Conditions: Primary Biliary Cholangitis Liver Stiffness
Keywords: Setanaxib Primary Biliary Cholangitis Elevated Liver Stiffness
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 76
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the effect of setanaxib on alkaline phosphatase (ALP) at Week 24 in participants with PBC and with elevated liver stiffness and intolerance or inadequate response to ursodeoxycholic acid (UDCA).

Detailed description:

Arms:
arm 1: Participants will be administered setanaxib at a dose of 1200 mg/day for the 24-week double-blind treatment period. arm 2: Participants will be administered setanaxib at a dose of 1600 mg/day for the 24-week double-blind treatment period. arm 3: Participants will be administered a placebo for the 24-week double-blind treatment period.

Interventions: intervention 1: Setanaxib intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets, 400mg per tablet intervention 2: Oral tablets

Protocol document:
Prot_000.pdf: 
 
Confidential 
 
 CLINICAL STUDY PROTOCOL 
 
Title: 
TRANSFORM: A 24-week, Randomized, Placebo-controlled, 
Double-blind, Phase 2b Trial of Setanaxib in Patients with 
Primary Biliary Cholangitis (PBC) and Elevated Liver 
Stiffness 
NCT number:  
NCT05014672 
Unique Protocol ID:  
GSN000350 
Document Date:  
27 September 2023 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
Page 1 of 126
 
 
Confidential 
 
 
 CLINICAL STUDY PROTOCOL 
Title: 
TRANSFORM: A 24-week, Randomized, Placebo-controlled, 
Double-blind, Phase 2b Trial of Setanaxib in Patients with 
Primary Biliary Cholangitis (PBC) and Elevated Liver 
Stiffness 
Short title:  
A Phase 2b Trial of Setanaxib in Patients with PBC and 
Elevated Liver Stiffness 
Protocol number:  
GSN000350 
Study Phase:  
Phase 2b 
Test product:  
Setanaxib 
Regulatory agency 
identifier number(s): 
Investigational New Drug number: 132135 
EudraCT (EU Drug Regulating Authorities Clinical Trials) 
number: 2021-001810-13 
Sponsor:  
Calliditas Therapeutics Suisse SA 
Chemin des Aulx 14 
1228 Plan-les-Ouates 
Switzerland 
Calliditas Therapeutics Suisse SA is a subsidiary of 
Calliditas Therapeutics AB 
Contract research 
organization:  
ICON plc 
Corporate Headquarters 
South County Business Park 
Leopardstown, Dublin 18  
Ireland 
Phone (IRL): +353 1 291 2000 
Phone (US): +1 215 616 3000  
Fax: +353 1 247 6260 
Coordinating 
Investigators: 
Division of Digestive Health and Liver Diseases 
Schiff Center for Liver Diseases 
University of Miami 
1500 NW 12th Avenue, Suite 1101 
Miami, FL 33136 
US 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
Page 2 of 126
 
 
Confidential 
 
 
 
NIHR Newcastle Biomedical Research Centre 
Newcastle upon Tyne NHS Foundation Trust & Newcastle 
University 
Newcastle upon Tyne, NE4 5P 
UK 
Protocol version and 
date:  
Version 5.0 (27 September 2023), incorporating Global 
Amendment 4 
This study will be performed in compliance with the principles of Good Clinical Practice. 
This document is a confidential communication of the Sponsor. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained 
herein shall be published or disclosed without prior written approval, except that this 
document will be disclosed to the appropriate Institutional Review Board(s)/Independent 
Ethics Committee(s) under the condition that they keep it confidential. 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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Confidential 
 
 
PROTOCOL SIGNATURE PAGE – SPONSOR 
This protocol has been reviewed and approved by the representative(s) listed below. 
Any modification of the protocol must be agreed upon by the Sponsor and the Investigator 
and must be documented in writing. 
Sponsor representative: 
 
 
 
 
Print Name 
 
 
Title 
 
 
 
 
Signature 
 
Date 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
Page 4 of 126
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – SPONSOR (CONTINUED) 
This protocol has been reviewed and approved by the representative(s) listed below. 
Any modification of the protocol must be agreed upon by the Sponsor and the Investigator 
and must be documented in writing. 
Sponsor representative: 
 
 
 
 
Print Name 
 
 
Title 
 
 
 
 
Signature 
 
Date 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
Page 5 of 126
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – COORDINATING 
INVESTIGATOR 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Council for Harmonisation 
guidelines on Good Clinical Practice (ICH GCP), and applicable regional regulatory 
requirements. 
Coordinating Investigator: 
 
 
 
 
Print Name 
 
 
Title 
 
Institution 
 
 
 
Signature 
 
Date 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
Page 6 of 126
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – COORDINATING 
INVESTIGATOR (CONTINUED) 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Council for Harmonisation 
guidelines on Good Clinical Practice (ICH GCP), and applicable regional regulatory 
requirements. 
Coordinating Investigator: 
 
 
 
 
Print Name 
 
 
Title 
 
Institution 
 
 
 
Signature 
 
Date 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
Page 7 of 126
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
I have read this protocol, which has been agreed by the Sponsor and given 
approval/favorable opinion by the Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC), and I agree that it contains all necessary details for my staff and I to 
conduct this study as described. I will provide copies of the protocol and any amendments 
to all study personnel under my supervision and provide access to all information provided 
by the Sponsor or their specified designees. I will discuss the material with the study 
personnel to ensure that they are fully informed about the study. 
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the ethical 
review of the study, without written authorization from the Sponsor. It is, however, 
permissible to provide information to a patient in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Council for Harmonisation 
guidelines on Good Clinical Practice (ICH GCP), and applicable regional regulatory 
requirements. 
I agree to comply with the procedures described for data recording and reporting and to 
permit monitoring and auditing by the Sponsor (or designee), and inspection by the 
appropriate regulatory authorities. 
I agree to make my patients’ study records available to the Sponsor’s personnel, their 
representatives, and relevant regulatory authorities in order to verify data that I have 
entered into the electronic case report forms (eCRFs). I will retain the study-related 
essential documents until the Sponsor indicates that they are no longer needed. I am aware 
of my responsibilities as an Investigator as per ICH GCP, local regulations, the study 
protocol, and the clinical trial agreement. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to the Sponsor (or designee). 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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Confidential 
 
 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR (continued) 
Investigator: 
 
 
 
 
Print Name 
 
 
Title 
 
Institution 
 
 
 
Signature 
 
Date 
 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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Confidential 
 
 
SERIOUS ADVERSE EVENT (SAE), ADVERSE EVENTS OF 
SPECIAL INTEREST (AESI), PREGNANCY, AND OVERDOSE 
CONTACT INFORMATION 
In the event of an SAE, the Investigator will send a safety report form within 24 hours of 
becoming aware of the SAE to the contact details below. 
Any AESIs, pregnancies, or overdoses will also be reported within 24 hours of becoming 
aware of the event to the contact details below. 
 
