stable pre-existing, chronic medical conditions present at baseline, or those medical 
conditions related to the underlying disease whose changes during the study that are consistent with 
natural disease progression are NOT considered as AEs and should not be recorded in the AE 
pages of the eCRF unless a worsening has occurred.  
9.2.1.1 
Severity of Adverse Events 
AEs will be graded according to the CTCAE v4 grading system. The CTCAE v4 grading criteria must 
be used when available for an AE. Only when CTCAE v4 grading criteria are not available for a 
specific AE, will the Investigator assess the severity of the AE based on the following definitions:  
 
Grade 1 (mild): the subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
 
Grade 2 (moderate): the subject experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity. 
 
Grade 3 (severe): the subject is unable to carry out usual activities due to significant impairment 
of functioning. 
 
Grade 4 (life-threatening): the subject’s life is at risk from the event. 
9.2.1.2 
Causality Assessment 
The Investigator will determine whether or not, in his/her opinion, the AEs are related to the IMP 
according to the following definitions: 
 
Unrelated: due to extraneous causes and does not meet criteria listed under unlikely, possible or 
probable. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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 
Unlikely (or improbable): relationship not likely according to present knowledge. Does not follow 
a reasonable temporal sequence from administration. May have been produced by the subject’s 
clinical state or by environmental factors or other therapies administered. 
 
Possible: follows a reasonable temporal sequence from administration: possibility that the AE 
may have been caused by the IMP but may also have been produced by the subject’s clinical 
state or by environmental factors or other therapies administered. 
 
Probable: clear-cut temporal association with improvement on cessation of IMP or reduction in 
dose. Reappears upon re-challenge. Follows a known pattern of response to IMP. 
9.2.1.3 Abnormal Laboratory Values/and Other Objective 
Measurements 
Abnormal laboratory findings and other objective measurements such as vital signs and ECGs, 
should NOT routinely be captured and reported as AEs as they will be collected and analyzed 
separately in the eCRF. However, abnormal laboratory findings and other objective measurements 
which (i) meet the criteria for a SAE (see Section 9.3.1), or (ii) result in discontinuation of the IMP or 
in treatment being withheld (see Sections 5.6.4 and 6.3, respectively), or (iii) require medical 
intervention should be captured and reported in the AE pages of the eCRF. 
If reporting an abnormal laboratory finding in the AE pages of the eCRF, a clinical diagnosis should 
be recorded rather than the abnormal value itself, if available (for example “anemia” rather than 
“decreased RBC count” or “hemoglobin = 10.5 g/dl”). 
9.2.2 Eliciting Adverse Events 
AEs will be obtained by the Investigator at scheduled or unscheduled study visits, following physical 
examination, based on information spontaneously provided by the subject and/or through 
questioning. 
To elicit AEs, simple questions with minimal connotations should be used as the initial questions at 
all evaluation points during the study. For example: 
 
How have you felt since your last visit? 
 
Have you had any health problems since you were here last? 
In the case that a subject was seen by a health care professional other than the Investigator (e.g., at 
a different institution) concerning an AE, every effort should be made by the Investigator to contact 
the treating physician in a timely manner in order to obtain all necessary information and report the 
event appropriately. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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9.2.3 Recording Adverse Events 
As quality and precision of acquired AE data is of key importance, the Investigator should use the 
AE definitions provided in above sections and observe the following guidelines when completing the 
AE pages of the eCRF: 
 
Whenever possible, recognized medical terms should be used to describe AEs rather than 
colloquialisms (for example, ‘influenza’ rather than ‘flu’), and abbreviations should be avoided. 
 
AEs should be described using a specific clinical diagnosis rather than component signs or 
symptoms, if this is available (for example, ‘congestive heart failure’ rather than ‘dyspnea, rales 
and cyanosis’). However, signs and symptoms considered unrelated to an identified disease or 
syndrome should be reported as individual AEs in the eCRF. 
 
AEs occurring secondary to other events (e.g., sequelae or complications) should be identified 
by the primary cause. A primary AE, if clearly identifiable, generally represents the most accurate 
clinical term to record in the AE pages of the eCRF. 
Additional guidance can be found in the eCRF completion conventions provided by the Sponsor. 
For the purposes of this study, any detrimental change in the subject’s condition, after signing the 
informed consent form (ICF) and up to completion of the 28-day follow-up period after the last 
administration of IMP, should be considered an AE. AEs should be followed-up in accordance with 
the procedures described in Section 9.2.4.  
9.2.4 Follow-up of Adverse Events 
The primary objective of the post-treatment period is to check for any withdrawal and/or residual 
effects of GKT137831 which manifest after discontinuation of IMP administration. Reporting of AEs 
during the post-treatment period is defined as follows: 
 
All AEs which occur within 28 days from the last administration of IMP will be recorded in the AE 
pages of the eCRF as defined above. 
 
All ongoing AEs considered at least possibly related to the IMP will be followed until resolution or 
until the Investigator assesses them as ‘chronic’ or ‘stable’. 
 
If the Investigator becomes aware of a SAE, including death, after the 28 days post-treatment 
period and the SAE is considered by the Investigator to be at least possibly related to the IMP, it 
will be reported to the designated CRO safety group in accordance with Section 9.3.2. 
Taking the above post-treatment safety surveillance reporting requirements into account, AE follow-
up information data will be recorded in the AE pages of the eCRF up until Last Subject Last Visit. 
After Last Subject Last Visit and prior to database lock, the status of all outstanding ongoing AEs will 
be checked and any up-to-date change made in the eCRF. At that stage, as considered appropriate 
by the Sponsor, follow-up information will continue to be requested from the Investigator on specific 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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AEs (and in any case all SAEs considered at least possibly related by the Investigator) although 
related details will not be recorded in the eCRF beyond database lock. 
9.3 
Serious Adverse Events 
9.3.1 Definition of Serious Adverse Event 
A SAE is defined as an AE which meets one of the following criteria: 
 
Results in death. 
 
Is life-threatening (defined as a subject at immediate risk of death at the time of the event). 
 
An event requiring inpatient hospitalization or prolongation of existing hospitalization.  
Note: In general, hospitalization signifies that a person has been detained (usually overnight) at a 
hospital or emergency ward for observation and/or treatment. Emergency room visits which do not 
result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., 
life-threatening; required intervention to prevent permanent impairment or damage; other serious, 
medically important event.  
 
Results in a persistent or significant disability/incapacity. 
Note: The term significant disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions, i.e., the AE resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical activities and/or 
quality of life. 
 
Is a congenital anomaly or birth defect. 
 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the above criteria. An AE of severe intensity might not 
necessarily be considered serious. For example, persistent nausea for several hours may be 
considered severe, but not a SAE. Conversely, a stroke resulting in only a limited degree of disability 
may be considered mild, but would be a SAE. 
All SAEs will be: 
 
Recorded in the eCRF from the time of signed informed consent until 28 days after the last dose 
of IMP, regardless of suspected relationship to IMP.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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 
Recorded on the appropriate SAE Report Form and reported in accordance with the procedures 
described in Section 9.3.2. 
 
Followed until resolution, stabilization or until determined to be chronic by the Investigator. 
 
Reviewed and evaluated by the Investigator. 
9.3.2 Reporting of Serious Adverse Events 
Any SAE occurring in a subject who has signed the informed consent and until 28 days after the last 
administration of IMP must be reported by the Investigator to the designated CRO safety group 
(Cmed) within 24 hours of first awareness even if the SAE does not appear to be associated with 
the IMP. Any SAEs experienced after this period should be reported to the designated CRO 
designee safety group if the investigator has assessed that the SAE is reasonably related to IMP 
administration.  
Information about the SAE (either initial or follow-up) should be collected and recorded on the paper 
Serious Adverse Event Report Form. A causality assessment must be provided at the time of 
reporting. The form should be completed in English and signed and dated by the investigator.  
SAEs should be reported by emailing or faxing a copy of the SAE Report form plus other relevant 
information to the designated CRO safety group. The SAE may be reported by telephone; however, 
this should be followed up within 24 hours with a copy of the SAE Report form. Additionally, it may 
be necessary for the designated CRO safety group to communicate with the Investigator if additional 
information is required.   
During both business and non-business hours, the email address, telephone and fax numbers listed 
below should be used to notify the designated CRO safety group: 
Reportable Events Hotline: 
Cmed Clinical Services 
Email: sae@cmedresearch.com 
24 Hour Phone: 0044 (0)1403 758462 
US Toll-Free Phone: 1 866 966 8429 
Fax: 0044 (0)1403 330459 
US Toll-Free Fax: 1 866 966 2970 
The SAE Report Form must be completed and forwarded via email or facsimile to the designated 
CRO safety group using the email address or fax number listed above within 24 hours of becoming 
aware of the event.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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All additional follow-up evaluations must be reported within 24 hours to the designated CRO safety 
group. All SAEs will be followed until resolution, stabilization or the Investigator determines the event 
to be chronic.  
The Sponsor is responsible for complying with applicable regulatory reporting requirements for SAEs 
and, where necessary, for ensuring the relevant authorities are notified (see Section 9.4). The 
Investigator will ensure the appropriate IRBs/IECs are notified of the SAE in accordance with ICH 
GCP and local regulatory requirements.  
9.4 
Regulatory Reporting of Serious, Unexpected, Adverse Reactions 
(SUSARs) 
Following notification from the Investigator, the Sponsor and/or it’s designee (CRO) will report events 
which are both serious and unexpected (not previously described in the reference safety information 
in the approved IB) and that are associated with the IMP to the FDA, EMA, other concerned 
Regulatory Authorities, IRB/IECs and investigators within the required timelines as specified in 21 
Code of Federal Regulations (CFR) Part 312.32, EU Directive 2001/20/EC, the European 
Commission’s “Detailed guidance on the collection, verification, and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for human use” (CT-3, June 
2011), ICH GCP Guidelines and other applicable national regulatory requirements. Typically, fatal 
and life-threatening events must be reported within 7 calendar days and all other SAEs must be 
notified in within 15 calendar days. All serious events designated as not related to the IMP, will be 
reported to the concerned Regulatory Authorities, and IRB/IECs at least annually in a summary 
format.  
Additionally, events may occur during a clinical trial which do not fall within the definition of a SUSAR 
and thus are not subject to the reporting requirements for SUSARs, even though they may be 
relevant in terms of subject safety. Examples are new events related to the conduct of a trial or the 
development of an IMP likely to affect the safety of subjects such as:  
 
A SAE which could be associated with the trial procedures and which could modify the conduct 
of the trial. 
 
A significant hazard to the subject population such as lack of efficacy of an IMP used for the 
treatment of a life-threatening disease. 
 
A major safety finding from a newly completed animal study (such as carcinogenicity). 
 
A temporary halt of a trial for safety reasons if the trial is conducted with the same IMP in another 
country by the same Sponsor, recommendations of the SMB, if any, where relevant for the safety 
of subjects. 
These events/observations are not to be reported as SUSARs, but they might require other action, 
such as urgent safety measures and their notification, substantial amendments, or early termination 
of the trial, and shall be reported in accordance with applicable local regulations and guidelines. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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9.5 
Drug-Induced Liver Injury 
If a study subject, who has been exposed to the IMP, presents signs or symptoms of DILI, a close 
monitoring must be initiated and documented by the investigator. The IMP must be discontinued until 
re-testing is performed, additional investigations completed and a diagnosis made. If DILI is 
confirmed or suspected by the investigator, the investigator will complete an Expedited Liver 
Assessment Report form (ELAR) and submit it to Sponsor in the same timelines as a SAE (see 
Section 9.3.2. The ELAR form must be completed and forwarded via email or facsimile to the 
designated CRO safety group using the email address or fax number listed in Section 9.3.2 within 24 
hours of the Investigator becoming aware of the confirmed or suspected DILI event.  
9.6 
Pregnancy 
If a female study subject who has been exposed to the IMP becomes pregnant, the course and 
outcome of the pregnancy should be monitored and documented. The IMP must be discontinued. If 
a female partner of a male study subject who has been exposed to the IMP becomes pregnant, and 
the subject provides this information, then the pregnancy will be documented, based on information 
provided by the subject. Any pregnancy (either female study participants or female partners of male 
study participants) must be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Consent to report information regarding 
pregnancy outcome should be obtained from the female partners of male study participants. The 
study treatment must be discontinued for pregnant participants.  
Although pregnancy itself is not considered as an AE, all pregnancies occurring inadvertently during 
the study pre-treatment, treatment and post-treatment period must be reported in the same timelines 
as a SAE, but by using the Clinical Trial Pregnancy Report Form. The form must be completed and 
forwarded via email or facsimile to the designated CRO safety group using the email address or fax 
number listed in Section 9.3.2 within 24 hours of the Investigator becoming aware of the pregnancy.  
If the outcome or course of the pregnancy involves a SAE (e.g., a congenital anomaly) then the SAE 
form should be completed in addition to the updated Clinical Trial Pregnancy Report Form. 
Spontaneous abortions and congenital birth defects should always be reported as SAEs (see 
Section 9.3). 
9.7 
Safety Monitoring Board 
In order to ensure subject safety, an independent SMB will conduct periodic, scheduled and 
unscheduled reviews of subject data while the study is in progress. The role and responsibilities of 
the SMB will be outlined in detail in a separate SMB charter. 
The predefined triggers, scope, and process for unscheduled SMB meetings will be outlined in the 
SMB charter. Briefly, at any time, the SMB, Study Director or Sponsor may request an unscheduled 
SMB review of the study data based on concern for subject safety. In addition, unscheduled SMB 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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meetings will take place if predefined events occur, including any death or immediately life-
threatening condition, or a permanent interruption of IMP administration due to DILI or anemia. 
The SMB will receive outputs of the unblinded eCRF and laboratory data, and adjudicate on subject 
status changes and dosing decisions (where appropriate). The data will include, but is not limited to, 
demographics, subject enrolment, baseline characteristics, AE data, SAE data (by severity and 
causality), laboratory data including PK, dose adjustments, protocol adherence, and subject 
withdrawals. The SMB will evaluate the progress of the study, assess data quality and timeliness, 
participant recruitment, accrual and retention, and participant risk versus benefit. In addition the SMB 
will monitor external factors relevant to the study. For example, scientific and therapeutic 
developments which may affect participant safety or ethical status. Based on the observed benefits 
or adverse effects, the SMB will make recommendations to the Sponsor concerning continuation, 
termination or modifications of the study. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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10 
STATISTICAL CONSIDERATIONS 
10.1 
Study Hypotheses 
The testing assumption for the primary endpoint, for each dose separately vs placebo, is: 
P
G
P
G
A
P
G
P
G
H
H












2
1
2
1
0
or     
    
:
  ,
:
 
Where: 
2
1,
G
G 

 
Mean percent change from baseline in serum GGT after 24 weeks in the active 
GKT137831 group.   
P