Contract Research Organization 
In Europe, Asia-Pacific, and Africa (EAPA): 
ICON Drug Safety Center EAPA 
Phone +49 621 8782 154 
Fax 
+44 1792 525 720 
Email MHGSafety@iconplc.com 
 
In the Americas: 
ICON Drug Safety Center Americas 
Phone +1 800 772 2215 
Fax 
+1 888 772 6919 
Email CHOsafetyfax@iconplc.com 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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Confidential 
 
 
PRODUCT COMPLAINTS 
Product complaints will be collected if they occur in the study. A product complaint is any 
alleged deficiency related to the identity or quality of a study drug, after it is released for 
distribution to a site or to a patient. This includes all components distributed with the drug, 
such as packaging, drug containers, labelling, and inserts. 
Examples include: 
• Packaging that is damaged or broken 
• Missing or illegible labelling 
• Inability of the enrolled patients to administer the investigational product 
• Product with an unexpected color, appearance (eg, broken tablets), or taste 
Product complaints should be reported by filling out the Product Complaint Report Form 
and emailing it to TRANSFORM-prs-DL-CADGS350-productcomplaints@iconplc.com. 
Any adverse events (AEs) that are associated with a product complaint should be reported 
per instructions for AE Reporting in Section 7.3. 
 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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Confidential 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Of note, version 2.0 (dated 16 December 2021) has been generated to implement changes 
mandated by the US Food and Drug Administration (FDA) and some European Regulatory 
Authorities. This version has only been submitted to the US FDA but has not been shared 
with any other regulatory authority and has not been implemented in any country. 
Thus, version 3.0 (dated 07 April 2022) has been generated from version 1.0 (dated 06 May 
2021), to implement all changes described in global amendment 2, as well as those 
introduced by global amendment 1. 
 
Version 5.0, 27 September 2023 
Global Amendment 4 (substantial) 
Description of change and rationale for change: 
The protocol has been amended to reflect the following key changes, which have been 
incorporated in the protocol and protocol summary where applicable: 
1. This study was initiated as a randomized, placebo-controlled, double-blind, 
parallel-group, multicenter, adaptive Phase 2b/3 study. The study was planned to 
consist of a 4-week Screening Period, a 52-week Double-blind Treatment Period, 
a 52-week Extension Phase Treatment Period, and a 12-week Follow-up Period. 
The total duration of the study for patients remaining in the study until their final 
follow-up assessment was planned to be approximately 2 years and 4 months. 
 The feasibility to conduct the study within an acceptable time frame under this 
design has proved challenging. This is considered to be related to new and more 
frequently used treatment options, which the current protocol allows for, such as 
obeticholic acid (OCA) and off-label use of bezafibrates. One consequence of 
this is that fewer patients than anticipated are meeting the inclusion criteria of 
alkaline phosphatase (ALP) ≥1.67 and liver stiffness ≥8.0 kPa. Therefore, the 
study design is revised to a Phase 2b study. The following key changes include: 
a. Revision of primary and secondary objectives, ie, the decrease in ALP 
from Baseline at 24 weeks as primary objective and no further selection 
of a key secondary parameter. 
b. Corresponding to the new primary endpoint 
i. A new sample size calculation was performed that resulted in 60 
to 70 patients instead of 318, and a reduced number of sites (80 to 
130). 
ii. The statistical methods planned to be applied were revised. 
c. Reduction of the Double-blind Treatment Period from 1 year to 24 weeks,  


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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d. The rationale for a 52-week Extension Phase Treatment Period is no 
longer applicable; therefore, this period as well as the 12-week Follow-
up Period have been removed. 
e. With the reduction of the Double-blind Treatment Period to 24 weeks, 
the optional liver biopsy at Week 52 has been removed, it is not expected 
to find effects at an earlier time point. 
f. The rationale for an interim analysis, ie, the assessment of futility and 
dose selection, is no longer applicable; therefore, the interim analysis has 
been removed. The study design is no longer adaptive. 
g. Corresponding to changes to the overall study design, the statistical 
methods planned to be applied were revised, including the definition of 
the Full Analyses Set (FAS) handling of missing data values, the plans 
for sensitivity and supplementary analyses. 
2. To enhance enrollment, the option for a second rescreening (ie, after failure of 
initial and first rescreening) has been added to Section 4.3. 
3. To enhance enrollment by limiting the number of assessments for patients, the 
magnetic resonance elastography (MRE) to assess liver and spleen stiffness has 
been removed. 
4. Exclusion criterion 18 has been removed. The FDA approved FibroScan® 
assessments in patients treated with or for planned treatment with a pacemaker, 
implanted cardioverter defibrillator, or other implanted electronic device. 
5. The criterion for premature discontinuation of the investigational medicinal 
product (IMP) has been amended for patients with a severe cardiac condition or 
QT prolongation or an increase in QTc greater than 60 milliseconds from 
Baseline. 
6. APPENDIX II – Detection and Management of Suspected or Confirmed Cases 
of Drug-Induced Liver Injury, has been updated according to FDA 
recommendations:  
a. Patient are instructed to return to the study center within 24 to 48 hours 
instead of 48 to 72 hours.  
b. In case of specified laboratory abnormalities the IMP will be discontinued 
instead of interrupted.  
c. Follow-Up procedures for patient(s) who meet suspected DILI evaluation 
criteria have been extended. 
7. Administrative changes in the address of the Sponsor and the address and safety 
center of the contract research organization (CRO). 
8. Editorial changes to increase readability and consistency. 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
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Special Note: Patients who are following the previous protocol schedule (protocol 
version 4) and are already beyond Week 24 should permanently discontinue IMP as soon 
as possible and have an End-of-Treatment Visit 30 days after their last dose. 
 