 
Mean percent change from baseline in serum GGT after 24 weeks in the Placebo group.   
The null hypothesis is that there is no difference in efficacy between the two doses of GKT137831 
and placebo. The alternative hypothesis is that there is a difference.  
10.2 
Sample Size Considerations 
A sample size of 34 randomized and treated subjects within each treatment group with an overall 
sample size of 102 subjects will have 80% power to detect a 28% difference in the means of the 
percent change from baseline in serum GGT. A Wilcoxon Mann-Whitney test has been used for the 
sample size estimate because this represents the worst-case scenario with regards to statistical 
power. A standard deviation of 30 for the active GKT137831 group and a standard deviation of 40 
for the placebo group have been assumed based on a recent phase 3 clinical trial of OCA [65].  
An overall two-sided Type I error of 5% has been considered for the sample size estimate. The 
Hochberg method will be used to adjust the alpha level for multiple comparisons, therefore the first 
dose level comparison at the final analysis will be tested against an alpha level of 0.04695 and the 
second dose level will be tested against an alpha level of 0.023475. The alpha level of 0.023475 has 
been used for the sample size calculation. 
The sample size calculation assumes all subjects, including withdrawals will be included in the 
analysis. Hence there has been no adjustment for dropouts.  
10.3 
Planned Interim Analyses 
An interim analysis is planned once 80-90% of the planned number of subjects to be randomized in 
the study have completed their Week 6 visit. The primary efficacy endpoint for the interim analysis is 
the percent change from baseline to the Week 6 visit in serum GGT. Only data collected for these 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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randomized subjects, prior to and including the date of the Week 6 visit for the last subject to be 
randomized into the interim analysis cohort, will be included in the interim analysis. The purpose of 
the interim analysis is to support decision making with regards to the further development of 
GKT137831. It is not intended to amend the study protocol or stop the trial due to futility or 
overwhelming efficacy.  
In addition to the analysis of the percent change from baseline to Week 6 in serum GGT, the interim 
analysis will include supportive analyses of the absolute change from baseline to Week 6 in serum 
GGT, as well as absolute and percent change from baseline to Week 6 in serum levels of ALP, 
hsCRP, fibrinogen, ALT, AST, conjugated and total bilirubin, as well as the absolute and percent 
change in the APRI and FIB-4 scores. The specific contents of the interim analysis will be 
documented in the SAP.   
The interim analysis will be conducted by the unblinded SMB statistician, who has no involvement 
with study conduct. The interim analysis outputs will be communicated to the SMB and to a 
predefined disclosure committee, to aid decision-making with regards to the further development of 
GKT137831. However, to maintain the integrity of the trial data, no unblinding information for 
individual subjects will be shared outside of the SMB. Detailed communication flow will be outlined in 
the SMB charter and SAP.  
In addition to the interim analysis described above a SMB will oversee the safety of the participating 
subjects as described in Section 9.7. 
10.4 
Analysis Methods 
10.4.1 Analysis Populations 
The Intent-To-Treat (ITT) population will include all randomized subjects who receive at least one 
dose of IMP or placebo. The ITT population will be analyzed by the randomized treatment and will 
be used as the primary population for all analyses of efficacy. 
The Safety population will be used for the analysis of all safety data and will include all subjects who 
received at least one dose of IMP or placebo, irrespective of whether they were randomized. The 
Safety population will be analyzed by the treatment received.  
The Per Protocol (PP) population will be a subset of the ITT population and will include all subjects 
without a major protocol deviation. Protocol deviations will be defined with the classification of 
subjects excluded from analysis populations prior to unblinding at end of study.   
The PP population will be analyzed by the randomized treatment. This population will be for 
supportive analysis of the primary endpoint and secondary endpoints where deemed relevant.  
Major protocol deviations will be summarized by treatment group. All protocol deviations deemed 
important even if not leading to subject exclusion from the PP population will be listed.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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The Pharmacokinetic (PK) population will be used for the analysis of pharmacokinetic data and will 
include all subjects who received at least one dose of IMP, who have at least one valid PK 
measurement and who have no major protocol deviations relating to PK data. The PK population will 
be analyzed by the treatment received.  
10.4.2 
Definition of Analysis Endpoints: Primary, Secondary, Tertiary, 
Exploratory, Safety and Pharmacokinetics 
10.4.2.1 Primary Efficacy Endpoint 
The percent change from baseline to Week 24 (Visit 7) in serum GGT 
10.4.2.2 Secondary Efficacy Endpoints 
 
Absolute and percent change in serum GGT from baseline to each assessment. 
 
Absolute change in ELF score from baseline to Weeks 12 and 24. 
 
Absolute and percent change in serum ALP from baseline to each assessment.  
 
Absolute and percent change in serum levels of hsCRP, and fibrinogen, from baseline to each 
assessment. 
 
Absolute and percent change in serum ALT, AST, and conjugated and total bilirubin, from 
baseline to each assessment. 
 
Absolute and percent change in the FIB-4 and APRI scores, from baseline to each assessment 
(FIB-4: age (years) x AST (IU/L)/(platelet count (109/L) x (ALT (IU/L)1⁄2, APRI: AST (IU/L)/ upper 
normal limit AST)x100/platelet count (109/L). 
 
Absolute and percent change in liver stiffness as assessed by transient elastography 
(FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline 
and Week 24. 
 
Absolute and percent change in serum levels of collagen fragments indicative of collagen 
formation and degradation, from baseline to Weeks 12 and 24. 
 
Absolute and percent change in Quality of Life, Fatigue and Pruritus scores based on the PBC-
40 and Pruritus VAS, from baseline to Weeks 12 and 24. 
10.4.2.3 Tertiary Efficacy Endpoints 
 
Absolute and percent change in total bile acid levels from baseline to Weeks 12 and 24. 
 
Proportion of subjects achieving a 15, 20, 30 and 40% reduction in serum ALP from baseline to 
each assessment. 
 
Proportion of subjects who meet the definition of PBC responder criteria applying the Paris I, 
Toronto I, Toronto II, Toronto III, Toronto IV, Mayo II and Barcelona disease prognostic risk 
criteria at Weeks 12 and 24. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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10.4.2.4 Exploratory Endpoints 
 
Optionally, absolute and percent change in serum C4, and FGF19 from baseline to Weeks 12 
and 24. 
 
Optionally, absolute and percent change in serum IL-6 and CK-18, from baseline to Weeks 12 
and 24. 
 
Optionally, absolute and percent change in serum IgM, IL-4, IL-12, IL-17A, and interferon γ, from 
baseline to Weeks 12 and 24. 
 
Optionally, assessment of metabolomics signatures. 
 
Optionally, assessment of additional biomarkers of interest. 
10.4.2.5 Safety Endpoints 
 
Treatment-Emergent Adverse Events (TEAEs) defined as any AE occurring after the first intake 
of IMP. 
 
Hematology: Blood levels and shift changes from baseline of hematocrit, hemoglobin, absolute 
and relative reticulocyte counts, RBC count, WBC count, differential WBC count, platelet count, 
absolute neutrophil count, mean cell volume and INR. 
 
Biochemistry: Blood levels and shift changes from baseline of glucose, total protein, albumin, 
creatinine, urea, creatine kinase, total cholesterol, triglycerides, sodium, potassium, chloride, 
ALP, AST, ALT, conjugated and total bilirubin and GGT. 
 
Urinalysis: quantitative test for pH and protein; qualitative tests for glucose, ketones, bilirubin, 
blood; microscopic examination of the sediment. 
 
TSH. 
 
Pulse rate, SBP and DBP. 
 
Body weight. 
 
12-lead ECG. 
10.4.2.6 Pharmacokinetic Endpoints 
 
Plasma concentration of GKT137831. 
 
Plasma concentration of GKT138184, the main phase 1 metabolite of GKT137831. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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10.4.3 Statistical Methodology  
10.4.3.1 Demography and Disease History 
Demography variables and key baseline disease characteristic variables such as baseline ALP, 
baseline UDCA dose and time since diagnosis will be summarized by treatment group using the ITT 
population. 
10.4.3.2 Primary Efficacy Analysis 
The mean of all assessments, including repeat assessments, prior to first dose will be considered as 
the baseline value for the analysis.   
Due to the small sample size the primary analysis will be conducted using a stepwise approach. The 
percent change from baseline to Week 24 in serum GGT will be analyzed using an Analysis of 
Covariance (ANCOVA) with treatment and disease severity as fixed effects, and baseline GGT as a 
continuous covariate. If the normality assumption for the analysis is not met then the percent change 
from baseline in GGT at Week 24 will be analyzed non-parametrically through a stratified Wilcoxon 
Mann-Whitney (van Elteren) test. The normality assumption will be assessed through the 
examination of diagnostic residual plots. Further details and assumption checking will be provided in 
the SAP.   
The difference between each dose of GKT137831 and placebo will be calculated, along with 95% 
and 97.5% confidence intervals of the difference (to account for Hochberg adjustment). 
The primary analysis will be performed using the ITT population and a sensitivity analysis will be 
done using the PP population. If the Wilcoxon Mann-Whitney test is used, a subgroup analysis for 
disease severity will also be performed.  
10.4.3.3 Second Efficacy Analysis 
Any analyses of the secondary efficacy endpoints should be interpreted with care. The study has not 
been powered for the interpretation of these endpoints. Inferential statistical analyses performed on 
the secondary endpoints are included to aid interpretation and should not be considered as an 
alternative to the primary analysis for determining efficacy. All analyses will be performed using the 
ITT population. Sensitivity analyses using the PP population may also be performed on secondary 
endpoints; these will be specified in the SAP. 
The difference in the percent change from baseline in serum GGT between each dose level of 
GKT137831 and placebo will be estimated for all scheduled visits using a repeated measures 
analysis of covariance model with treatment, visit and disease severity as fixed effects, the baseline 
value as a continuous covariate and the interaction effect between treatment and visit. Should the 
repeated measures analysis not converge or the normality assumption fail, data from each visit will 
be compared individually using the same method as the primary analysis.  


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Descriptive summary statistics by treatment group and visit will be presented for the change from 
baseline and absolute values of ELF score. The difference in the change from baseline in ELF score 
between each dose level of GKT137831 and placebo will be estimated for all scheduled visits using 
the same methodology as for serum GGT. 
Serum ALP will be summarized in the same way and analyzed using the same methodology as for 
serum GGT.  
In addition the proportion of subjects achieving a 15, 20, 30, and 40% reduction in serum ALP will be 
tabulated. 
Summary statistics will also be presented for the percent change from baseline, change from 
baseline and absolute values for all continuous secondary efficacy endpoints. The change from 
baseline in liver function tests other than ALP may also be analyzed in an exploratory manner using 
the same statistical methodology as for the serum GGT.   
With regard to the PBC-40, analysis is by domain, with the scoring explained in the coded-PBC-40. 
Data should be considered by domain rather than in terms of a cumulative PBC-40 score. If data are 
missing from a domain (typically missed or duplicated answers) the whole domain should be 
discarded if <50% of items are completed. If >50% of responses are present then the median value 
for the completed items in the domain should be ascribed to the missing item.  
The number and percentage of subjects belonging to each group for categorical efficacy endpoints 
will be presented by visit and treatment group. Such endpoints include but are not limited to, 
responders to the Paris I, Toronto I, Toronto II, Toronto III, Toronto IV, Mayo II, and Barcelona 
disease prognostic risk criteria for PBC. 
All descriptive statistics will be presented overall, by treatment severity and by any other appropriate 
subgroups as defined in the SAP provided sufficient subject numbers are available within each 
subgroup level, within each treatment group.  
10.4.3.4 Safety 
All analyses of safety endpoints will be analyzed using the safety population. 
Adverse Events:  
The number and percentage of subjects experiencing an AE will be summarized by treatment group 
as per the following criteria, both overall and by system organ class and preferred term:  
 
TEAEs;  
 
Related TEAEs;  
 
Serious TEAEs;  
 
Related and serious TEAEs;  


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Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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 
TEAEs leading to discontinuation.  
TEAEs will be defined as AEs that start on or after the date of the first dose of IMP. In addition, 
summaries of the number and percentage of subjects experiencing an AE by system organ class, 
preferred term and maximum severity will be produced as per the following criteria: 
 
TEAEs;  
 
Related TEAEs. 
Clinical Laboratory Tests: 
The number and percentage of abnormal biochemical (including TSH), hematological and urinalysis 
laboratory results will be presented by treatment group, laboratory parameter, planned visit and 
severity, where applicable. For dipstick parameters with a categorical response any positive results 
will be considered abnormal. The CTCAE criteria will be used to determine severity. Shift tables for 
the change from baseline to each planned visit will also be presented. In addition descriptive 
summary statistics will be produced for all biochemical (including TSH) and hematological lab 
parameters which are not considered efficacy endpoints. For the calculation of summary statistics all 
laboratory results will be converted to SI units. Differential counts will be presented both as absolute 
values and as percentages of white blood cells.    
Prior and Concomitant Medications: 
The number and percentage of subjects taking a medication will be summarized by treatment group, 
anatomical therapeutic chemical level 2 and preferred term. Summaries will be produced for any 
medications started prior to first dose (and ongoing at baseline) and medications started on or after 
the date of first dose.  
Vital Signs and Body Weight:  
Pulse rate, SBP, DBP and body weight will be summarized using descriptive statistics by treatment 
group and planned visit. 
Both the absolute values and the change from baseline will be considered. 
12-lead ECG:  
Heart rate, QT interval (both uncorrected and corrected using Bazett's and Fredericia's formulas), 
will be summarized using descriptive statistics by treatment group and planned visit. 
Both the absolute values and the change from baseline will be considered. 


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Adverse Events of Special Interest: 
Potential effect of GKT137831 on arterial blood pressure and its clinical relevance will be evaluated. 
Systolic and diastolic blood pressure values will be examined together with temporally associated 
blood pressure related events including adverse events and serious adverse events, changes in 
study drug administration and other related changes in concomitant medications. Medical history 
and other possible contributing risk factors will also be assessed. Results will be presented by 
treatment group and planned visit. 
10.4.3.5 Pharmacokinetics 
Plasma concentrations of GKT137831 and its main phase 1 metabolite GKT138184 will be 
summarized using descriptive statistics by dose level and planned visit. Any plasma concentrations 
below the limit of quantification will be considered as 0 for the calculation of the summary statistics. 
The actual sampling time will be presented in listings. Pre-dose samples collected post dose will 
automatically be flagged for exclusion in the summary statistics. 
10.4.3.6 Pharmacokinetic/Pharmacodynamic Analysis  
Samples will be analyzed to determine plasma drug concentrations and thus to aid investigation of 
any PK/PD relationship with PD and/or efficacy endpoints, and optionally for the relationships 
between plasma drug concentrations and pharmacogenomics data. 
A population PK model describing the plasma concentrations of GKT137831 and GKT138184 will be 
developed using non-linear mixed-effects modelling. Relationships between drug concentrations/ 
exposure measures and selected PD and/or therapeutic efficacy endpoints in the same subject will 
be graphically explored and formal PK/PD (exposure-response) analyses may be performed. A 
separate Modeling and Simulation Analysis Plan (MSAP) for the PK/PD modeling describing the 
general approach to be taken will be finalized prior to database lock. The actual execution of any 
PK/PD modeling will depend upon the data, and full details of this will be provided in a separate 
report, which will be appended to the clinical study report (CSR). 
10.4.3.7 Missing Data/Outliers/Dropout Considerations 
For the primary analysis all subjects will be included with missing data imputed using method MAR 
(missing at random) or MNAR (missing not at random), as appropriate. This same approach will be 
used regardless of whether an ANCOVA or Wilcoxon Mann-Whitney test is used to analyze the 
primary endpoint. More details, including sensitivity analyses, will be provided in the SAP. The 
complete case approach will be used for the analysis of categorical variables using a worst-case 
imputation strategy. For all other analyses and summaries no imputation will be performed. 
10.4.3.8 Other Statistical Analysis Considerations 
All safety and efficacy data collected by visit will be summarized regardless of the visit window. For 
ECG, vital signs, laboratory results and efficacy assessments if there is more than one result 


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recorded for the same visit the non-missing value closest (if it is a planned, repeat or unscheduled 
assessment) to the planned day will be used in the summary tables and will be flagged into the 
corresponding listing. If there is more than one value closest to the planned day, the latest value will 
be used if the assessment was performed prior to the last dose of IMP.  


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11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site shall maintain appropriate medical and research records for this trial, in 
compliance with ICH GCP and regulatory and institutional requirements for the protection of subject 
confidentiality. The Investigator/institution shall provide direct access to source data/documents for 
study related monitoring, audits, IRB/IEC review and regulatory inspection.  
Source data are all information, original records of clinical findings, observations, or other activities in 
a clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, recorded audio tapes of counseling 
sessions, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files and 
records kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial.  
The eCRF is not a source document. 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Conduct of the Study 
The Sponsor and Cmed shall implement and maintain quality control (QC) and quality assurance 
(QA) procedures with written standard operating procedures (SOPs) to ensure the study is 
conducted and data are generated, documented and reported in compliance with the protocol, ICH 
GCP and applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 1996) and all revisions thereof, and in accordance with USA FDA regulations (CFR, 
Sections 312.50 and 312.56) and with ICH GCP. 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by the IRB/IEC and the concerned Regulatory Authorities, when 
applicable, except when necessary to eliminate immediate hazards to the subject or when the 
change(s) involve(s) only logistical or administrative aspects of the study. Any deviations may result 
in the subject having to be withdrawn from the study or render that subject non-evaluable. 
All participating sites are required to have procedures in place for assuring the quality of the 
research being conducted, including, but not limited to:  
 
How data will be evaluated for compliance with the protocol and for accuracy in relation to 
source documents.  
 
The documents to be reviewed (e.g., eCRFs, clinic notes, product accountability), who is 
responsible, and the frequency for reviews.  
 