 
Version 4.0, 14 March 2023 
Global Amendment 3 (substantial) 
Description of change and rationale for change: 
The protocol has been amended to reflect the following key changes, which have been 
incorporated in the protocol and protocol summary where applicable: 
1. If futility is not met for the setanaxib 1200 mg/day and 1600 mg/day doses, the 
Independent Data Monitoring Committee (IDMC) will select one dose for 
Stage 2. Ongoing patients who are receiving the selected dose will continue the 
study at the same dose. Ongoing patients who are receiving a dose that is 
discontinued will have their dose escalated/de-escalated to the selected dose. 
Patients enrolled after the interim analysis will be randomized to setanaxib (dose 
selected by the IDMC), or placebo, according to a 1:1 randomization ratio, up to 
full enrollment. 
2. An analysis of the proportion of patients with alkaline phosphatase (ALP) 
reduction of ≥70% reduction from Baseline at Week 52 and changes in markers 
of cholestasis as assessed by proportion of patients at Week 52 with ALP 
reduction to <1.5×upper limit of normal (ULN) and total bilirubin ≤1×ULN and 
with a ≥40% ALP reduction from Baseline have been added following 
recommendations from the FDA and the European Medicines Agency, 
respectively. 
3. The exploratory endpoint of changes in markers of cholestasis has been upgraded 
to secondary endpoint (as above mentioned). 
4. The list of prohibited medications was updated with regard to corticosteroid use 
and removal of biologics. 
 
 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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Version 3.0, 07 April 2022 
Global Amendment 2 (substantial) 
Description of change and rationale for change: 
The protocol has been amended to reflect changes to the Concomitant Medication and 
Procedures Section 6.7 based on a request from the Belgian regulatory authority. 
In addition, the following non-substantial revisions and corrections have been 
incorporated in the protocol and protocol summary where applicable: 
1. Genkyotex Suisse SA has been renamed Calliditas Therapeutics Suisse SA 
effective 01 April 2022. 
2. Clarification of Inclusion Criterion #10b 
3. The exclusion criteria numbering has been revised to ensure alignment and 
consistency across all versions of the protocol. 
4. Background Section 1.1 includes minor revisions to align with the Investigator 
Brochure, Edition 12.0. 
 
 
Version 2.0, 16 December 2021 
Global Amendment 1 (substantial) 
Description of change and rationale for change: 
The protocol has been amended to reflect the following key changes, which have been 
incorporated in the protocol and protocol summary where applicable: 
1. Based on FDA requests, changes have been made to the Patient-Reported 
Outcome measures used in the study and Key Secondary Endpoints. 
2. The 2 errors that had been identified and described in the protocol clarification 
letter dated 05 Jul 2021 have been corrected. 
3. Changes implemented in the local UK, Spanish, Austrian, and German revised 
protocols have been incorporated in the global amendment. This includes an 
added on-site visit at Week 4. 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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4. Language on product complaint reporting was added. 
Additionally, the protocol amendment includes minor revisions for 
consistency/clarification purposes. 
 
 
Version 1.0, 06 May 2021 
Initial creation 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
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PROTOCOL SUMMARY 
Protocol number: GSN000350 
Protocol title: TRANSFORM: A 24-week, Randomized, Placebo-controlled, Double-blind, Phase 2b 
Trial of Setanaxib in Patients with Primary Biliary Cholangitis (PBC) and Elevated Liver Stiffness 
Short title: A Phase 2b Trial of Setanaxib in Patients with PBC and Elevated Liver Stiffness 
Sponsor: Calliditas Therapeutics Suisse SA 
Study phase: Phase 2b 
Study sites: It is planned to recruit 80 to 130 investigational centers in North America, Europe, Israel, 
Australia, and New Zealand. 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoint 
• 
To evaluate the effect of setanaxib on alkaline 
phosphatase (ALP) at Week 24 in patients 
with PBC and with elevated liver stiffness and 
intolerance 
or 
inadequate 
response 
to 
ursodeoxycholic acid (UDCA) 
• 
Change in ALP at Week 24 compared to 
Baseline 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of setanaxib on fatigue 
at Week 24 
• 
Change in fatigue at Week 24 compared to 
Baseline, as assessed by  
○ 
the 
Patient-Reported 
Outcomes 
Measurement 
Information 
System 
(PROMIS) short form-Fatigue 7b Daily  
○ 
the Patient’s Global Impression of 
Severity (PGIS) fatigue 
○ 
the Patient’s Global Impression of 
Change (PGIC) fatigue  
○ 
the 
PBC-40 questionnaire 
(PBC-40) 
fatigue domain 
• 
To evaluate the effect of setanaxib on liver 
stiffness at Week 24 
• 
Change in liver stiffness at Week 24 
compared to Screening, as assessed by 
transient elastography (FibroScan®) 
• 
To evaluate the effect of setanaxib on ALP, 
fatigue, and liver stiffness at Week 24, where 
setanaxib doses are combined 
• 
Change in ALP at Week 24 compared to 
Baseline, 
where 
setanaxib 
doses 
are 
combined 
• 
Change in fatigue at Week 24 compared to 
Baseline, as assessed by the PROMIS short 
form-Fatigue 7b Daily, the PGIS fatigue, the 
PGIC fatigue, and the PBC-40 fatigue 
domain, where setanaxib doses are combined 
• 
Change in liver stiffness at Week 24 
compared to Screening, as assessed by 
transient elastography (FibroScan®), where 
setanaxib doses are combined 
• 
To evaluate the effect of setanaxib on pruritus 
at Week 24 
• 
Change in pruritus at Week 24 compared to 
Baseline, as assessed by the Worst Itch 
Numerical Rating Scale (WI-NRS), the 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
Protocol Version and Date: Version 5.0 (27 September 2023) 
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PBC-40 itch domain, and the PGIS and PGIC 
pruritus 
• 
To evaluate the effect of setanaxib on markers 
of cholestasis at Week 24 
• 
Changes in markers of cholestasis as assessed 
by proportion of patients at Week 24 with: 
○ 
ALP reduction to <1.67×upper limit of 
normal (ULN) and total bilirubin 
≤1×ULN and a ≥15% or ≥30% or ≥40% 
or ≥70% ALP reduction from Baseline, 
respectively 
○ 
ALP reduction to <1.5×ULN and total 
bilirubin ≤1×ULN and a ≥40% ALP 
reduction from Baseline 
○ 
ALP <1×ULN and total bilirubin 
≤1×ULN 
○ 
Total bilirubin <0.6×ULN 
• 
To evaluate the safety and tolerability of 
setanaxib over a 24-week Treatment Period 
• 
Adverse events (AEs). Monitoring for AEs at 
all visits 
• 
AEs of special interest (AESIs): 
○ 
Drug-induced liver injury (DILI) 
○ 
Anemia 
○ 
Hypothyroidism 
• 
Laboratory tests: 
○ 
Hematology 
○ 
Biochemistry 
○ 
Urinalysis 
○ 
Thyroid function 
• 
Vital signs 
• 
12-lead 
electrocardiograms 
(ECGs): 
clinically significant abnormalities 
 