Methods of training for staff, and methods of tracking such training. 
12.2 
Study Monitoring 
During the course of the study, a CRA will conduct routine site visits to review protocol compliance, 
compare eCRF entries with individual subject’s original source documents (accessed by the 
Investigator), assess product accountability and ensure the study is conducted according to 
applicable regulatory requirements. The review of the subject’s original medical records shall be 
performed in a manner which ensures subject confidentiality is maintained. 
The Investigator shall permit the CRA to review study data as frequently as deemed necessary to 
ensure that data are recorded in an adequate manner and that protocol adherence is satisfactory. 
The Investigator may not enroll subjects into the study until such time that an initiation visit, or with 
the agreement of the Sponsor, attendance at the Investigator meeting, has been performed by the 
CRA to conduct a detailed training of the protocol and eCRF. 


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13 
ETHICS 
13.1 
Ethical Standard 
This clinical study was designed and shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for GCP, with applicable local regulations (including European 
Directive 2001/20/EC, US CFR Title 21), and with the ethical principles laid down in the Declaration 
of Helsinki. 
Records that may reveal the identities of subjects must be well protected, with consideration given to 
confidentiality and the right to privacy. 
Each Principal Investigator will complete, sign and date the FDA 1572 form prior to conducting any 
study-related activities. Each Principal Investigator and Sub-Investigator will complete, sign and date 
the Financial Disclosure Form to declare any financial or other competing interests. Participating 
investigators will receive protocol training either at the Site Initiation Visit (SIV) or via attendance at 
an Investigator Meeting. 
13.2 
Institutional Review Board/Independent Ethics Committee 
Before initiating the study, the Investigator/institution should obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, ICF updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. The IRB/IEC shall be 
appropriately constituted and perform its functions in accordance with FDA, EU, ICH GCP, and local 
requirements as applicable. 
Prior to study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to the CRA, 
auditors, the Sponsor’s QA representatives, designated agents of the Sponsor, IRBs/IECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform the Sponsor immediately that this request has been made. 
13.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the subject’s agreeing to participate in the 
study and continues throughout the subject’s study participation. Written documentation of informed 
consent is required prior to any performance of study procedures. 
A site-specific, IRB/IEC-approved ICF, describing in detail the study treatments and procedures, visit 
schedule, restrictions and risks and possible benefits, will be given to the subject during a clinic visit. 
The subject will be asked to read and review the document. The Investigator will explain the 
research study to the subject and answer any questions that may arise. The subject should have the 


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opportunity to discuss the study with others if they wish and should be given adequate time to 
consider their decision before to agreeing to participate. If the subject agrees to participate, he/she 
will sign and date the ICF with the Investigator. A copy of the signed informed consent document will 
be given to the subject to keep. 
The subject may withdraw consent at any time throughout the course of the trial without affecting 
their legal rights or incurring loss of benefits to which they are otherwise entitled. The rights and 
welfare of the subject will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study, or by withdrawal of consent. 
13.3.1 Exclusion of Women, Minorities, and Children 
Women and minorities are not automatically excluded. Participants must meet all of the inclusion 
criteria listed in Section 5.2 and none of the exclusion criteria listed in Section 5.3 to be eligible to 
participate. Subjects aged <18 years will not be included in this study. 
13.4 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
The CRA or other authorized representatives of the sponsor may inspect all documents and records 
which require maintenance by the investigator, as described in Section 12.2. 
13.5 
Treatment Plan in the Event of Study Discontinuation 
In the event the study is prematurely discontinued, arrangements will be made for the subjects’ care 
to continue according to local standard clinical practice. Any subject still in the treatment period at 
the time of premature study discontinuation will have an early termination visit scheduled and the 
assessments listed in Section 7.5 performed. A final follow-up visit should be performed within 4 
weeks following the early termination visit, as described in Section 7.4. 
At the end of the study, subjects randomized to the placebo arm will not be crossed over to 
GKT137831 treatment. 
13.6 
Future Use of Stored Samples 
Samples will not be labelled with information that directly identifies the subject but will be coded with 
the identification number for the subject. 


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Collected samples may be transferred for analysis to the Sponsor, or to other laboratories working 
for the Sponsor. 
Biological samples will be stored for the time established by regulatory requirements or destroyed 
after the final clinical study report has been finalized if storage is not required. There might be a new 
request for these samples to be used for purposes related to the QA of the laboratory tests 
described in this protocol, in which case they will be used for this purpose. This may include the 
assessment of the quality of current tests, the maintenance or improvement of these tests, the 
development of new test methods for the markers described in this protocol, as well as making sure 
that new tests are comparable to previous methods and work reliably. 
If study results suggest that further investigations using stored biological samples are warranted, 
these tests might be carried out on an exploratory basis. In addition, biological samples may be used 
by the Sponsor or their research partners for further research that is not related to the disease or the 
product under study. This testing will be done on anonymized samples (meaning that any 
identification linking the subject to the sample is destroyed). Subjects will be asked to sign an 
additional, separate consent form for this optional testing and refusal of consent will not affect their 
possibility of participating in the study. 
13.7 
Insurance 
The Sponsor has established an insurance policy for the total anticipated duration of the study, 
covering the subjects with respect to the risks involved in taking part in this study in accordance with 
this protocol. In the case of injury or disability deriving from participation in the study, subjects are 
requested to inform the Investigator or his/her staff responsible for the study at the institution without 
delay. 


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14 
DATA HANDLING AND RECORD KEEPING 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness of 
the source data. Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the Investigator.  
The Sponsor and/or its designee, Cmed, will provide guidance to investigators on recording trial data 
in the eCRF. 
14.1 
Data Capture Methods 
Clinical data (including AEs, concomitant medications, safety assessments and outcome measures) 
will be entered by the site staff into a 21 CFR Part 11-compliant data capture system provided by 
Cmed. Clinical laboratory data will be entered by a central laboratory, with reports provided 
electronically to the sites for their records and to Cmed for loading into the database. The data 
capture system includes password protection and internal quality checks, such as automatic range 
checks, to identify data appearing inconsistent, incomplete or inaccurate.  
CRO personnel will be responsible for training of investigator-designated site staff on the correct use 
of the EDC system. Authorized study staff will only be given access once they have received 
training. 
Subjects will be provided with separate paper-based PBC-40 questionnaires and pruritus VAS at 
baseline/Day 1 and Weeks 12 and 24 (Visits 2, 5 and 7, respectively). Authorized site staff will then 
enter the responses provided in the eCRF with the original questionnaires being retained as part of 
the source documents. 
14.2 
Study Site Responsibilities 
All data requested on the eCRF must be recorded. Data will be transcribed by authorized personnel 
at the study site from the source documents into the eCRF for enrolled subjects. All information on 
the eCRF must be traceable to these source documents. All electronic entries (including any 
changes or updates) will be traceable through the system. Only the Principal Investigator or 
authorized staff may enter or modify data in the database using their unique password and User 
Identification. The Investigator must certify that the data entered in the eCRFs are complete and 
accurate by electronically signing the eCRF. 
14.3 
Data Management Responsibilities 
The Cmed Data and Analytics department will serve as the Statistical and Data Management Center 
for this study and will be responsible for data management, quality review, analysis and reporting of 
the study data. 


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Data management staff at the CRO will review the data in the eCRFs according to their internal 
SOPs and systematically validate the data using appropriate electronic checks in addition to relevant 
manual checks. For any errors identified in the data, the CRO will generate a formal query to be 
addressed by the investigational site staff within the EDC system. 
For classification purposes, concomitant medications, AEs and medical history entered into the 
eCRF will be coded using relevant medication and medical term dictionaries. These will be specified 
in the study-specific Data Management Plan. 
14.4 
Study Records Retention 
After the trial is completed, the investigator will receive a CD-ROM with the eCRFs of the subject 
data for the site for archiving at the investigational study site. No records will be destroyed without 
the written consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to inform the 
investigator when these documents no longer need to be retained. 
14.5 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures requirements. The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity. All major deviations must be promptly reported to Cmed and the Sponsor.  
All deviations from the protocol must be addressed in study subject source documents. A completed 
copy of the Protocol Deviation Form must be maintained in the regulatory file, as well as in the 
subject’s source document. Protocol deviations must be sent to the local IRB/IEC per their 
guidelines. The Investigator and his/her staff are responsible for knowing and adhering to their 
IRB/IEC requirements. 


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15 
PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data. When the study is complete the Sponsor shall 
arrange the analysis and tabulation of data. A clinical study report shall then be prepared, which may 
be used for publication, presentation at scientific meetings or submission to regulatory authorities. All 
proposed publications based on this study must be subject to the Sponsor's approval requirements. 
Prior to subject enrollment the study will be registered with ClinicalTrials.gov. A summary of the 
study results will be published ClinicalTrials.gov. 


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16 
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of non-alcoholic steatohepatitis (NASH). Keystone Symposia Conference. Fibrosis: from bench 
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31. Tahan V, Canbakan B, Balci H, Dane F, Akin H, Can G, Hatemi I, Olgac V, Sonsuz A, Ozbay G, 
Yurdakul I, Senturk H. Serum gamma-glutamyltranspeptidase distinguishes non-alcoholic fatty 
liver disease at high risk. Hepatogastroenterology. 2008 Jul-Aug;55(85):1433-8. 
32. Arab JP, Barrera F, Gallego C, Valderas JP, Uribe S, Tejos C, Serrano C, Serrano C, Huete Á, 
Liberona J, Labbé P, Quiroga T, Benítez C, Irarrázaval P, Riquelme A, Arrese M. High 
prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients. Ann 
Hepatol. 2016 Sep-Oct;15(5):721-8. doi: 10.5604/16652681.1212434. 
33. Friedrich-Rust M, Rosenberg W, Parkes J, Herrmann E, Zeuzem S, Sarrazin C. Comparison of 
ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis. BMC 
Gastroenterol. 2010 Sep 9;10:103. doi: 10.1186/1471-230X-10-103. 
34. Nishikawa H, Hasegawa K, Ishii A, Takata R, Enomoto H, Yoh K, Kishino K, Shimono Y, Iwata 
Y, Nakano C, Nishimura T, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. A 
proposed predictive model for advanced fibrosis in patients with chronic hepatitis B and its 
validation. Medicine (Baltimore). 2016 Aug;95(35):e4679. doi: 10.1097/MD.0000000000004679. 
35. Vardar R, Vardar E, Demiri S, et al. Is there any non-invasive marker replace the needle liver 
biopsy predictive for liver fibrosis, in patients with chronic hepatitis? Hepatogastroenterology 
2009;56:1459–65. 
36. Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical 
markers in patients with chronic hepatitis B. J Hepatol 2003;39:222–30. 
37. Lemoine M, Shimakawa Y, Nayagam S, Khalil M, Suso P, Lloyd J, Goldin R, Njai HF, Ndow G, 
Taal M, Cooke G, D'Alessandro U, Vray M, Mbaye PS, Njie R, Mallet V, Thursz M. The gamma-
glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in 
patients with chronic HBV infection in West Africa. Gut. 2016 Aug;65(8):1369-76. doi: 
10.1136/gutjnl-2015-309260. Epub 2015 Jun 24. 
38. Zeremski M, Dimova RB, Benjamin S, Makeyeva J, Yantiss RK, Gambarin-Gelwan M, Talal AH. 
FibroSURE as a noninvasive marker of liver fibrosis and inflammation in chronic hepatitis B. 
BMC Gastroenterol. 2014 Jul 3;14:118. doi: 10.1186/1471-230X-14-118. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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39. Zhang Y, Li S, He L, Wang F, Chen K, Li J, Liu T, Zheng Y, Wang J, Lu W, Zhou Y, Yin Q, Xia Y, 
Zhou Y, Lu J, Guo C. Combination therapy of fenofibrate and ursodeoxycholic acid in patients 
with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis. 
Drug Des Devel Ther. 2015 May 25;9:2757-66. doi: 10.2147/DDDT.S79837. eCollection 2015. 
40. Lee DH, Blomho R , and Jacobs Jr DR., “Is serum gamma glutamyltransferase a marker of 
oxidative stress?” Free Radical Research, vol. 38, no. 6, pp. 535–539, 2004. 
41. Zhang H and Forman HJ. Redox Regulation of γ-Glutamyl Transpeptidase. Am J Respir Cell Mol 
Biol. 2009 Nov; 41(5): 509–515. ePub 2009 Aug 14. doi:  10.1165/rcmb.2009-0169TR. PMCID: 
PMC2778158. 
42. Koenig G and Sene S, “Gamma-glutamyltransferase: a pre- dictive biomarker of cellular 
antioxidant inadequacy and dis- ease risk,” Disease Markers, vol. 2015, Article ID 818570, 18 
pages, 2015. 
43. Postorino M, Marino C, Tripepi G, and Zoccali C, “Gamma glutamyltransferase in ESRD as a 
predictor of all-cause and cardiovascular mortality: another facet of oxidative stress burden,” 
Kidney International, vol. 74, no. 111, pp. S64–S66, 2008. 
44. Wannamethee G, Ebrahim S, and Shaper AG, “Gamma- glutamyltransferase: determinants and 
association with mortality from ischemic heart disease and all causes,” American Journal of 
Epidemiology, vol. 142, no. 7, pp. 699–708, 1995. 
45. Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C, Heathcote EJ, Hirschfield 
GM. Baseline ductopenia and treatment response predict long-term histological progression in 
primary 
biliary 
cirrhosis. 
Am 
J 
Gastroenterol. 
2010 
Oct;105(10):2186-94. 
doi: 
10.1038/ajg.2010.216. Epub 2010 May 25. 
46. Martinez, S. M., Fernández-Varo, G., González, P., Sampson, E., Bruguera, M., Navasa, M., 
Jiménez, W., Sánchez-Tapias, J. M. and Forns, X. (2011), Assessment of liver fibrosis before 
and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C. 
Alimentary Pharmacology & Therapeutics, 33: 138–148. 
47. Eriksson S, Fraser JR, Laurent TC, Pertoft H, Smedsrod B. Endothelial cells are a site of uptake 
and degradation of hyaluronic acid in the liver. Exp Cell Res (1983) 144: 223–228. 
48. Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: 
structure, regulation and biological functions. Eur J Cell Biol (1997) 74: 111–122. 
49. Arthur MJ, Mann DA, Iredale JP. Tissue inhibitors of metalloproteinases, hepatic stellate cells 
and liver fibrosis. J Gastroenterol Hepatol (1998) 13Suppl: S33–38. 
50. Prakobwong S, Pinlaor S, Yongvanit P, Sithithaworn P, Pairojkul C, et al. Time profiles of the 
expression of metalloproteinases, tissue inhibitors of metalloproteases, cytokines and collagens 
in hamsters infected with Opisthorchis viverrini with special reference to peribiliary fibrosis and 
liver injury. Int J Parasitol (2009) 39: 825–835. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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51. Kossakowska AE, Edwards DR, Lee SS, Urbanski LS, Stabbler AL, et al. Altered balance 
between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Am J 
Pathol (1998) 153: 1895–1902. 
52. Herbst H, Wege T, Milani S, Pellegrini G, Orzechowski HD, et al. Tissue inhibitor of 
metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol (1997) 
150: 1647–1659. 
53. Kivirikko KI, Myllyla R. Post-translational processing of procollagens. Ann N Y Acad Sci (1985) 
460: 187–201. 
54. Horslev-Petersen K. Circulating extracellular matrix components as markers for connective 
tissue response to inflammation. A clinical and experimental study with special emphasis on 
serum aminoterminal type III procollagen peptide in rheumatic diseases. Dan Med Bull (1990) 
37: 308–329. 
55. Entzian P, Huckstadt A, Kreipe H, Barth J. Determination of serum concentrations of type III 
procollagen peptide in mechanically ventilated patients. Pronounced augmented concentrations 
in the adult respiratory distress syndrome. Am Rev Respir Dis (1990) 142: 1079–1082 
56. Waydhas C, Nast-Kolb D, Trupka A, Lenk S, Duswald KH, et al. Increased serum concentrations 
of procollagen type III peptide in severely injured patients: an indicator of fibrosing activity? Crit 
Care Med (1993) 21: 240–247. 
57. Mayo MJ, Parkes J, Adams-Huet B, Combes B, Mills AS, et al. Prediction of clinical outcomes in 
primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology (2008) 48: 1549–
1557. 
58. Tanwar S, Trembling PM, Hogan BJ, et al. Noninvasive markers of liver fibrosis: on-treatment 
changes of serum markers predict the outcome of antifibrotic therapy. Eur J Gastroenterol 
Hepatol. 2017 Mar;29(3):289-296. 
59. Xie Q, Zhou X, Huang P, Wei J, Wang W, Zheng S. The performance of enhanced liver fibrosis 
(ELF) test for the staging of liver fibrosis: a meta-analysis. PLoS One. 2014 Apr 15;9(4):e92772. 
doi: 10.1371/journal.pone.0092772. eCollection 2014.  
60. Zarski JP, Sturm N, Guechot J, Zafrani ES, Vaubourdolle M, et al. Contribution of the ELFG test 
in algorithms of non-invasive markers towards the diagnosis of significant fibrosis in chronic 
hepatitis C. PLoS One. (2013) 8: e59088. 
61. Yoo EJ, Kim BK, Kim SU, Park JY, Kim do Y, et al. Normal enhanced liver fibrosis (ELF) values 
in apparently healthy subjects undergoing a health check-up and in living liver donors in South 
Korea. Liver Int (2013) 33: 706–713. 
62. Janciauskiene S, Wallmark A, Piitulainen E, Kohnlein T, Welted T, et al. Performance of 
enhanced liver fibrosis plasma markers in asymptomatic individuals with ZZ alpha1-antitrypsin 
deficiency. Eur J Gastroenterol Hepatol (2011) 23: 716–720. 
63. Parkes J, Roderick P, Harris S, Day C, Mutimer D, et al. Enhanced liver fibrosis test can predict 
clinical outcomes in patients with chronic liver disease. Gut (2010) 59: 1245–1251. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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64. Trepo E, Potthoff A, Pradat P, Bakshi R, Young B, et al. Role of a cirrhosis risk score for the 
early prediction of fibrosis progression in hepatitis C patients with minimal liver disease. J 
Hepatol (2011) 55: 38–44. 
65. New Drug Application (NDA) 207999 submitted by Intercept Pharmaceuticals, Inc. for obeticholic 
acid (OCA) proposed for the treatment of Primary Biliary Cirrhosis (PBC), Gastrointestinal Drug 
Advisory Committee (GIDAC) Meeting, April 7th, 2016. 
66. Reich A, Heisig M, Phan NQ, Taneda K, Takamori K, et al. Visual Analogue Scale: Evaluation of 
the Instrument for the Assessment of Pruritus. Acta Derm Venereol (2012); 92: 497–501. 
 