 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
Protocol Number: GSN000350 
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Exploratory Objectives 
Exploratory Endpoints 
• 
To evaluate the effect of setanaxib over a 
24-week Treatment Period on markers of 
liver 
fibrosis, 
cholestasis, 
bile 
acid 
metabolism, and liver function 
• 
Changes in markers of liver fibrosis, as 
assessed by the Enhanced Liver Fibrosis 
(ELF) score, PRO-C3 (released N-terminal 
propeptide of Type III collagen), C3M 
(a peptide of helical collagen Type III 
degradation), and PRO-C3/C3M ratio over 
24 weeks compared to Baseline 
• 
Changes in total and conjugated bilirubin 
over 24 weeks compared to Baseline 
• 
Changes in markers of bile acid metabolism, 
as assessed by total bile acids, C4 (7α-OH-4-
cholesten-3-one), fibroblast growth factor 
(FGF)19, 
and 
FGF21 
over 
24 weeks 
compared to Baseline 
• 
Changes in markers of liver function over 
24 weeks compared to Baseline, as assessed 
by: 
○ 
Serum 
fibrinogen, 
albumin, 
and 
international normalized ratio (INR) 
○ 
Alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase 
(AST), 
gamma glutamyl transpeptidase (GGT), 
high 
sensitivity 
C-reactive 
protein 
(hsCRP), and immunoglobulin M (IgM) 
indicating liver inflammation and injury 
• 
To evaluate the effect of setanaxib on adverse 
clinical outcomes 
• 
Assessment over 24 weeks of: 
○ 
All-cause mortality 
○ 
Proportion of patients requiring a liver 
transplant (transplant list inclusion) 
○ 
Proportion 
of 
patients 
with 
a 
Model for End Stage 
Liver 
Disease 
(MELD) score of ≥15 
○ 
Proportion of patients with new onset of 
variceal/portal hypertension bleed and/or 
hepatic encephalopathy (West Haven 
criteria), 
spontaneous 
bacterial 
peritonitis, 
and 
ascites 
requiring 
treatment 
• 
To further evaluate the effect of setanaxib on 
patient-reported outcomes 
• 
Change over 24 weeks compared to Baseline 
in: 
○ 
Social isolation symptoms, as assessed 
by the PBC-40 social domain 
○ 
Overall health-related quality of life, as 
assessed by the PROMIS-29 
questionnaire 
○ 
EuroQol five-dimensional (EQ-5D) 
Utility Index 
• 
To determine the predose plasma levels of 
setanaxib and its metabolite GKT138184 
• 
Predose plasma concentrations of setanaxib 
and GKT138184 over 24 weeks 
 


Sponsor Name: Calliditas Therapeutics Suisse SA 
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Study design: 
This study is a randomized, placebo-controlled, double-blind, parallel-group, multicenter, Phase 2b study 
assessing oral setanaxib administered as an add-on therapy in patients with PBC, elevated liver stiffness, 
and intolerance or inadequate response to UDCA. The safety and efficacy of 1200 mg/day and 
1600 mg/day setanaxib will be assessed against matching placebo over 24 weeks of treatment. It is planned 
to enroll approximately 60 to 70 patients at 80 to 130 investigational centers in North America, Europe, 
Israel, Australia, and New Zealand. 
The study design is outlined in Figure 1, and the visit schedule and planned assessments at each visit are 
detailed in Table 1. 
The study will consist of a 4-week Screening Period, a 24-week Double-blind Treatment Period, and a 
4-week Follow-up Period. The total duration of the study for patients remaining in the study until their 
final follow-up assessment (End-of-Treatment [EoT] Visit 30 days after the last investigational medicinal 
product [IMP] dose) will be approximately 32 weeks (approximately 8 months). 
The Investigator will obtain signed informed consent from the patient before any study procedures are 
performed. Patients will be assessed for eligibility during the Screening Period. All patients will attend 
Screening Visit 1. If liver biochemistry (see Footnote i of Table 1) and/or serum pregnancy (see Footnote l 
of Table 1) retests are required, patients will attend Screening Visit 2. Screening Visit 1 and, if required, 
Screening Visit 2 should be completed within 4 weeks prior to Randomization. If required, Screening 
Visit 2 should be conducted by Day -4. 
At a subset of study sites that accept referral patients or where sparse transient elastography (FibroScan®) 
assessments are standard of care, a pre-Screening visit including local laboratory liver function tests and 
transient elastography can be performed to assess patient eligibility. The Investigator will then obtain 
signed pre-screening consent. Data obtained at a pre-Screening visit cannot be re-used for screening. Full 
standard screening must be repeated for patient enrollment. 
Baseline assessments will be performed on Day 1 (Visit 3). Post-Baseline assessments will be performed 
at Weeks 2 (Visit 4), 4 (Visit 5), 8 (Visit 6), 12 (Visit 7), and 24 (Visit 8). In addition, study patients will 
be contacted by phone by the study site staff at Weeks 16 and 20. 
Following permanent IMP discontinuation at any time during the study, patients will undergo an EoT Visit 
30 days after their last dose. If IMP is permanently discontinued, the study assessments should continue 
until completion of the Week 24 Visit (Visit 8). If it is not feasible to complete all the visits, every possible 
effort should be made to complete the Week 24 Visit. 
The Investigator, the site personnel, the Sponsor, and their representatives involved in monitoring and 
conducting the study, and the patients will be blinded to treatment assignments until the database is locked 
and the study is unblinded for analysis. 
If applicable, patients will continue UDCA, obeticholic acid (OCA), and bezafibrate or fenofibrate 
treatment at a stable dose during the Double-blind Treatment Period. Patients should not start additional 
treatments for PBC after Randomization. All medications will be recorded in the electronic Case Report 
Form (eCRF). 
Throughout the study, particular attention will be given to the detection and management of AESIs; 
suspected cases of DILI, potential cases of bone marrow toxicity, and potential cases of hypothyroidism. 
The Independent Data Monitoring Committee (IDMC) will oversee the safety of participating patients. 
The role and responsibilities of the IDMC will be outlined in an IDMC Charter. An Adjudication 
Committee, who will remain blinded to patient treatment assignment, will adjudicate the AESIs and the 
adverse clinical outcomes. The roles and responsibilities of the Adjudication Committee will be outlined 
in an Adjudication Charter. 