 
 
 
 
 
 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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APPENDICES 
 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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APPENDIX A: 
SCHEDULE OF EVENTS 
Study period 
Screening 
Double-blind treatment period 
Follow-up 
Study weeks 
-4 to -1 
Baseline 
(Day 1)1 
Week 2 
±3 days 
Week 6 
±3 days 
Week 
12 ±3 
days 
Week 
18 ±3 
days 
Week 
24 ±3 
days9 
Week 28 
±3 days 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
 
 
 
 
 
 
 
Determination of eligibility2 
X 
X 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
Body weight 
 
X 
 
 
 
 
X 
 
Height and oral or tympanic temperature 
X 
 
 
 
 
 
 
 
Pregnancy test3 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for viral serology (HIV antibodies 1 and 2, hepatitis B surface antigen and hepatitis C virus 
antibodies) 
X 
 
 
 
 
 
 
 
Optional collection of DNA sample 
 
X 
 
 
 
 
 
 
Blood samples for the determination of anti-mitochondrial antibodies (anti-AMA, anti-GP210, anti-SP100, 
antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]) 
X 
 
 
 
 
 
 
 
Blood samples for markers of inflammation (hsCRP, fibrinogen)4  
 
X 
X 
X 
X 
X 
X 
X 
Blood samples for optional11 markers of inflammation and liver injury (IL-6, CK-18)4 
 
X 
 
 
X 
 
X 
 
Blood samples for markers of fibrosis (ELF score, collagen fragments)4 
 
X 
 
 
X 
 
X 
 
Blood samples for optional11 assessments of immunological markers (IgM, IL-4, IL-12, IL-17A, IFN- 
 
X 
 
 
X 
 
X 
 
Blood samples for total bile acids4 
 
X 
 
 
X 
 
X 
 
Blood samples for optional11 assessments of bile acid metabolism (serum C4 and FGF-19)4 
 
X 
 
 
X 
 
X 
 
Blood samples for optional11 additional biomarkers4 
 
X 
 
 
X 
 
X 
X 
Blood samples for optional11 metabolomic studies4 
 
X 
 
 
X 
 
X 
 
Transient elastography (FibroScan® or similar technology) 
 
X 
 
 
 
 
X 
 
Safety hematology and biochemistry including blood lipids, triglycerides, liver function tests and INR 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function tests 
 
X 
X 
X 
X 
X 
X 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Page 98 of 113 
Study period 
Screening 
Double-blind treatment period 
Follow-up 
Study weeks 
-4 to -1 
Baseline 
(Day 1)1 
Week 2 
±3 days 
Week 6 
±3 days 
Week 
12 ±3 
days 
Week 
18 ±3 
days 
Week 
24 ±3 
days9 
Week 28 
±3 days 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Urinalysis (dipstick) 
X 
 
 
 
X 
 
X 
X 
Subject questionnaires (PBC 40, Pruritus VAS) 
 
X 
 
 
X 
 
X 
 
Pulse rate, SBP and DBP 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG5 
X 
 
X 
 
X 
 
X 
 
Physical examination6 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medication recording7 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
Dispense IMP8 
 
X 
X 
X 
X 
X 
 
 
Supervise subject during first administration of IMP 
 
X 
 
 
 
 
 
 
Blood samples for PK9 
 
 
X 
 
X 
X 
 
 
Recording of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Subject compliance with treatment 
 
 
X 
X 
X 
X 
X 
 
Keys: 
1. Day 1 (Visit 2) is also considered baseline of the 24-week double-blind treatment period (except for the determination of the primary endpoint where the mean of Screening 
(Visit 1) and Day 1 values will be defined as baseline). 
2. Eligibility to enter the double-blind treatment period will be determined during Visits 1 and 2. Not every eligibility assessment needs to be repeated at Visit 2 i.e., confirmatory 
laboratory and diagnostic tests. Subjects with AEs at baseline may need to be withdrawn in accordance with the eligibility and withdrawal criteria. 
3. At Screening (Visit 1), a serum pregnancy test will be performed.  At all subsequent visits including baseline (Visit 2), urine pregnancy tests will be performed. 
4. For the Baseline visit and all subsequent visits, subjects must remain fasted overnight from 10 pm and bring their morning dose to the clinic. Pre-dose samples will be 
collected and subjects will receive a breakfast meal. Subjects will then self–administer the morning dose up to 30 minutes after eating their meal. Post dose samples will be 
collected as described.   
5. Post-dose, 12-lead ECG is to be performed around Tmax, (i.e. 1 to 4 hours post dose). 
6. A complete physical examination will be performed during the Screening visit (Visit 1) and at the follow-up (Visit 8).  On all other visits a symptoms-directed physical 
examination will be performed. 
7. Prior medication will be recorded at Screening only. 
8. The IMP will be orally self-administered BID, once in the morning and once in the evening with meals or up to 30 minutes after eating a meal. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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9. PK sampling: one pre-dose PK sample will be collected. Subjects must bring their morning dose to the clinic) and two post-dose samples (first sample to be taken 1-2 hours 
after morning dose; second sample to be taken before subject leaves clinic but no earlier than 2 hours after the first post-dose sample) at Weeks 2 and 12 (Visits 3 and 5).  A 
single post-dose sample (to be taken before subject leaves clinic at 3-4 hours after morning dose) at Week 18 (Visit 6). 
10. Week 24 (Visit 7) is the End of Treatment visit. Subjects who discontinue treatment before Week 24 will have an Early Termination Visit. The assessments to be performed at 
the Early Termination visit are the same as those at the Week 24 Visit, but must be recorded on the Early Termination eCFR page Subjects should return for a Final Study 
visit (Visit 8) within 4 weeks after the End of Treatment or Early Termination visit. 
11. These sample collections are not optional for the subject. It is the subsequent analysis of these samples which is optional. 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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APPENDIX B: 
SCHEDULE OF BLOOD SAMPLING 
  
Blood Volume (mL) 
Total 
Volume 
in Study 
Assessment 
Screening 
Double-blind treatment period 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Serum pregnancy test (if applicable) 
2 
- 
- 
- 
- 
- 
- 
- 
2 
HIV1, HIV2, HBVAb, HCVAb 
4 
- 
- 
- 
- 
- 
- 
- 
4 
DNA sample (separate consent required) 
- 
5 
- 
- 
- 
- 
- 
- 
5 
Antibodies: anti-AMA, anti-GP210, anti-
SP100, anti-M2 component 
1 
- 
- 
- 
- 
- 
- 
- 
1 
PD inflammation markers (hsCRP, 
fibrinogen) 
- 
4 
4 
4 
4 
4 
4 
4 
28 
Optional1 PD inflammation markers (IL-6, 
CK-18) 
- 
4 
- 
- 
4 
- 
4 
- 
12 
PD fibrosis markers (ELF score, collagen 
fragments) 
- 
4 
- 
- 
4 
- 
4 
- 
12 
Optional1 immunological markers (IgM, IL-4, 
Il-2, IL-17A, IFNγ) 
- 
3 
- 
- 
3 
- 
3 
- 
9 
Mandatory total bile acids 
- 
2 
- 
- 
2 
- 
2 
- 
6 
Optional1 bile acid metabolism markers 
(serum C4, FGF-19) 
 
2 
 
 
2 
 
2 
 
6 
Optional1 additional biomarkers 
- 
3 
- 
- 
3 
- 
3 
3 
12 
Optional1 PD metabolomic markers 
- 
1.5 
- 
- 
1.5 
- 
1.5 
- 
4.5 
Chemistry panel 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
68 
Hematology panel 
3 
3 
3 
3 
3 
3 
3 
3 
24 
INR 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
21.6 
Thyroid panel 
- 
2 
2 
2 
2 
2 
2 
-  
12 
PK 
- 
- 
6 
- 
6 
2 
- 
- 
14 
Total volume to be drawn at each visit / in 
the study 
21.2 
44.7 
26.2 
20.2 
45.7 
22.2 
39.7 
21.2 
241.1 
1. These samples are not optional for the subject. It is the subsequent analysis of these samples which is optional.


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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APPENDIX C: 
DECLARATION OF HELSINKI 2013 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
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APPENDIX D: 
PRURITUS VAS  
Guidance on completing the pruritus VAS: 
 
Write the number between 0 and 10 underneath the scale which best represents the intensity of 
your itch over the last 24 hours. Do not include a decimal. 
 
A score of 0 = no itch; a score of 10 = maximum itch, i.e., severe, continuous, day and night 
intolerable itch. 
 
Do not mark a cross on the actual line.  
 
 
 
 
Score in the last 24 hours: ___________________ (write the number from 0 to 10 which best represents 
the intensity of your itch, with no decimal). 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Page 107 of 113 
APPENDIX E: 
PBC-40 QUESTIONNAIRE 
 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
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APPENDIX F: 
CLOSE OBSERVATION PROCEDURES 
1. 
Interrupt the investigational agent administration 
2. 
Repeat liver biochemistries and additional testing within 24-72 hours 
3. 
Monitor patient twice or thrice a week until liver biochemistries (ALT, AST, alkaline 
phosphatase, total bilirubin, and coagulation profile [INR]) resolve, stabilize or return to within 
baseline values 
4. 
Monitor liver biochemistries once a week if abnormalities stabilize and the patient is 
asymptomatic 
5. 
Obtain a detailed history for symptoms assessment:  appearance or worsening of clinical 
symptoms of hepatitis (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash or eosinophilia). If a patient is symptomatic, the drug must be discontinued 
immediately and a potential DILI evaluation must be performed. 
6. 
Obtain a more detailed history of symptoms and prior or concomitant diseases; 
7. 
Obtain a history for concomitant medications, acetaminophen, dietary supplements, herbal 
remedies, other over the counter medications, recreational drug use, and special diets  
8. 
If possible quantify the alcohol consumption to assess for alcoholic hepatitis 
9. 
Obtain a history of exposure to environmental chemical agents. 
10. 
If INR is also elevated, a trial of intravenous vitamin K administration may be considered, 
especially in cholestatic patients. 
  
Follow-Up Procedures for patient(s) who meet potential DILI evaluation criteria: 
1. 
Viral hepatitis serology including: 
a. 
Hepatitis A IgM antibody; 
b. 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
c. 
Hepatitis C RNA; 
d. 
Hepatitis E IgM antibody.  
e. 
Cytomegalovirus IgM antibody; 
f. 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); however IgM antibodies must be sent out asap  
g. 
Blood sample for pharmacokinetic (PK) analysis, obtained within 12 hours of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study treatment prior to blood sample draw on the CRF. If the date or time of the last 
dose is unclear, provide the participant’s best approximation.  
h. 
Serum Creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
i. 
Fractionate bilirubin, if total bilirubin >2xULN 
j. 
Assess for peripheral eosinophilia 
k. 
Assess for hypoxic/ischemic hepatopathy; and biliary tract disease 
  
The following are required for patients who meet the stopping criteria for both ALT and total bilirubin 
OR experiences clinical symptoms of hepatitis: 
1. 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies and quantitative total immunoglobulin G (IgG or gamma globulins). 


Protocol No.: GSN000300 
Compound No.: GKT137831 
Protocol Version No.: Final 4.0; Amendment 3 
Sponsor: Genkyotex 
Protocol Date: 24 July 2018 
Author: Cmed Clinical Services 
 
MASOP006/F1; Template Version 2.0 12FEB2015 
CONFIDENTIAL 
Page 113 of 113 
2. 
If required evaluation of competing undiagnosed liver disease (hemochromatosis, Wilson’s 
disease, alpha-1 anti-trypsin deficiency) 
3. 
Serum acetaminophen levels OR serum acetaminophen adducts by HPLC assay (quantifies 
potential acetaminophen contribution to liver injury in participants with definite or likely 
acetaminophen use in the preceding week). 
4. 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver 
disease. 
5. 
A Liver Biopsy 
  
Treatment with investigational agent could be re-initiated if these abnormalities stabilize, return to 
pre-trial baseline or normalize and a causative agent was found.  
Investigational agent must be discontinued and patient must be followed until the clinical and 
laboratory abnormalities stabilize or normalize if the following criteria are met: 
1. 
If close monitoring of a patient is not possible. 
2. 
In presence of total bilirubin elevation (>2 x ULN or >1.5 x baseline); with any degree of 
aminotransferase elevation; AND if there is appearance of symptoms i.e., fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).  
3. 
If any degree of total bilirubin, ALT, or AST elevation recurs following re-challenge with study 
drug. 
 
 

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Final version 2.0 / 15MAR2019 
 
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SPONSOR: 
 
 
Genkyotex 
 
 
PROTOCOL NUMBER: 
 
GSN000300 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Author: 
Jean-Luc Beffy 
Version: 
Final version 2.0 
Date: 
15MAR2019 




 
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Table of Contents 
 
1 
Cover and signature pages ...................................................................................................... 2 
2 
List of Abbreviations and Definition of Terms ......................................................................... 5 
3 
Introduction ............................................................................................................................. 7 
4 
Study Objectives ...................................................................................................................... 7 
5 
Study Design ............................................................................................................................ 7 
5.1 
STUDY DESIGN AND POPULATION ..................................................................................... 7 
5.2 
STUDY TREATMENTS AND ASSESSMENTS ......................................................................... 8 
5.3 
RANDOMIZATION AND BLINDING ...................................................................................... 9 
5.4 
SAMPLE SIZE JUSTIFICATION .............................................................................................. 9 
6 
Statistical Considerations ...................................................................................................... 10 
6.1 
TIMING FOR THE FINAL ANALYSIS .....................................................................................10 
6.2 
MISSING DATA HANDLING ................................................................................................11 
6.3 
PARTIAL DATE IMPUTATION .............................................................................................11 
6.4 
VISIT WINDOWING ............................................................................................................13 
6.5 
BASELINE ............................................................................................................................13 
6.6 
REPORTING GUIDELINES ....................................................................................................14 
7 
Analysis Sets .......................................................................................................................... 16 
8 
Methods of Analyses and Presentations ............................................................................... 17 
8.1 
SUBJECT DISPOSITION .......................................................................................................17 
8.2 
PROTOCOL DEVIATIONS AND/OR VIOLATIONS ................................................................18 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..........................................................18 
8.4 
MEDICAL HISTORY .............................................................................................................19 
8.5 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................................19 
8.6 
STUDY DRUG EXPOSURE AND/OR COMPLIANCE .............................................................20 
8.7 
EFFICACY DATA ENDPOINTS AND ANALYSES ....................................................................21 
8.7.1 
Primary Efficacy Endpoint and Analyses ............................................................... 21 
8.7.2 
Secondary and Tertiary Efficacy Endpoints and Analyses ..................................... 21 
8.7.3 
Exploratory Efficacy Endpoints and Analyses ........................................................ 25 
8.7.4 
Subgroup Analysis ................................................................................................. 26 
8.8 
PHARMACOKINETIC/ PHARMACODYNAMIC ENDPOINTS AND ANALYSES .....................27 
8.9 
QUALITY OF LIFE OR PHARMACOECONOMIC ENDPOINTS AND ANALYSES ....................27 
8.10 
SAFETY DATA ENDPOINTS AND ANALYSES .......................................................................27 
8.10.1 
Adverse Events (AEs) ............................................................................................. 28 
8.10.2 
Clinical Laboratory Evaluations ............................................................................. 29 
8.10.3 
Vital Signs .............................................................................................................. 30 


 
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8.10.4 
ECG ........................................................................................................................ 30 
9 
Interim Analyses .................................................................................................................... 31 
10 
Changes to Planned Analyses ............................................................................................ 32 
11 
Document History.............................................................................................................. 33 
12 
References ......................................................................................................................... 33 
13 
Appendix 1: List of Top Line tables .................................................................................... 34 
 
 


 
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2 List of Abbreviations and Definition of Terms 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
APRI 
AST to Platelet Ratio Index 
AST 
Aspartate Aminotransferase 
BID 
Twice Daily 
CK-18 
Cytokeratin-18 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELF 
Enhanced Liver Fibrosis 
FDA 
Food and Drug Administration 
FIB-4 
Fibrosis-4 
GGT 
Gamma Glutamyl Transferase 
hsCRP 
High Sensitivity C-Reactive Protein 
ICH 
International Conference on Harmonization 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IPF 
Idiopathic Pulmonary Fibrosis 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web-Based Randomization System 
LOCF 
Last Observation Carried Forward 
MSAP 
Modeling and Simulation Analysis Plan 
NADPH 
Nicotinamide Adenine Dinucleotide Phosphate 
OCA 
Obeticholic Acid 
OD 
Once Daily 
PBC 
Primary Biliary Cholangitis 


 
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PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QTcF 
Corrected QT Interval (Fredericia’s Formula) 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SMB 
Safety Monitoring Board 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid-Stimulating Hormone 
UDCA 
Ursodeoxycholic Acid 
ULN 
Upper Limit Of Normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 


 
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3 Introduction 
The purpose of this document is to describe the statistical methods, data derivations and data 
summaries to be employed in the analysis of study GSN000300 set up by Genkyotex in order to 
assess the efficacy and safety of oral GKT137831, a selective inhibitor of NOX 1 and 4 isoforms of 
the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase family of enzymes, in 
patients with primary biliary cholangitis (PBC) receiving ursodeoxycholic acid (UDCA) and with 
persistently elevated alkaline phosphatase (ALP). 
The preparation of this statistical analysis plan (SAP) has been based on International 
Conference on Harmonisation (ICH) E3 and E9 Guidelines and in reference to Protocol 
GSN000300 Version 4.0 (Amendment 3, 24 July 2018) and CRF Version 6.4 (12 February 2019). 
4 Study Objectives 
PRIMARY OBJECTIVE 
The primary objective of the study is defined as follows: 
• 
To evaluate the efficacy of oral GKT137831 in comparison with placebo, in subjects with 
PBC receiving UDCA and with persistently elevated serum ALP. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are defined as follows: 
• 
To evaluate the safety of oral GKT137831 in comparison with placebo, in subjects with 
PBC receiving UDCA and with persistently elevated serum ALP. 
• 
To estimate the pharmacokinetics (PK) population of GKT137831 and explore any 
potential PK-PD (pharmacodynamics) relationships in this subject population. 
• 
To explore any relationship between genetic parameters and therapeutic responses in a 
subset of subjects. 
 
5 Study Design 
5.1  STUDY DESIGN AND POPULATION 
The study population consists of approximately 100 subjects with PBC receiving a stable dose of 
UDCA and with persistently elevated ALP. 
The study is a double-blind, randomized, placebo-controlled, multicenter, parallel group phase 2 
trial assessing a 24-week period of treatment with oral GKT137831 administered in addition to 
standard of care medication (UDCA) in subjects with PBC. Subjects will be followed up for 28 
days after the end of the treatment period. 


 
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An overview of the study design is presented in Figure 1 below. 
Figure 1: 
Study Design Flowchart 
 
 
5.2 STUDY TREATMENTS AND ASSESSMENTS  
Subjects will be assessed for their eligibility during the screening period (Visit 1), which will last 
up to 4 weeks, until the baseline/Day 1 visit (Visit 2). 
Eligible subjects will be allocated to oral GKT137831 (400 mg Once Daily (OD) or 400 mg Twice 
Daily (BID) or placebo, according to a 1:1:1 randomization ratio stratified by disease severity 
level at study entry defined as baseline serum Gamma Glutamyl Transferase (GGT) < 2.5 x Upper 
Limit of Normal (ULN) or ≥ 2.5 x ULN.  
Subjects will self-administer orally 400 mg OD or 400 mg BID of oral GKT137831 or matching 
placebo for a total of 24 weeks. 
Baseline assessments will be performed at baseline/Day 1 (Visit 2). The 24-week treatment 
period will include assessments after 2 weeks of treatment (Visit 3), after 6 weeks of treatment 
(Visit 4), after 12 weeks of treatment (Visit 5), after 18 weeks of treatment (Visit 6) and after 24 
weeks of treatment (End of Treatment/Visit 7). Subjects will be followed up to 28 days after the 
end of treatment (Week 28/Visit 8), totaling 6 post-baseline visits. Subjects who discontinue 
treatment before Week 24 visit will attend an Early Termination visit (premature end of 
treatment). 
Pharmacokinetic samples will be taken at baseline, Week 2, Week 12 and Week 18 visits (see 
Protocol Version 3.0 - Section 8.8.2 for further details regarding the sampling time points). 
Subjects will be taking a stable dose of UDCA at enrollment and will continue their UDCA 
treatment at a stable dose (no changes at all) during the treatment period.  
A Safety Monitoring Board will oversee the conduct of the study to ensure the safety of 


 
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participating subjects (see Protocol Version 3.0 - Section 9.7 for more details). An interim 
analysis will be conducted when at least 80-90% of the planned number of subjects to be 
randomized in the study have completed their Week 6 visit (see Section 9). This IA analysis will 
assess demographics and efficacy data collected up to Week 6. 
5.3 RANDOMIZATION AND BLINDING 
Approximately 100 subjects will be randomly allocated to placebo or one of the 2 active 
treatment arms, according to a 1:1:1 randomization ratio stratified at study entry by disease 
severity level defined as baseline serum GGT < 2.5 x ULN or ≥ 2.5 x ULN).  
Accordingly, approximately 33-34 subjects will be allocated to each of the 3 treatment arms.   
A master reproducible randomization list will be produced by or under the responsibility of 
Cmed accounting for block size and stratification. The Interactive Web-Based Randomization 
System (IWRS) will assign a unique randomization number in ascending, sequential order (with 
associated treatment arm) to the subject, based on the pre-determined randomization 
schedule. The system will assign the pre-determined blocks of randomization numbers for each 
stratification level to ensure similarly balanced treatment groups. Assignment will be in 
sequential order within blocks and stratification level. The investigator will enter the 
randomization number in the electronic case report form (eCRF). 
The Sponsor, subjects, investigator staff, persons performing the assessments, data reviewers 
and statisticians will remain blinded to the identity of the study treatments.  
The identity of the study treatments will be concealed by the use of Investigational Medicinal 
Products (IMPs) which are all identical in packaging, labeling, schedule of administration, 
appearance and odor. 
Randomization data will be kept strictly confidential and be accessible only to authorized 
personnel (e.g., unblinded pharmacist or authorized designee), until unblinding of the trial as 
described in this SAP. 
Unblinding will only occur for the following reasons: 
• 
Subject emergencies (see Protocol Section 5.6.3 for more details) 
• 
Scheduled and unscheduled safety reviews by the Safety Monitoring Board (SMB) (see 
Protocol Section 9.7 for more details) 
• 
At the time of the interim analysis (see Section 9) 
• 
At the end of the study. 
5.4 SAMPLE SIZE JUSTIFICATION 
A sample size of 34 randomly allocated and treated subjects within each treatment group with 
an overall sample size of 102 subjects will have 80% power to detect a 28% difference in the 
means of the percent change from baseline in serum GGT. A Wilcoxon Mann-Whitney test has 
been used for the sample size estimate because this represents the worst-case scenario with 
regards to the statistical power. A standard deviation of 30 for the active GKT137831 group and 
a standard deviation of 40 for the placebo group have been assumed based on a recent phase 3 
clinical trial of OCA [1].  


 
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An overall two-sided Type I error of 5% has been considered for the sample size calculation.  
The Hochberg method will be used to adjust the alpha level for multiple comparisons. 
Therefore, the first dose level comparison at the final analysis will be tested against an alpha 
level of 0.04695 and the second dose level will be tested against an alpha level of 0.023475. The 
alpha level of 0.023475 has been used for the sample size calculation. 
The sample size calculation assumes all subjects (including withdrawals) will be included in the 
analysis. As a result, there has been no adjustment for dropouts.  
6 Statistical Considerations 
The SAS system version 9.4 (or higher), will be used for all analysis, unless otherwise specified. 
6.1 TIMING FOR THE FINAL ANALYSIS 
The final analysis will be performed according to a 2-stage process as detailed hereafter: 
• 
Stage 1: end of the double-blind treatment period  
The double-blind treatment period will be completed once the last subject last Week 24 visit will 
have been attended. 
The date of the last subject last Week 24 visit will be referred to as the cut-off date for Stage 1. 
All the data collected until the cut-off date will be taken into consideration for a first database 
lock.  
As a result, all the efficacy data required for the efficacy endpoints defined in Section 8.7 will be 
included in this first locked database. 
This first database lock is requested by Genkyotex to enable Cmed to produce and deliver Top 
Line tables (see the list in Appendix 1) as soon as all Week 24 visit efficacy data has been 
collected, cleaned, and locked. This first database lock will also include all Week 28 follow-up 
visit data which will have been collected until the cut-off date and cleaned prior to the database 
lock. The second database lock (see Stage 2 below) is to be carried out once all remaining 
follow-up (V8) data has been collected and cleaned. Week 28 follow-up visit data not included in 
the first database lock will be listed separately in the clinical study report and in any other 
relevant document. 
• 
Stage 2: end of the follow-up period  
The follow-up period will be completed once the last subject last Week 28 follow-up visit will 
have been attended. It will be considered as the end of the study. 
The date of the last subject last Week 28 follow-up visit will be referred to as the cut-off date for 
Stage 2. 
All the data collected until the cut-off date will be taken into consideration for a second 
database lock. It will be regarded as the final database lock. 
Cmed will produce and deliver both the remaining planned efficacy outputs and all the other 
planned outputs to Genkyotex after the final database lock. 


 
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6.2 MISSING DATA HANDLING 
In the event of missing data at Week 24 visit for efficacy endpoints (see the list below), the Last 
Observation Carried Forward (LOCF) method will be applied by imputing Week 24 visit data with 
the last non-missing post-baseline data available at Week 12 visit (or at a later visit). If there is no 
non-missing post-baseline data or if the last non-missing post-baseline data is available at an 
earlier visit than Week 12 visit then the LOCF method will not be applied and no data will be 
imputed at Week 24 visit. Accordingly, the LOCF method will not be used for the interim analysis. 
The above-described use of the LOCF method for the imputation of missing data at Week 24 
visit is based on recently published studies that have shown that the reductions in liver function 
tests are close to maximal effects after 12 weeks of treatment [2]. 
The LOCF method will be applied for the following efficacy endpoints: 
• Primary efficacy endpoint; 
• Week 24-defined secondary efficacy endpoints (except those defined for ELF and liver 
stiffness); 
• Week 24-defined tertiary efficacy endpoint for total bile acids; 
• Week 24-defined exploratory efficacy endpoints (except those from the assessments of 
the metabolomics signatures and additional biomarkers of interest) 
 
The complete case approach will be applied for the analysis of categorical variables using a 
worst-case imputation strategy.  
For all other analyses and summaries, no imputation will be performed other than to complete 
partial dates using standard imputation techniques as described below. 
6.3 PARTIAL DATE IMPUTATION 
The following rules should be used when modifying partial or missing dates for reporting 
purposes such as defining on treatment flags.  
A permanent new date variable should be created if there is a requirement to be used in 
determining flags, sort orders and other derived variables needed for a table, listing or figure. 
Imputed date variable names will be defined in the derived dataset specifications. 
Original (raw) date variables must not be overwritten. Imputed dates will not be displayed in the 
listings. 
General rules 
Adverse events (AE) or prior and concomitant medications are considered to have started at the 
earliest possible date and end at the latest possible date.  
In case of partial dates with missing day:  
For any AE or concomitant medication starting during the month of first dose, the partial start 
date will be imputed at the date of first dose, taking the worst case scenario.  
For any AE or concomitant medication starting after the month of first dose, the start date will 
be imputed at the first day of the month.  


 
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For any AE or concomitant medication starting before the month of first dose, the start date will 
be imputed at the last day of the month.  
For any AE or concomitant medication, a partial end date will be imputed at the last day of the 
month or at the date of study discontinuation, whichever occurs first. 
In case of partial dates with missing day and month:  
For any AE or concomitant medication starting during the year of first dose, the partial start date 
will be imputed at the date of first dose, taking the worst case scenario.  
For any AE or concomitant medication starting after the year of first dose, the partial start date 
will be imputed at the first of January.  
For any AE or concomitant medication started before the year of first dose, the partial start date 
will be imputed as the last day of the year.  
For any AE or concomitant medication, a partial end date will be imputed at the last day of the 
year or at the date of study discontinuation, whichever occurs first 
Some examples are given below (YYYY-MM-DD). 
In most cases, start dates are imputed as first day of the month or first day of the year.  
Data Type 
Start Date 
Imputed Start 
Date 
First dose 
Date of 
disconti-
nuation 
End Date 
Imputed End 
Date 
Adverse Event, 
Prior/Concomit
ant Meds 
2017-02 
2017-02-01 
2016-12-17 
- 
2017-02 
2017-02-29 
Adverse Event, 
Prior/Concomit
ant Meds 
2017-02 
2017-02-03 
2017-02-03 
- 
2017-02 
2017-02-29 
Adverse Event, 
Prior/Concomit
ant Meds 
2017-02 
2017-02-03 
2017-02-03 
- 
2017-03 
2017-03-31 
Adverse Event, 
Prior/Concomit
ant Meds 
2017-03 
2017-03-01 
2017-02-03 
- 
2017-03 
2017-03-31 
Adverse Event, 
Prior/Concomit
ant Meds 
2017-01 
2017-01-31 
2017-03-03 
- 
2017-01 
2017-01-31 
Adverse Event, 
Prior/Concomit
ant Meds 
2016 
2016-12-31 
2017-02-03 
2017-03-16 
2017-03 
2017-03-16 
Adverse Event, 
Prior/Concomit
ant Meds 
2017 
2017-02-03 
2017-02-03 
2017-04-08 
2017-03 
2017-03-31 
Partial dates for initial diagnosis of PBC will be imputed as the 15th of the month if the month 
and the year are recorded, or the 1st of July if only the year is recorded. 