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Study duration: 
The study is expected to be conducted from Q3 2021 to Q2 2024. The start of the study will be the date 
on which the first patient provides informed consent, and the end of the study will be the last patient’s last 
assessment. 
The total study duration for an individual patient is up to approximately 32 weeks (approximately 
8 months): A 4-week Screening Period, a 24-week Double-blind Treatment Period, and a 4-week Follow-
up Period. 
Planned number of patients: It is planned to enroll approximately 60 to 70 patients. Patients will be 
randomized and allocated to placebo, setanaxib 1200 mg/day, or setanaxib 1600 mg/day according to a 
1:1:1 randomization ratio. 
This study is designed to detect a >25% reduction in ALP in setanaxib-treated patients versus a 2.5% 
reduction in the placebo arm with an overall 2-sided p<0.05. Standard deviations are assumed to be 19% 
and 24%, respectively, based on the Phase 2a study with setanaxib and the Phase 3 POISE study with 
Ocaliva. With approximately 16 evaluable patients per arm (48 patients overall) and using a Hochberg 
step-up test to control alpha across 2 dose comparisons versus placebo, this study has 88.2% global power 
to detect at least 1 treatment arm as significantly different from placebo and 68.3% power to detect both 
treatment arms as statistically significant. Also, for the secondary endpoint of change in fatigue, there will 
be >80% power to detect a 20% reduction in fatigue versus a 2.5% increase in the placebo arm. 
An assumed dropout rate of approximately 25% leads to a target sample size of 66 enrolled patients (22 per 
arm). A range of approximately 60 to 70 enrolled patients allows for variability in the assumed dropout 
rate. 
Target population: Male or female patients aged ≥18 years with a definite or probable PBC diagnosis, 
serum ALP levels of ≥1.67×ULN at Screening, and liver stiffness measured by transient elastography 
(FibroScan®) of ≥8.0 kPa at Screening, will be included. Patients must have taken a UDCA prescriptional 
dose for the past 6 months (at a stable dose for >3 months prior to Screening) OR be intolerant to UDCA 
(last dose of UDCA >3 months prior to Screening). Intolerance to UDCA is defined as patients unable to 
tolerate the full-labeled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported gastrointestinal 
symptoms such as diarrhea and abdominal pain. Any patients receiving OCA, fenofibrate, or bezafibrate 
must have been taking the agent(s) for at least 6 months and at a stable dose for >3 months prior to 
Screening. 
Patients with any historical or current hepatic decompensation event, cirrhosis with complications, 
or competing etiology for liver disease will be excluded, as will patients with total bilirubin levels of 
>2×ULN or plasma ALT and/or AST levels of >3×ULN. Patients with an INR of >1.2 will also be 
excluded, unless the patient is on anticoagulant therapy. 


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Test product: 
Name: Setanaxib 
Setanaxib film-coated tablets will contain 400 mg setanaxib per tablet formulated with excipients and will 
be provided in high-density polyethylene (HDPE) bottles. 
Dose: 1200 mg/day or 1600 mg/day for 24 weeks. 
Mode of administration: Patients will self-administer IMP with food or up to 30 minutes after eating a 
meal. 
• 
Patients allocated to setanaxib 1200 mg/day will self-administer 2 tablets of setanaxib 400 mg in the 
morning and 1 tablet of setanaxib 400 mg together with 1 tablet of placebo in the evening (ie, a total 
of 2 tablets in the morning and 2 tablets in the evening). 
• 
Patients allocated to setanaxib 1600 mg/day will self-administer 2 tablets of setanaxib 400 mg in the 
morning and 2 tablets of setanaxib 400 mg in the evening (ie, a total of 2 tablets in the morning and 
2 tablets in the evening). 
Reference therapy: 
Name: Placebo 
Matching and visually identical placebo film-coated tablets, containing only excipients, will be provided 
in HDPE bottles. 
Dose: Placebo will be self-administered twice daily for 24 weeks. 
Mode of administration: Patients will self-administer IMP with food or up to 30 minutes after eating a 
meal. Patients allocated to placebo will self-administer 2 placebo tablets in the morning and 2 placebo 
tablets in the evening (ie, a total of 2 tablets in the morning and 2 tablets in the evening). 