 
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Partial dates are not expected for efficacy-related assessments and death.  
However, should a partial date be recorded for any efficacy-related assessment then this date 
will be imputed as the first day of the month if the month and the year are recorded or the 
latest between first of January and date of first dose if only the year is recorded.  
In case of partial date for death, the date will be imputed as the day after the last 
visit/assessment date when the patient was known alive. 
6.4 VISIT WINDOWING 
Visit windowing will be considered only for efficacy and pharmacodynamic assessments.  
The halfway point corresponding to the visits will be considered in relation to the date of first 
dose. Efficacy assessments are planned to be conducted at Week 2, Week 6, Week 12, Week 18, 
Week 24 and Week 28 visits. The following windowing rules will be taken into account to 
establish the visit corresponding to each efficacy and pharmacodynamic assessment: 
• 
Week 2: any efficacy or pharmacodynamic assessment performed between 2 to 28 days 
after the first dose; 
• 
Week 6: any efficacy or pharmacodynamic assessment performed between 29 days to 
63 days after the first dose; 
• 
Week 12: any efficacy or pharmacodynamic assessment performed between 64 days to 
105 days after the first dose; 
• 
Week 18: any efficacy or pharmacodynamic assessment performed between 106 days to 
147 days after the first dose; 
• 
Week 24: any efficacy or pharmacodynamic assessment performed between 148 days to 
182 days after the first dose; 
• 
Week 28: any efficacy or pharmacodynamic assessment performed between 183 days to 
203 days after the first dose; 
If two (or more) assessments are recorded within a visit window, the closer (closest) to the 
halfway point will be taken into account for the analyses. If two assessments within a visit 
window are the same number of days from the halfway point, the second one will be taken into 
account for the summaries assuming that it is more reliable than the first one. 
No programmatic windowing of visits will be considered for safety data. Post-baseline data will 
be presented according to the visit at which it was collected on the eCRF or as described in this 
SAP. 
6.5 BASELINE 
Baseline is defined as the last non-missing value/result where assessment date is less than or 
equal to the date of first dose, unless otherwise specified for individual assessments. 
Baseline will be determined based on all assessments, including additional assessments. 
Change from baseline is defined as the difference between the post-baseline assessment value 
and the baseline value. 


 
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6.6 REPORTING GUIDELINES 
The following guidelines will be followed: 
• 
Page Orientation: Landscape. 
• 
Post-text tables and listings: will be generated in .lst and converted to rtf.  
• 
Post-text figures: will be generated directly in .rtf. 
• 
Font: Courier New font with minimum of 9 points font size. 
• 
Margins: Left: 3.8 cm, Right: 2 cm, Top: 3 cm, Bottom 2 cm on A4 paper. 
• 
Columns headers will be left aligned. 
• 
Treatment labels will be the following and displayed in the following order, unless 
otherwise stated: 
o GKT831 400mg OD 
o GKT831 400mg BID 
o Placebo 
o Total 
• 
Visit labels: the visit labels displayed in Table 1 will be used as required. 
Table 1: Visit Labels 
Study Stage 
CRF Visit 
Tables, Figures and 
Listings Label 
Screening 
Visit 1 (Screening): Day -28 to -7 
SCR 
Treatment phase 
Visit 2 (Baseline): Day 1 
BAS 
Visit 3: Week 2 +/- 3 days 
TRT W2 
Visit 4: Week 6 +/- 3 days 
TRT W6 
Visit 5: Week 12 +/- 3 days 
TRT W12 
Visit 6: Week 18 +/- 3 days 
TRT W18 
Visit 7: Week 24 +/- 3 days 
TRT W24 
Follow-up phase 
Visit 8: Week 28 +/- 3 days 
FU W28 
 
 


 
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• 
Unscheduled visit / repeat assessments: Data obtained at unscheduled or repeat 
assessments will be taken into account in baseline determination and efficacy 
summaries based on windowed visits. All other data from unscheduled or repeat 
assessment will not be included in summaries but only be presented in data listings, 
unless otherwise specified.  
• 
N: The number of subjects in the specified population.   
• 
Treatment presentation: The summaries will be presented by allocated or actual 
treatment group (see more details in Section 7) and overall for disposition, 
demographics 
and 
baseline 
characteristics, 
protocol 
deviations, 
concomitant 
medications, study drug exposure and compliance. 
• 
Continuous data will be summarized using number of subjects (n), mean, standard 
deviation (SD), median, minimum value, maximum value and number of missing data (if 
there are any).  
• 
Categorical data will be summarized using n and percentage based on number of non-
missing data.   
o All categories will be presented, even if no subjects are counted in a particular 
category. 
o In case 1 or more subjects have missing data for the summary, the number of 
missing data will be presented as a separate category, labelled accordingly as 
‘Missing’, if not otherwise stated.   
o Counts of zero in any category will be presented without percentage.  
o For AEs, medical history, prior and concomitant medications the counts are 
based on single counts of subjects with multiple events/treatments under same 
category, while the percentages are calculated using N.  
• Precision of summary statistics: 
o Integer – Sample size (n, N) and number of missing data (if displayed); 
o One additional decimal place than reported/collected – mean, median, other 
percentile, confidence interval; 
o Two additional decimal places than reported/collected – standard deviation; 
o Same number of decimal places as reported/collected – minimum, maximum; 
o Percentages – one decimal place. 
• 
Study day for an assessment will be calculated with reference to the date of first dose as 
Day 1.  
This will be calculated as follows:  
(assessment date - date of first dose) + 1 if the assessment date is on or after the date of 
first dose, 
(assessment date - date of first dose) if the assessment date is prior to the date of first 
dose. 


 
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• 
Data will be presented in listings by allocated treatment group. The order will be subject 
ID, visit, assessment date/time and assessment type/parameters (in the order collected 
on e-CRF, unless otherwise specified). For clinical laboratory results, the listings will be 
presented in the order of allocated treatment group, subject ID, parameter, assessment 
date/time, visit. 
• 
Dates will be presented in format DD-MMM-YYYY. 
• 
Version 4.03 of the NCI-CTC grading criteria (CTCAE v4) will be used for relevant tables 
[3].  
• 
Latest version of the Medical Dictionary for Regulatory Activities (MedDRA) will be used 
for the adverse events coding. The version will be specified in the footnote of the 
corresponding TFLs. 
• 
Latest version of the WHO-DRUG dictionary will be used for the medications coding. The 
version will be specified in the footnote of the corresponding TFLs. 
• 
File naming: The name of each TFL output file will start with a t (for a table), f (for a 
figure) or l (for a listing) to denote the output type and will include an appropriate 
numbering as well as a reference to the associated domain and analysis set.  
 
7 Analysis Sets 
The following populations will be considered in the data analysis: 
Randomized population 
The Randomized population will include all subjects randomly allocated to a treatment arm.  
The Randomized population will be analysed by the allocated treatment group. 
Intent-To-Treat (ITT) population 
The Intent-To-Treat (ITT) population will include all subjects randomly allocated to a treatment 
arm who have received at least one dose of GKT831 or placebo.  
The ITT population will be analyzed by the allocated treatment group and will be the primary 
population for all analyses of efficacy data. 
Per Protocol (PP) population 
The Per Protocol (PP) population will include the subjects of the ITT population without a major 
protocol deviation.  
The PP population will be regarded as a secondary population for supportive analyses of efficacy 
data.  
The outputs planned for the PP population will be produced only if there are at least 10% fewer 
subjects in the PP population compared to the ITT population. That being the case, the PP 
population will be analyzed by the dispensed study treatment. 


 
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Protocol deviations will be defined with the classification of subjects excluded from analysis 
populations at the end of the study prior to unblinding.   
Major protocol deviations will be summarized by the allocated treatment group.  
All protocol deviations deemed important will be listed even if not leading to subjects’ exclusion 
from the PP population.  
Safety population 
The Safety population will include all subjects who have received at least one dose of GKT831 or 
placebo, irrespective of whether they were randomly allocated to a treatment arm, and had at 
least one safety assessment.  
The Safety population will be analyzed by the dispensed study treatment and will be the primary 
population for all analyses of safety data.  
Pharmacokinetic (PK) population 
The Pharmacokinetic (PK) population will include all subjects who have received at least one 
dose of GKT831, have had at least one valid PK measurement and have had no major protocol 
deviations relating to PK data.  
The PK population will be analyzed by the received treatment group and will be the primary 
population for the analyses of PK data. 
 
8 Methods of Analyses and Presentations 
8.1 SUBJECT DISPOSITION  
The subject disposition summaries will be presented by allocated treatment group and overall 
on the randomized population.  
The number and percentages of subjects in each analysis population will be summarized. 
The summary of subject disposition will be showing the number and percentages of subjects 
belonging to the following categories: 
• 
Subjects treated (i.e. with at least one capsule of received treatment self-
administration); 
• 
Subjects for whom the received treatment is different from the allocated treatment; 
• 
Subjects who completed the treatment period (i.e. attended visit Week 24); 
• 
Subjects who discontinued from the treatment period and the reasons for 
discontinuation; 
• 
Subjects who completed the follow-up period (i.e. attended the follow-up visit Week 
28); 
• 
Subjects who discontinued from the follow-up period and the reasons for 
discontinuation. 
Information on analysis populations, study completion and discontinuation will also be displayed 
in subject listings. 


 
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8.2 PROTOCOL DEVIATIONS AND/OR VIOLATIONS 
The full list of types of protocol deviations (PDvs) and their relation to the analysis sets, along 
with the method of identification of each PDv, are detailed in the protocol deviation criteria 
form which is separate to this SAP. Major PDvs are identified as ‘key’ deviations on the protocol 
deviation criteria form. This will be used as a basis for identifying subjects with PDvs throughout 
the study. 
Protocol deviations noted during the trial by the Clinical Research Associates (CRAs), Medical 
Monitors or Data managers will be tracked throughout the study. In addition, PDvs will be 
identified programmatically in SAS® using data from the clinical database.  
At the PDvs review meetings, a consolidated list of PDvs will be reviewed by the team. Prior to 
database lock, there will be a final review of PDvs and an agreement on the subjects final 
membership to or exclusion from each analysis set.  
Key PDvs as well as other PDvs-related events will be summarized separately by PDv category 
and preferred term on the ITT population.  
A listing presenting all key PDvs as well as other PDvs-related events by patient will also be 
provided. 
 
8.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The following demographic and baseline characteristics will be summarised by allocated 
treatment group and overall, on the ITT population:  
• 
Age 
• 
Age (< 65 years, ≥ 65 years) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height 
• 
Weight 
• 
Body mass index (BMI), derived as: weight (kg)/ height(m)^2 
• 
Child bearing potential status (females only) 
• 
Country 
• 
Stratification factor (disease severity level based on baseline serum GGT: < 2.5 x ULN,    
≥ 2.5 x ULN) 
Separately, the following disease characteristics will be summarised by allocated treatment 
group and overall on the ITT population:  
• 
Duration of PBC: Time between diagnosis of BPC and randomization, derived as the 
number of months between the BPC diagnosis date and the randomization date:  
(date of randomization – date of BPC diagnosis)/30.4375 
• 
PBC diagnosis age 
• 
Liver biopsy at the BPC diagnosis date (Yes, No) 


 
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• 
Stage of liver fibrosis at the BPC diagnosis date (from 0 to 4) 
• 
History of liver decompensation (Yes, No) 
• 
Bleeding from oesophageal varices (Yes, No, Unknown) 
• 
Upper Gastrointestinal bleed (Yes, No, Unknown) 
• 
Ascites (Yes, No, Unknown) 
• 
Spontaneous bacterial peritonitis (Yes, No, Unknown) 
• 
Encephalopathy (Yes, No, Unknown) 
• 
Baseline UDCA dose 
• 
Duration of UDCA treatment: Time between start of UDCA treatment and randomization, 
derived as the number of months between the start date of UDCA treatment and the 
randomization date: (date of randomization – start date of UDCA treatment)/30.4375 
• 
Baseline serum GGT 
• 
Baseline serum ALP 
• 
Baseline serum ALT 
• 
Baseline serum AST 
• 
Baseline total serum bilirubin 
• 
Baseline serum hsCRP 
In addition, listings of the above variables will be produced.  
8.4 MEDICAL HISTORY  
Medical history is defined as a medical (or surgical) history reported in e-CRF not ongoing at the 
date of first dose. 
Concomitant disease is defined as a medical (or surgical) history reported in e-CRF ongoing at 
date of first dose. 
Medical histories and concomitant diseases will be coded using MedDRA. 
Summaries of subjects’ medical histories and concomitant diseases will be displayed by system 
organ class and MedDRA preferred term for each allocated treatment group and overall on the 
ITT population.  
Listing of medical history will be produced. Also, a separate listing presenting surgical and 
medical procedures will be provided. 
8.5 PRIOR AND CONCOMITANT MEDICATIONS 
Medications other than GKT137831 will be coded using the WHO-DRUG dictionary.  
Medications will be defined as follows: 
• 
Prior Medication: Any medication whose end date is before the date of first dose. 
• 
Concomitant Medication: Any medication that started before the date of first dose and 
stopped on (or is ongoing after) the date of first dose OR any medication whose start 
date is either the same as (or after) the date of first dose.  


 
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In case of partial start and end dates, the imputation rules detailed in section 6.2 will be used. 
Any medication with a missing end date will be assumed to be a concomitant medication.  
Summaries of subjects’ prior and concomitant medications will be displayed by INN class and 
preferred term for each dose group and overall on the Safety population. 
 
In addition, a listing of prior and concomitant medications will be presented with associated 
flags to identify these two categories of medications. 
8.6 STUDY DRUG EXPOSURE AND/OR COMPLIANCE 
The study drug exposure is defined as the number of days between the first dose and the last 
dose taken + 1 day, and it will be summarized by allocated treatment for subjects in the Safety 
population. 
Each day during the treatment period, subjects will self-administer 4 capsules in the morning 
and 4 capsules in the evening. 
At each dispensing visit, each subject will be given individual packs containing a number of 
allocated treatment bottles (70 capsules of 100 mg GKT137831 and/or matching placebo per 
bottle) as detailed below: 
• 
2 bottles at baseline/Day 1 (Visit 2) and the self-administration will be performed as follows: 
o 
When allocated to GKT137831 400 mg OD: 4 capsules of GKT137831 100 mg from 
one bottle in the morning and 4 capsules of placebo from the other bottle in the 
evening. 
o 
When allocated to GKT137831 400 mg BID: 4 capsules of GKT137831 100 mg from 
one bottle in the morning and 4 capsules of GKT137831 100 mg from the other 
bottle in the evening.  
o 
When allocated to placebo: 4 capsules of placebo from one bottle in the morning 
and 4 capsules of placebo from the other bottle in the evening  
• 
4 bottles at Week 2 (Visit 3): the self-administration will be performed as described above. 
• 
6 bottles at Week 6 (Visit 4), Week 12 (Visit 5) and Week 18 (Visit 6): the self-administration 
will be performed as described above. 
In order to assess the compliance, the investigator or designee will count the remaining unused 
(i.e. returned) capsules of the received treatment at each visit.  
The compliance will be recorded in the eCRF. 
Overall study drug compliance is assessed as: 
 
 
100
8
x 
 
exposure
 
drug
Study 
returned
 
capsules
 
of
number 
 
Total
 -
dispensed
 
capsules
 
of
number 
 
Total







 
 
The overall study drug compliance calculation assumes a subject starts dosing in the morning 
and finishes on their last day in the evening. Consideration of the timing (morning/evening) of 
the first and last dosing will be taken into account for the compliance calculation. 
In addition, a compliance per visit will be listed using the same calculation. 
Overall study drug compliance will be summarized using descriptive statistics by received 


 
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treatment group on the Safety population. The number (%) of subjects with compliance < 80 %, 
between 80% and 120% and > 120% will also be reported. 
All data related to the assessment of the compliance will be listed. 
8.7  EFFICACY DATA ENDPOINTS AND ANALYSES  
8.7.1 
Primary Efficacy Endpoint and Analyses 
The clinical response to GKT137831 is defined as the percent change from baseline to Week 24 
visit in serum GGT (primary efficacy endpoint).  
Absolute serum GGT values as well as absolute change and percent change from baseline to 
Week 24 visit in serum GGT values will be provided at baseline and Week 24 visit for each 
allocated treatment group using summary statistics.  
Due to the small sample size, the primary analysis will be conducted using a stepwise approach. 
The percent change from baseline to Week 24 visit in serum GGT will be analyzed using an 
Analysis of Covariance (ANCOVA) with the allocated treatment and disease severity at baseline 
as fixed effects, and the serum GGT baseline value as a continuous covariate. 
The least square means estimate of the difference between each dose of GKT137831 and 
placebo alongside the 95% confidence interval will be calculated. Given two doses of GKT137831 
are tested versus placebo, the 97.5% confidence interval of the least square mean of the 
difference between each dose of GKT137831 and placebo will also be calculated to account for 
the multiple testing using Hochberg adjustment. 
If the normality assumption for the primary analysis is not met then the percent change from 
baseline in serum GGT at Week 24 will be analyzed non-parametrically through a stratified 
Wilcoxon Mann-Whitney (van Elteren) test. The normality assumption will be assessed through 
the examination of diagnostic residual plots.  
The primary analysis will be performed using the ITT population and a sensitivity analysis will be 
done using the PP population. If the Wilcoxon Mann-Whitney test is used, a subgroup analysis 
for disease severity will also be performed. 
 