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Statistical methods: 
Efficacy Analysis: The Full Analysis Set (FAS) will be the primary set used for all efficacy analyses, along 
with the summary of disposition, demographics, and Baseline characteristics. Patients will be analyzed 
according to the treatment group they were randomized to regardless of the actual treatment received. 
Primary Efficacy Analysis: Each setanaxib treatment group (1600 mg/day and 1200 mg/day) will be 
compared with placebo. The primary estimand is to assess the change in ALP (%) over 24 weeks in patients 
with PBC, elevated liver stiffness, and intolerance or inadequate response to UDCA. 
The following intercurrent events will be considered and further detailed in the Statistical Analysis Plan 
(SAP). Patients who start additional PBC-related medication(s) after Randomization will have their IMP 
discontinued. These patients will be included in the analysis, but efficacy data collected after the start of 
the new therapy will be excluded. For all other patients who discontinue from treatment prior to Week 24 
but return for the Week 24 Visit (Visit 8), the Week 24 result will be included in the analysis. Patients with 
a missing Week 24 result will have their value imputed based on observed data. 
The primary endpoint will be evaluated using a mixed model for repeated measures (MMRM) with 
log(ALP) – log(Baseline) as response with log(Baseline) as a continuous covariate, ALP stratification 
(<3.0×ULN or ≥3.0×ULN), treatment and visit as categorical covariates and treatment by visit as 
interaction term. All ALP data captured at Weeks 2, 4, 8, 12, and 24 will be included in the model. The 
relative mean change from Baseline at Week 24 will be estimated and corresponding 2-sided 95% 
confidence intervals will be calculated. In the case of outliers in the ALP data, a sensitivity analysis will 
utilize robust regression; this will be defined in the SAP.  
A Hochberg step-up procedure will be used to control type I error across 2 individual dose comparisons 
versus placebo for the primary endpoint. 
The 2 setanaxib treatment arms also will be combined in a secondary analysis for ALP, fatigue, and liver 
stiffness. 
Safety Analysis: The Safety Analysis Set will be used for the analysis of safety data (AEs, including 
AESIs, clinical laboratory tests, vital signs, 12-lead ECGs, and physical examination). 
Protocol version and date: Version 5.0 (27 September 2023) 


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STUDY SCHEMATIC 
Figure 1 
Study Schematic 
 
EoS=End-of-Study; EoT=End-of-Treatment; IDMC=Independent Data Monitoring Committee; V=Visit 
a The IDMC may recommend change(s) to the setanaxib dose regimen(s), or interruption or discontinuation of an active treatment group(s) based on the regular 
IDMC safety data reviews (as defined in the IDMC Charter). 
b Eligible patients will be randomized to oral setanaxib 1200 mg/day, 1600 mg/day, or placebo, according to a 1:1:1 randomization ratio. 
c Patients who permanently discontinue IMP prior to Week 24 Visit (Visit 8) will have an EoS Visit 30 days after the last IMP dose, after which every possible 
effort should be made to complete the Week 24 Visit (Visit 8). 
 


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SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
Study Period 
Screeninga 
Double-blind Treatment Period 
Follow-upb,c,d 
Study Weeks: 
-4 to -1 
BL 
2 
4 
8 
12 
16, 20 
24 
28 
Study Days 
(Visit Window): 
-28 to -4 
1 
15 
(±3) 
29 
(±3) 
57 
(±7) 
85 
(±7) 
113, 141 
(±3) 
169 
(±14) 
last IMP 
dose+30 
(+7) 
Visit: 
1a 
2a 
3 
4 
5 
6 
7 
Phonee 
8 
EoT 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Determination of eligibilityf 
X 
X 
Xf 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Demographics and relevant medical history 
X 
 
X 
 
 
 
 
 
 
 
Height and body temperature 
X 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
X 
X 
Physical examinationg 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pulse rate, SBP, and DBP 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Liver stiffness using transient elastographyh 
X 
X 
 
 
 
 
X 
 
X 
X 
Blood sampling: 
 
 
 
 
 
 
 
 
 
 
  Liver biochemistryi 
X 
Xi 
X 
X 
X 
X 
X 
 
X 
X 
  ELF score, PRO-C3, and C3M 
 
 
X 
 
 
 
 
 
X 
X 
  hsCRP, IgM 
 
 
X 
X 
 
 
X 
 
X 
X 
  Total bile acids, C4, FGF19, FGF21 
 
 
X 
 
 
 
 
 
X 
X 
  Autoantibodies,j viral serologyk 
X 
 
 
 
 
 
 
 
 
 
  Pregnancy test (serum)l 
Xl 
Xl 
 
 
 
 
 
 
 
 
  Hematology and biochemistrym 
X 
Xi 
X 
X 
X 
X 
X 
 
X 
X 
  TSH and free T4 
X 
Xi 
X 
X 
X 
X 
 
 
X 
 
  PK (morning predose) 
 
 
 
 
X 
 
 
 
X 
 
  Biomarker (optional) 
 
 
X 
 
 
 
 
 
X 
 
  Optional collection of DNA sample 
 
 
X 
 
 
 
 
 
 
 
Urine collection: 
 
 
 
 
 
 
 
 
 
 
  Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
  Urinalysisn 
X 
 
 
 
 
 
X 
 
X 
X 
  Pregnancy test (urine) 
 
 
X 
X 
X 
X 
X 
 
X 
X 


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Table 1 
Schedule of Assessments 
Study Period 
Screeninga 
Double-blind Treatment Period 
Follow-upb,c,d 
Study Weeks: 
-4 to -1 
BL 
2 
4 
8 
12 
16, 20 
24 
28 
Study Days 
(Visit Window): 
-28 to -4 
1 
15 
(±3) 
29 
(±3) 
57 
(±7) 
85 
(±7) 
113, 141 
(±3) 
169 
(±14) 
last IMP 
dose+30 
(+7) 
Visit: 
1a 
2a 
3 
4 
5 
6 
7 
Phonee 
8 
EoT 
Patient questionnaires: 
 
 
 
 
 
 
 
 
 
 
  PBC-40 
 
 
X 
 
X 
 
X 
 
X 
 
  PROMIS sf-Fatigue 7b Daily, and 
  PGIS fatigueo 
 
 
X 
 
X 
 
X 
 
X 
 
  WI-NRS, and PGIS prurituso 
 
 
X 
 
X 
 
X 
 
X 
 
  PGIC fatigue and PGIC prurituso 
 
 
 
 
X 
 
X 
 
X 
 
  PROMIS-29 
 
 
X 
 
 
 
X 
 
X 
 
  EQ-5D 
 
 
X 
 
X 
 
X 
 
X 
 
Dispense IMP 
 
 
X 
 
X 
 
X 
 
 
 