8.7.2 
Secondary and Tertiary Efficacy Endpoints and Analyses 
Any analyses of the secondary and tertiary efficacy endpoints should be interpreted with care. 
The study has not been powered for the interpretation of these endpoints. Inferential statistical 
analyses performed on the secondary endpoints are included to aid interpretation and should 
not be considered as an alternative to the primary analysis for determining efficacy. 
All the analyses on the secondary and tertiary efficacy endpoints will be performed on the ITT 
population.  
The need for sensitivity analyses of the secondary endpoints on the PP population will be 
assessed after the blinded review of the major protocol deviations. 
Secondary efficacy endpoints 
The summaries and analyses planned for the secondary efficacy endpoints are described below.  


 
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•Absolute and percent change in serum GGT from baseline to each post-baseline assessment. 
Absolute serum GGT values as well as absolute change and percent change from baseline in 
serum GGT will be provided at baseline and each post-baseline visit for each allocated treatment 
group using summary statistics.  
The percent change from baseline to each post-baseline visit in serum GGT will be analyzed 
using a repeated measures ANCOVA model with the allocated treatment, the post-baseline visit 
and disease severity at baseline as fixed effects, the baseline serum GGT as a continuous 
covariate, and the interaction effect between treatment and visit. 
Estimation will be performed using SAS® PROC MIXED with LSMEANS and REPEATED statement. 
An unstructured covariance matrix will be selected for the repeated measure analysis. 
The least square means estimate of the percent change from baseline in serum GGT considered 
at each post baseline visit alongside its two-sided 95% CI and 97.5% CI will be presented as well 
as the associated standard error and the two-sided p-value.  
Should the repeated measures analysis not converge or the normality assumption fail, data from 
each visit will be compared separately using the same method as the primary analysis.  
 
•Absolute change in ELF score from baseline to Weeks 12 and 24 visits 
Absolute ELF scores and absolute changes from baseline to Weeks 12 and 24 visits in ELF scores 
will be provided at baseline, Week 12 and Week 24 visits for each allocated treatment group 
using summary statistics.  
The absolute change from baseline to Week 12 visit in ELF score will be analyzed using an 
ANCOVA with the allocated treatment and disease severity at baseline as fixed effects, and the 
baseline ELF score as a covariate. 
The absolute change from baseline to Week 24 visit in ELF score will be analyzed similarly. 
 
•Absolute and percent change in serum ALP from baseline to each post-baseline assessment. 
Absolute serum ALP values as well as absolute change and percent change from baseline to each 
post-baseline assessment in serum ALP will be provided at baseline and each post-baseline visit 
for each allocated treatment group using summary statistics.  
In addition, the proportion of subjects achieving a 15, 20, 30, and 40% reduction in serum ALP at 
each post-baseline visit will be tabulated for each allocated treatment group. 
The percent change from baseline to each post-baseline visit in serum ALP will be analyzed using 
a repeated measures ANCOVA model with the allocated treatment, the post-baseline visit and 
disease severity at baseline as fixed effects, the baseline serum ALP as a continuous covariate, 
and the interaction effect between treatment and visit. 
Estimation will be performed using SAS® PROC MIXED with LSMEANS and REPEATED statement. 
An unstructured covariance matrix will be selected for the repeated measure analysis. 
The least square means estimate of the percent change from baseline in serum ALP considered 
at each post baseline visit alongside its two-sided 95% CI and 97.5% CI will be presented as well 
as the associated standard error and the two-sided p-value.  
Should the repeated measures analysis not converge or the normality assumption fail, data from 
each visit will be compared separately using the same method as the primary analysis.  


 
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•Absolute and percent change in serum levels of hsCRP and fibrinogen from baseline to each 
post-baseline assessment. 
Absolute serum levels of hsCRP as well as absolute change and percent change from baseline to 
each post-baseline assessment in serum levels of hsCRP will be provided at baseline and each 
post-baseline visit for each allocated treatment group using summary statistics.  
The percent change from baseline to each post-baseline visit in serum level of hsCRP will be 
analyzed using a repeated measures ANCOVA model with the allocated treatment, the post-
baseline visit and disease severity at baseline as fixed effects, the baseline serum level of hsCRP 
as a continuous covariate, and the interaction effect between treatment and visit. 
Estimation will be performed using SAS® PROC MIXED with LSMEANS and REPEATED statement. 
An unstructured covariance matrix will be selected for the repeated measure analysis. 
The least square means estimate of the percent change from baseline in serum level of hsCRP 
considered at each post baseline visit alongside its two-sided 95% CI and 97.5% CI will be 
presented as well as the associated standard error and the two-sided p-value.  
Should the repeated measures analysis not converge or the normality assumption fail, data from 
each visit will be compared separately using the same method as the primary analysis.  
Similar summary statistics will also be provided on absolute serum levels of fibrinogen as well as 
on absolute change and percent change from baseline to each post-baseline assessment. 
The percent change from baseline to Week 24 visit in serum level of fibrinogen will be analyzed 
using an Analysis of Covariance (ANCOVA) with the allocated treatment and disease severity at 
baseline as fixed effects, and the baseline value of the serum level of fibrinogen as a continuous 
covariate. 
 
•Absolute and percent change in serum ALT, AST, conjugated and total bilirubin from 
baseline to each post-baseline assessment. 
Absolute serum ALT values as well as absolute change and percent change from baseline to each 
post-baseline assessment in serum ALT values will be provided at baseline and each post-
baseline visit for each allocated treatment group using summary statistics.  
The percent change from baseline to each post-baseline visit in serum ALT values will be 
analyzed using a repeated measures ANCOVA model with the allocated treatment, the post-
baseline visit and disease severity at baseline as fixed effects, the baseline serum ALT value as a 
continuous covariate, and the interaction effect between treatment and visit. 
Estimation will be performed using SAS® PROC MIXED with LSMEANS and REPEATED statement. 
An unstructured covariance matrix will be selected for the repeated measure analysis. 
The least square means estimate of the percent change from baseline in serum ALT considered 
at each post baseline visit alongside its two-sided 95% CI and 97.5% CI will be presented as well 
as the associated standard error and the two-sided p-value.  
Should the repeated measures analysis not converge or the normality assumption fail, data from 
each visit will be compared separately using the same method as the primary analysis.  
Serum AST and serum level of total bilirubin will be summarized and analysed similarly. 


 
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Similar summary statistics will also be provided on absolute serum level of conjugated bilirubin 
as well as on absolute change and percent change from baseline to each post-baseline 
assessment. 
The percent change from baseline to Week 24 visit in serum level of conjugated bilirubin will be 
analyzed using an Analysis of Covariance (ANCOVA) with the allocated treatment and disease 
severity at baseline as fixed effects, and the baseline value of the serum level of conjugated 
bilirubin as a continuous covariate. 
 
•Absolute and percent change in the FIB-4 and APRI scores from baseline to each post-
baseline assessment 
Absolute FIB-4 scores as well as absolute change and percent change from baseline to each 
post-baseline assessment in FIB-4 scores will be provided at baseline and each post-baseline 
visit for each allocated treatment group using summary statistics.  
The percent change from baseline to Week 24 visit in FIB-4 score will be analyzed using an 
Analysis of Covariance (ANCOVA) with the allocated treatment and disease severity at baseline 
as fixed effects, and the baseline value FIB-4 score of as a continuous covariate. 
The APRI scores will be summarized and analysed similarly. 
 
•Absolute and percent change in liver stiffness from baseline to Week 24 visit.  
Only subjects with liver stiffness values at both baseline and Week 24 visits will be taken into 
account for the summaries and analyses. 
Absolute liver stiffness values as well as absolute change and percent change from baseline to 
Week 24 visit in liver stiffness values will be provided at baseline and Week 24 visit for each 
allocated treatment group using summary statistics.  
The percent change from baseline to Week 24 visit in liver stiffness will be analyzed using an 
ANCOVA with the allocated treatment and disease severity at baseline as fixed effects, and the 
baseline liver stiffness value as a continuous covariate. 
 
•Absolute and percent change in serum levels of collagen fragments (ProC3, ProC5, C3M, 
C4M, and BGM) from baseline to Weeks 12 and 24 visits. 
Absolute serum levels of collagen fragments and absolute changes from baseline to Week 12 
and Week 24 visits in serum levels of collagen fragments will be provided at baseline, Week 12 
and Week 24 visits for each allocated treatment group using summary statistics.  
The percent change from baseline to Week 12 visit in serum level of collagen fragments will be 
analyzed using an ANCOVA with the allocated treatment and disease severity at baseline as 
fixed effects, and the baseline serum level of collagen fragments as a continuous covariate. 
The percent change from baseline to Week 24 visit in serum level of collagen fragments will be 
analyzed similarly. 
 


 
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• 
Absolute change in Quality of Life scores (based on the 6 domains of the PBC-40 
Questionnaire) and Pruritus score (based on Pruritus VAS) from baseline to Weeks 12 and 
24 visits. 
The PBC-40 questionnaire will be summarized by domain using the scoring described in the 
coded-PBC-40 document.  
If data are missing from a domain (typically missed or duplicated answers), the whole domain 
should be discarded if <50% of the items are completed. If >50% of the items have responses 
then the median value for the completed items in the domain should be ascribed to the missing 
items.  
For each of the 6 domains (symptoms, itch, fatigue, cognition, social, emotional), the total 
scores as well as the absolute and percent changes from baseline to Week 12 and Week 24 visits 
in the domain’s total scores will be provided at baseline, Week 12 and Week 24 visits for each 
allocated treatment group using summary statistics.  
The Pruritus scores will be summarized similarly. 
Tertiary efficacy endpoints 
The summaries and analyses planned for the tertiary efficacy endpoints are described below.  
• 
Absolute and percent change in serum level of total bile acids from baseline to Weeks 12 
and 24 visits. 
Absolute serum level of total bile acids and absolute changes from baseline to Weeks 12 and 24 
visits in serum level of total bile acids will be provided at baseline, Week 12 and Week 24 visits 
for each allocated treatment group using summary statistics.  
The percent change from baseline to Week 12 visit in serum level of total bile acids will be 
analyzed using an ANCOVA with the allocated treatment and disease severity at baseline as 
fixed effects, and the baseline serum level of total bile acids as a covariate. 
The percent change from baseline to Week 24 visit in serum level of total bile acids will be 
analyzed similarly. 
 
• 
Proportion of subjects who meet the definition of PBC responder applying the following 
two criteria: 
• 
ALP < 1.67xULN 
• 
ALP < 1.67xULN, ALP reduction ≥ 15%, and total bilirubin < ULN (composite criterion)  
For each of the two above PBC response criteria, the proportion of responders at Weeks 12 and 
24 visits will be presented for each allocated treatment group. 
8.7.3 
Exploratory Efficacy Endpoints and Analyses  
The below planned analyses on the exploratory efficacy endpoints will be performed only on the 
ITT subjects who meet the following two criteria:  
• 
A sample of the exploratory efficacy parameter is available at Baseline (V2) visit 
• 
At least one follow-up sample of the exploratory efficacy parameter is available either at 
Week 12 (V5) visit or at Week 24 (V7) visit 


 
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• 
Absolute and percent change in serum C4 and FGF19 from baseline to Weeks 12 and 24 
visits. 
Absolute serum C4 values as well as absolute and percent changes from baseline to Week 12 
and Week 24 visits in serum C4 values will be provided at baseline, Week 12 and Week 24 visits 
for each allocated treatment group using summary statistics.  
FGF19 values will be summarized similarly. 
 
• 
Absolute and percent change in serum IL-6, CK-18 M30, and CK-18 M65, from baseline to 
Weeks 12 and 24. 
The summaries on serum IL-6 and CK-18 M30 and M65 fractions will be similar to those above-
described for serum C4. 
 
• 
Absolute and percent change in serum IgM, IL-4, IL-12, IL-17A, and interferon γ, from 
baseline to Weeks 12 and 24. 
The summaries on serum IgM, IL-4, IL-12, IL-17A, and interferon γ will be similar to those above-
described for serum C4. 
 
• 
Assessment of additional biomarkers of interest. 
If relevant, data-driven analyses on additional biomarkers of interest will be performed. If 
performed, these post-hoc analyses will be described in a SAP Change Log and the results will be 
included in the exploratory efficacy analyses. 
 
• 
Assessment of metabolomics signatures. 
If relevant, metabolomics analyses will be performed. If performed, these analyses will be 
outlined in a separate analysis plan and reported in a dedicated study report included as an 
appendix to the clinical study report. 
 
• 
Assessment of pharmacogenetics. 
If relevant, pharmacogenetics analyses of interest will be performed. If performed, these 
analyses will be outlined in a separate analysis plan and reported in a dedicated study report 
included as an appendix to the clinical study report. 
8.7.4 
Subgroup Analysis  
Subgroup summaries/analyses will be performed using the following subgroups of interest:  
 
• 
Subgroups of interest 1: subjects with GGT values below and above the stratification cut 
off value (≥2.5xULN) (for the primary efficacy endpoint analysis only) 
• 
Subgroups of interest 2: subjects with hsCRP value below and above the ULN at Baseline 
(for the analysis of hsCRP only).  


 
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• 
Subgroups of interest 3: subjects with ELF score value below 9.8 at Baseline and subjects 
with ELF score value equal to or greater then 9.8 at Baseline (for the analysis of ELF 
scores only). 
• 
Subgroups of interest 4: subjects with liver stiffness value below 9.6 kPa at Baseline and 
subjects with liver stiffness value equal to or greater than 9.6 kPa at Baseline (for the 
analysis of liver stiffness only). 
• 
Subgroups of interest 5: subjects with any Baseline pruritus VAS value and subjects with 
a Baseline pruritus VAS value greater than 0. 
 
For each subgroup of interest, any subject with a missing/unknown result will be excluded from 
the subgroup summaries/analyses. 
Subgroup summaries/analyses will only be performed for a minimum subgroup size of at least 
20% of the analyzed population, unless otherwise specified.  
For a given endpoint, the subgroup summaries/analyses will be run on each of the analysis 
populations considered for the global summaries/analyses unless otherwise specified. 
8.8 PHARMACOKINETIC/ PHARMACODYNAMIC ENDPOINTS AND ANALYSES 
Plasma concentrations of GKT137831 and its main phase 1 metabolite GKT138184 will be 
summarized using descriptive statistics by received dose level and planned visit. Any plasma 
concentrations below the limit of quantification will be considered as 0 for the calculation of the 
summary statistics. 
The actual sampling time will be presented in listings. Pre-dose samples collected post dose will 
automatically be flagged for exclusion in the summary statistics. 
Samples will be analyzed to determine plasma drug concentrations and thus to aid investigation 
of any PK/PD relationship with PD and/or efficacy endpoints, and optionally for the relationships 
between plasma drug concentrations and pharmacogenomics data. 
A population PK model describing the plasma concentrations of GKT137831 and GKT138184 will 
be developed using non-linear mixed-effects modelling.  
Relationships between drug concentrations/exposure measures and selected PD and/or 
therapeutic efficacy endpoints in the same subject will be graphically explored and formal PK/PD 
(exposure-response) analyses may be performed.  
A separate Modeling and Simulation Analysis Plan (MSAP) for the PK/PD modeling describing the 
general approach to be taken will be finalized prior to database lock. The actual execution of any 
PK/PD modeling will depend upon the data, and full details of this will be provided in a separate 
report, which will be appended to the clinical study report (CSR). 
8.9 QUALITY OF LIFE OR PHARMACOECONOMIC ENDPOINTS AND ANALYSES 
For the Quality of life questionnaire see subsection ‘Tertiary efficacy endpoints’ in Section 8.7.2. 
8.10 
SAFETY DATA ENDPOINTS AND ANALYSES 
All Safety analyses will be performed on the Safety Population. 