Prior and concomitant medicationsp,q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MELD score 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Recording of AEsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AMA=antimitochondrial antibodies; AST=aspartate aminotransferase; 
BL=Baseline; C3M=a peptide of helical collagen Type III degradation; C4=7α-OH-4-cholesten-3-one; DBP=diastolic blood pressure; ECG=electrocardiogram; 
eCRF=electronic Case Report Form; ELF=Enhanced Liver Fibrosis; EoS=End-of-Study; EoT=End-of-Treatment; EQ-5D=EuroQol-5 dimension; FGF=fibroblast 
growth factor; GGT=gamma glutamyl transpeptidase; hsCRP=high sensitivity C-reactive protein; IgM=immunoglobulin M; IMP=investigational medicinal 
product; INR=international normalized ratio; MELD=Model for End Stage Liver Disease; PBC=Primary Biliary Cholangitis; PBC-40=primary biliary cholangitis 
40 questionnaire; PGIC=Patient’s Global Impression of Change; PGIS=Patient’s Global Impression of Severity; PK=pharmacokinetics; PRO-C3=released 
N-terminal propeptide of Type III collagen; PROMIS=Patient-Reported Outcomes Measurement Information System; RBC=red blood cell; SBP=systolic blood 
pressure; sf=short form; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell; WI-NRS=Worst Itch Numerical Rating Scale 
a All patients will attend Screening Visit 1. If liver stiffness (see Footnote h) and/or liver biochemistry (see Footnote i) and/or serum pregnancy (see Footnote l) 
retests are required, patients will attend Screening Visit 2. Screening Visit 1 and, if required, Screening Visit 2 should be completed within 4 weeks prior to 
Randomization. If required, Screening Visit 2 should be conducted by Day -4. Screening Period extensions of up to 7 days may be considered on a case-by-case 
basis, if agreed by the Investigator and Medical Monitor. 
b Patients who permanently discontinue IMP prior to completion of the 24-week Double-blind Treatment Period will have an EoT Visit 30 days after the last IMP 
dose, after which every possible effort should be made to complete the Week 24 Visit (Visit 8). 
c Patients who complete the 24-week Double-blind Treatment Period will have an EoT Visit at 30 days after the last IMP dose. 
d The EoT Visit will be the EoS Visit for a) patients who withdraw from the study before the Week 24 Visit (Visit 8), and b) patients who are following the 
previous protocol schedule and are already beyond Week 24. 


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Table 1 
Schedule of Assessments 
Study Period 
Screeninga 
Double-blind Treatment Period 
Follow-upb,c,d 
Study Weeks: 
-4 to -1 
BL 
2 
4 
8 
12 
16, 20 
24 
28 
Study Days 
(Visit Window): 
-28 to -4 
1 
15 
(±3) 
29 
(±3) 
57 
(±7) 
85 
(±7) 
113, 141 
(±3) 
169 
(±14) 
last IMP 
dose+30 
(+7) 
Visit: 
1a 
2a 
3 
4 
5 
6 
7 
Phonee 
8 
EoT 
e Patients will be contacted by phone by study site staff at Weeks 16 and 20 to review AEs and any changes to concomitant medications. The phone calls will be 
documented in the eCRF by the study site. 
f Eligibility to enter the Double-blind Treatment Period will be determined during Visit 1 and, if required, Visit 2, with a final check before Randomization on 
Day 1.  
g A complete physical examination will be performed during Screening Visit 1 and at the Week 24 Visit (Visit 8). Patients who permanently discontinue IMP 
prior to or at the Week 24 Visit will have a complete physical examination at the EoT Visit. For Visits 2 to 7, when applicable, a symptoms-directed physical 
examination will be performed. 
h Liver stiffness measurements using transient elastography (FibroScan®) will be carried out in the morning in the fasting state and at predose. 
For assessments carried out on a different day than the study visit, FibroScan® assessments can be performed on any day during the specified visit windows 
predose or postdose but always after a 3-hour fasting. 
During the Screening Period, the FibroScan® assessment can be performed on any day between 28 and 4 days prior to the Randomization/Baseline actual visit, 
after a 3-hour fasting. One repeat liver stiffness measurement can be performed within the Screening Period (at Screening Visit 2) at the discretion of the 
Investigator for patients who do not meet the inclusion criterion at the initial screening assessment. FibroScan® images will be read locally. 
i Liver biochemistry: ALP, ALT, AST, total and conjugated bilirubin, and GGT. One repeat blood sampling (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who do not meet the serum ALP inclusion criterion and/or who meet the total 
bilirubin and/or ALT/AST and/or TSH exclusion criteria at Screening Visit 1. The INR and creatinine are to be repeated in case the liver biochemistry test panel 
is taken at Screening Visit 2. 
j AMA titer, PBC-specific antibodies (anti-GP210, anti-SP100, and antibodies against major M2 components). 
k Viral serology: HIV antibodies (1 and 2) and, if positive for HIV antibodies, HIV RNA; hepatitis B surface antigen and hepatitis C virus antibodies and, if 
positive for HCV antibody, HCV RNA. 
l A blood sample for the serum pregnancy test must be taken within 7 days of Day 1 (female patients of childbearing potential only). Therefore, if Screening 
Visit 1 is performed more than 7 days prior to Day 1, the serum pregnancy test must be repeated at Screening Visit 2 within 7 days of Day 1. 
m Hematology: 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: glucose, total protein, albumin, fibrinogen, creatinine, urea, total cholesterol, triglycerides, sodium, potassium, and chloride. 
n Quantitative test for urine pH and protein; qualitative tests for glucose, ketones, bilirubin, blood, and microscopic examination of the sediment. 
o Patient questionnaires PROMIS sf-Fatigue 7b Daily and WI-NRS are completed at home every evening for 7 days prior to the site visits. PGIS and PGIC for 
fatigue and pruritus, respectively, are completed at home in the evening prior to the site visits.  
p Prior medication will be recorded during Screening only. 