 
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8.10.1 Adverse Events (AEs) 
All AEs will be coded using MedDRA dictionary. The version of the dictionary will be provided in 
the adverse events tables, figures and listing footnotes.  
All information on AEs will be listed by subject.  
Treatment-Emergent Adverse Events (TEAEs) will be defined as AEs that started on or after the 
date of the first dose of the received treatment. 
AEs that occurred prior to the first dose of the received treatment and increased in severity 
and/or relationship after the first dose of the received treatment will also be regarded as TEAEs. 
If it is not possible to determine whether an AE is a TEAE due to a missing start date, the AE will 
be regarded as a TEAE unless the stop date indicates that the AE occurred prior to the first dose 
of the received treatment. 
All reported TEAEs will be summarized. 
The number and percentage of subjects experiencing the following categories of AEs will be 
summarized for each received treatment group and for all received treatment groups combined 
both overall and by system organ class and preferred term: 
• 
TEAEs 
• 
Related TEAEs 
• 
Serious TEAEs 
• 
Related and serious TEAEs 
• 
TEAEs leading to study drug discontinuation 
• 
TEAEs leading to study drug interruption 
• 
Non-TEAEs 
In addition, the number and percentage of subjects experiencing the following categories of AEs 
will be summarized for each received treatment group and for all received treatment groups 
combined by system organ class, preferred term and maximal severity: 
• 
TEAEs 
• 
Related TEAEs 
For all system organ classes and preferred terms with a TEAE incidence rate of at least 5% over 
all received treatment groups combined, the number and percentage of subjects will be 
summarized for each received treatment group and for all received treatment groups combined 
by system organ class and preferred term. 
Subjects will be counted only once within each system organ class, preferred term and severity.  
• 
If a subject has experienced more than one adverse events coded within the same 
system organ class then this subject will be counted only once within that system organ 
class. 
• 
If a subject has experienced more than one adverse events coded to the same preferred 
term within a system organ class then the subject will be counted only once for that 
preferred term and within that system organ class. 
• 
If a subject has experienced more than one adverse events coded to the same preferred 
term within a system organ class then the subject will be counted only once under the 


 
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maximum severity for that preferred term and within that system organ class. The 
maximal severity is defined as first death (the highest possible level of severity), then 
life-threatening followed by severe, moderate, and mild (the lowest possible level of 
severity). 
If a subject has experienced any AE with a missing severity then the AE’s grade will be imputed 
as the maximal reported grade over all AEs experienced by that subject (excluding death).  
If a subject has experienced any AE with a missing relationship then the AE’s relationship will be 
assumed to be related to study drug. 
Adverse Events of Special Interest (AESI) 
Potential effect of GKT137831 on arterial blood pressure and its clinical relevance will be 
evaluated. Systolic and diastolic blood pressure values will be examined together with 
temporally associated blood pressure related events including adverse events and serious 
adverse events, changes in study drug administration and other related changes in concomitant 
medications.  
Drug induced liver injury related events will be considered as AESI as well.   
In addition, the medical history and other possible contributing risk factors will be assessed. 
The following categories of AEs will be listed by subject: 
• 
All adverse events 
• 
All TEAEs 
• 
All serious AEs 
• 
All AEs leading to study drug discontinuation 
• 
All AEs leading to study drug interruption 
• 
All AEs leading to death  
• 
All AESI 
8.10.2 Clinical Laboratory Evaluations 
Laboratory parameters (hematology, biochemistry, TSH levels, urinalysis) results and changes 
from baseline will be summarized with descriptive statistics by visit for each received treatment 
group and for all received treatment groups combined. 
The changes from baseline will also be displayed by visit for each received treatment group 
using box plots. 
For each laboratory parameter, the incidence of abnormal results (i.e. outside of the normal 
range) will be summarized by visit for each received treatment group and for all received 
treatment groups combined. For dipstick parameters with a categorical response, any positive 
result will be considered abnormal.  
For each parameter, the shift from baseline to each planned post-baseline visit in the range of 
values (low, normal, high and abnormal [low/high]) will be summarized by post-baseline visit 
with the number and percentages of subjects.  
For the calculation of descriptive statistics, all laboratory results will be converted to SI units. 
Differential counts will be presented both as absolute values and as percentages of white blood 
cells. 
The NCI-CTCAE criteria v4.0 [3] will be used to determine severity. 


 
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For each hematological parameter, the number and percentage of the worst NCI-CTCAE grades 
will be presented for each received treatment group. The shift from baseline grade to the worst 
NCI-CTCAE grade will also be presented by received treatment group for each hematological 
parameter. 
For each biochemistry parameter, the same summaries on the worst NCI-CTCAE grades will be 
produced. 
All data will be listed in subject data listings and abnormal results will be flagged. 
The laboratory parameters assessments reported as ‘<LOQ’ will be imputed with and displayed 
as the calculated value equal to LOQ/2 in the listings. 
8.10.3 Vital Signs 
Vital signs include Pulse rate, Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP). 
Pulse rate, SBP and DBP values as well as change from baseline to each planned visit will be 
summarized with descriptive statistics by visit for each received treatment group and for all 
received treatment groups combined. 
The shift from baseline to each planned post-baseline visit for each of the criteria specified in 
Table 2 will be summarized by post-baseline visit for each received treatment group and for all 
received treatment groups combined. 
Table 2: Vital sign values of clinical importance 
Vital Sign 
Criteria 
Flag 
Pulse Rate 
< 55 bpm 
Low (L) 
≥ 55 to ≤ 100 bpm 
Normal 
> 100 bpm 
High (H) 
Systolic Blood Pressure 
< 90 mmHg 
Low (L) 
≥ 90 to ≤ 140 mmHg 
Normal 
> 140 mmHg 
High (H) 
Diastolic Blood Pressure 
< 45 mmHg 
Low (L) 
≥ 45 to ≤ 90 mmHg 
Normal 
> 90 mmHg 
High (H) 
Box plots will be produced to plot the vital signs change from baseline at each visit. 
Vital signs (including Body Weight) will be listed by subject and visit with both conventional and 
Standard International values and all results considered abnormal as per criteria defined in 
Table 2 will be flagged.  
8.10.4 ECG 
ECG parameters include Heart Rate, QRS axis, PR interval, RR interval, QRS duration and QT 
interval. 


 
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In addition, QTcB interval and QTcF interval will be calculated based on the following formulae: 
QTcB = QT interval/Square root of RR interval 
QTcF = QT interval/Cubed root of RR interval 
For all the above ECG parameters, the values as well as the changes from baseline to each 
planned visit will be summarized with descriptive statistics by visit for each received treatment 
group and for all received treatment groups combined. 
For all the above ECG parameters, the number and percentage of subjects with abnormal results 
will be presented by visit for each received treatment group and for all received treatment 
groups combined. 
In addition, the shift from baseline to each planned post-baseline visit in the overall ECG 
interpretation (normal, abnormal not clinically significant and abnormal clinically significant) will 
be summarized by post-baseline visit for each received treatment group and for all received 
treatment groups combined. 
ECG parameters values will be listed by subject and visit and all results considered abnormal as 
per criteria defined in Table 3 will be flagged.  
Table 3: Abnormal ECG -Criteria 
QTc Interval 
Criteria (msec) 
Flag 
Change from Baseline 
≤ 30 
Low (L) 
> 30 to ≤ 60 
Mid (M) 
> 60 
High (H) 
Actual Value 
> 450 to ≤ 480   
Low (L) 
> 480 to ≤ 500 
Mid (M) 
> 500 
High (H) 
For QTcB interval and QTcF interval, the categorized values at each visit and the categorized 
changes from baseline to each post-baseline visit will be summarized by post-baseline visit with 
the number and percentage of subjects for each received treatment group and for all received 
treatment groups combined. For both parameters, the categorized worst change from baseline 
over all planned post-baseline visits will be summarized similarly. 
Box plots will be produced for each ECG parameter (Heart Rate, QRS axis, PR interval, RR interval, 
QRS duration, QT interval, QTcB interval and QTcF interval) showing change from baseline at 
each visit. 
All ECG parameters values will be listed by subject and visit and all results considered abnormal 
as per criteria defined in Table 3 will be flagged. 
9 Interim Analyses 
An interim analysis is planned once at least 80-90% of the planned number of subjects to be 
randomized in the study have completed their Week 6 visit.  
Only data collected for these subjects, prior to and including the date of the Week 6 visit for the 
last randomized subject included in the interim analysis cohort, will be taken into consideration 
for the interim analysis.  


 
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The purpose of the interim analysis is to support decision-making regarding the further 
development of GKT137831. It is not intended to amend the study protocol or stop the trial due 
to futility or overwhelming efficacy. 
The primary efficacy endpoint of the interim analysis is the percent change from baseline to 
Week 6 visit in serum GGT. 
The interim analysis will only be run on this primary efficacy endpoint and on the following 
secondary efficacy endpoints (no other endpoint will be analysed): 
• 
Absolute change from baseline to Week 6 visit in serum GGT 
• 
Absolute and percent change from baseline to Week 6 visit in serum levels of ALP 
• 
Absolute and percent change from baseline to Week 6 visit in serum levels of hsCRP and 
fibrinogen 
• 
Absolute and percent change from baseline to Week 6 visit in serum levels of ALT, AST, 
conjugated and total bilirubin. 
• 
Absolute and percent change from baseline to Week 6 visit in the FIB-4 and APRI scores. 
The interim analyses will also be run for the following 4 subgroups of interest:  
• 
Subgroups of interest 1: subjects with GGT values below and above the stratification cut 
off value (≥2.5 x ULN) (for the primary efficacy endpoint of the interim analysis only). 
If only very few subjects have a Baseline GGT below 2.5 x ULN then the stratification cut 
off value for the analysis will be the median GGT at Baseline. 
• 
Subgroups of interest 2: subjects below and above 65 years of age (for the primary 
efficacy endpoint of the interim analysis only) 
• 
Subgroups of interest 3: subjects with ALP value below and above median at Baseline 
(for the primary efficacy endpoint of the interim analysis only) 
• 
Subgroups of interest 4: subjects with hsCRP value below and above the ULN at Baseline 
(for the analysis of hsCRP only) 
Subgroup summaries/analyses will only be performed for a minimum subgroup size of at least 
20% of the interim analysis population, unless otherwise specified. 
 
In addition, the gender and the age as well as the serum GGT, the serum levels of ALP, ALT, and 
hsCRP values will be summarized at Baseline for each allocated treatment group. 
 
The interim analysis will be conducted by the unblinded SMB statistician, who has no 
involvement with the study conduct. The interim analysis outputs will be communicated to the 
Sponsor’s Chief Medical Officer. 
The interim analysis described above does not include assessments of safety data. The safety 
data will be reviewed periodically and separately as described in the study SMB charter. 
10 Changes to Planned Analyses 
The final analysis will be performed according to a 2-stage process detailed in Section 6.1. 


 
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11 Document History 
Date 
Version Modified by 
Brief details of changes made to template 
15OCT2018 
1.0 
Jean-Luc Beffy 
Initial final version 
15MAR2019 
2.0 
Jean-Luc Beffy 
Updated final version 
The main changes are the following: 
1. Addition of Section 6.1 to clarify the 
timing of the final analysis. 
2. Addition of Appendix 1 to provide the 
list of Top Line tables. 
12 References 
[1] New Drug Application (NDA) 207999 submitted by Intercept Pharmaceuticals, Inc. for 
obeticholic acid (OCA) proposed for the treatment of Primary Biliary Cirrhosis (PBC), 
Gastrointestinal Drug Advisory Committee (GIDAC) Meeting, April 7th, 2016. 
[2] Hirschfield GM et al. Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and 
Inadequate Response to Ursodeoxycholic Acid. Gastroenterology 2015; 148: 751-761. 
[3] CTCAE v4.03: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


 
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13 Appendix 1: List of Top Line tables 
 
Table 
order 
Table   
number 
Table title 
1 
14.1-1 
Subject Disposition (Randomized Population) 
2 
14.1-3 
Summary of Demographic and Baseline Characteristics (ITT Population) 
3 
14.1-5.1 
Disease Characteristics (ITT Population) 
4 
14.2-1.1.1 
Summary of Absolute and Percent Change from Baseline to Week 24 
Visit in Serum GGT (ITT Population) 
5 
14.2-1.1.2 
Analysis of Percent Change from Baseline to Week 24 Visit in Serum GGT 
(ITT Population) 
6 
14.2-1.3.1.1 
Summary of Percent Change from Baseline to Week 24 Visit in Serum 
GGT by Subgroup of Baseline GGT values (ITT Population) 
7 
14.2-1.3.1.2 
Analysis of Percent Change from Baseline to Week 24 Visit in Serum GGT 
by Subgroup of Baseline GGT values (ITT Population) 
8 
14.2-2.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in Serum GGT (ITT Population) 
9 
14.2-2.1.2 
Analysis of Percent Changes from Baseline in Serum GGT across all Post 
Baseline Visits [a] Model Estimates (ITT Population) 
10 
14.2-4.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in Serum Level of ALP (ITT Population) 
11 
14.2-4.1.2 
Analysis of Percent Change from Baseline to each Post-Baseline Visit in 
Serum Level of ALP Model Estimates (ITT Population) 
12 
14.2-5.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in Serum Level of hsCRP (ITT Population) 
13 
14.2-5.1.2 
Analysis of Percent Change from Baseline to each Post-Baseline Visit in 
Serum Level of hsCRP Model Estimates (ITT Population) 
14 
14.2-7.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in Serum Level of ALT (ITT Population) 
15 
14.2-7.1.2 
Analysis of Percent Change from Baseline to each Post-Baseline Visit in 
Serum Level of ALT Model Estimates (ITT Population) 
16 
14.2-8.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in Serum Level of AST (ITT Population) 


 
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Table 
order 
Table   
number 
Table title 
17 
14.2-9.2.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in Serum Level of Total Bilirubin (ITT Population) 
18 
14.2-10.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in FIB-4 score (ITT Population) 
19 
14.2-10.1.2 
Analysis of Percent Change from Baseline to Week 24 Visit in FIB-4 score 
(ITT Population) 
20 
14.2-11.1.1 
Summary of Absolute and Percent Change from Baseline to each Post-
Baseline Visit in APRI score (ITT Population) 
21 
14.2-11.1.2 
Analysis of Percent Change from Baseline to Week 24 Visit in APRI score  
(ITT Population) 
22 
14.2-12.1.1 
Summary of Change from Baseline to Week 24 Visit in Liver Stiffness (ITT 
Population) 
23 
14.2-12.1.2 
Analysis of Change from Baseline to Week 24 Visit in Liver Stiffness (ITT 
Population) 
24 
14.2-12.2.1 
Summary of Change from Baseline to Week 24 Visit in Liver Stiffness by 
Baseline Liver Stiffness Value Subgroup (ITT Population) 
25 
14.2-12.2.2 
Analysis of Change from Baseline to Week 24 Visit in Liver Stiffness by 
Baseline Liver Stiffness Value Subgroup (ITT Population) 
26 
14.2-13.2.1.1 
Summary of Change from Baseline to Week 24 Visit in Serum Level of 
Collagen Fragments (ITT Population)  
27 
14.2-13.2.1.2 
Analysis of Change from Baseline to Week 24 Visit in Serum Level of 
Collagen Fragments (ITT Population)  
28 
14.2-15.2 
Summary of Change from Baseline to Week 24 Visit in each Domain 
Score of the PBC-40 Questionnaire (ITT Population) 
29 
14.2-16 
Summary of Change from Baseline to Week 12 and Week 24 Visits in 
Pruritus Score (VAS) (ITT Population) 
30 
14.2-17 
PBC Responders Rates at Week 12 and 24 Visits Applying Two Response 
Criteria: Serum ALP < 1.67xULN and Combined Criterion Serum ALP < 
1.67xULN, ALP Reduction ≥ 15%, and total bilirubin < ULN (ITT 
Population)