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Table 1 
Schedule of Assessments 
Study Period 
Screeninga 
Double-blind Treatment Period 
Follow-upb,c,d 
Study Weeks: 
-4 to -1 
BL 
2 
4 
8 
12 
16, 20 
24 
28 
Study Days 
(Visit Window): 
-28 to -4 
1 
15 
(±3) 
29 
(±3) 
57 
(±7) 
85 
(±7) 
113, 141 
(±3) 
169 
(±14) 
last IMP 
dose+30 
(+7) 
Visit: 
1a 
2a 
3 
4 
5 
6 
7 
Phonee 
8 
EoT 
q AEs and changes to concomitant medications will be recorded at each visit and each phone contact. 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................. 1 
PROTOCOL SIGNATURE PAGE – SPONSOR ......................................... 3 
PROTOCOL SIGNATURE PAGE – SPONSOR (CONTINUED) ............. 4 
PROTOCOL SIGNATURE PAGE – COORDINATING 
INVESTIGATOR ..................................................................................... 5 
PROTOCOL SIGNATURE PAGE – COORDINATING 
INVESTIGATOR (CONTINUED) ......................................................... 6 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR ............................. 7 
SERIOUS ADVERSE EVENT (SAE), ADVERSE EVENTS OF 
SPECIAL INTEREST (AESI), PREGNANCY, AND OVERDOSE 
CONTACT INFORMATION.................................................................. 9 
PRODUCT COMPLAINTS .......................................................................... 10 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..................... 11 
PROTOCOL SUMMARY ............................................................................ 16 
STUDY SCHEMATIC .................................................................................. 23 
SCHEDULE OF ASSESSMENTS ............................................................... 24 
TABLE OF CONTENTS .............................................................................. 28 
LIST OF TABLES ......................................................................................... 31 
LIST OF FIGURES ....................................................................................... 31 
LIST OF ABBREVIATIONS ....................................................................... 32 
1 
INTRODUCTION AND RATIONALE ............................................... 35 
1.1 
Background ........................................................................................ 35 
1.1.1 
Primary Biliary Cholangitis ........................................................ 35 
1.1.1.1 
Management and Treatment of Primary Biliary Cholangitis
.................................................................................................. 35 
1.1.2 
Setanaxib (Investigational Medicinal Product) ......................... 37 
1.1.3 
Nonclinical Studies ....................................................................... 37 
1.1.4 
Clinical Studies ............................................................................. 40 
1.2 
Study Rationale .................................................................................. 43 
1.3 
Benefit/Risk Assessment .................................................................... 45 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................ 48 
2.1 
Primary Objective and Endpoint ..................................................... 48 
2.2 
Secondary Objectives and Endpoints............................................... 48 
2.3 
Exploratory Objectives and Endpoints ............................................ 50 
3 
STUDY PLAN ......................................................................................... 52 
3.1 
Overall Study Design and Plan ......................................................... 52 
3.2 
Discussion of Study Design ................................................................ 53 
3.2.1 
Setanaxib Dose Rationale and Justification of Safety Margins
........................................................................................................ 55 
3.3 
End of Study ....................................................................................... 55 
4 
STUDY POPULATION ......................................................................... 56 
4.1 
Inclusion Criteria ............................................................................... 56 
4.2 
Exclusion Criteria .............................................................................. 58 
4.3 
Screen Failures ................................................................................... 60 
4.4 
Premature Discontinuation ............................................................... 61 


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4.4.1 
Premature Discontinuation of Investigational Medicinal 
Product .......................................................................................... 61 
4.4.2 
Premature Discontinuation from the Study .............................. 62 
4.4.3 
Lost to Follow-up ......................................................................... 63 
5 
DESCRIPTION OF STUDY ASSESSMENTS .................................... 64 
5.1 
Demographics and Other Screening Assessments .......................... 64 
5.1.1 
Medical History ............................................................................ 65 
5.1.2 
Demographics ............................................................................... 65 
5.1.3 
Estimated Glomerular Filtration Rate....................................... 65 
5.1.4 
Child-Pugh Score ......................................................................... 65 
5.2 
Efficacy Assessments ......................................................................... 65 
5.2.1 
Biochemical Response .................................................................. 65 
5.2.2 
Liver Stiffness, Transient Elastography (FibroScan®) ............. 65 
5.2.3 
Patient-reported Outcomes ......................................................... 66 
5.2.3.1 
Primary Biliary Cholangitis-40 Questionnaire ................... 67 
5.2.3.2 
Patient-Reported Outcomes Measurement Information 
System Short Form-Fatigue 7b Daily ................................... 68 
5.2.3.3 
Worst Itch Numerical Rating Scale...................................... 68 
5.2.3.4 
Patient-Reported Outcomes Measurement Information 
System Questionnaire ............................................................ 68 
5.2.3.5 
Patient’s Global Impression of Severity and Patient’s 
Global Impression of Change Fatigue and Pruritus ........... 68 
5.2.3.6 
EuroQoL 5-Dimension Utility Index .................................... 68 
5.2.4 
Laboratory Markers of Liver Fibrosis, Cholestasis, and Liver 
Function ........................................................................................ 69 
5.2.4.1 
Liver Fibrosis ......................................................................... 69 
5.2.4.2 
Cholestasis and Bile Acid Metabolism ................................. 69 
5.2.4.3 
Liver Function ........................................................................ 69 
5.3 
Safety Assessments ............................................................................. 69 
5.3.1 
Adverse Events ............................................................................. 69 
5.3.2 
Clinical Laboratory Evaluations ................................................ 70 
5.3.2.1 
Suspected Drug-induced Liver Injury ................................. 72 
5.3.2.2 
Detection and Management of Potential Bone Marrow 
Toxicity.................................................................................... 73 
5.3.2.3 
Detection and Management of Hypothyroidism ................. 73 
5.3.3 
Pregnancy ..................................................................................... 73 
5.3.4 
Breastfeeding ................................................................................ 75 
5.3.5 
Vital Signs ..................................................................................... 75 
5.3.6 
12-lead Electrocardiogram .......................................................... 75 
5.3.7 
Physical Examination, Including Height and Body Weight .... 76 
5.4 
Adverse Clinical Outcomes ............................................................... 76 
5.5 
Pharmacokinetics ............................................................................... 77 
5.6 
Future Biomarker Research ............................................................. 77 
5.7 
Future Genetic Research ................................................................... 78 
6 
TREATMENTS ...................................................................................... 79 
6.1 
Investigational Product(s) ................................................................. 79 
6.1.1 
Description of Investigational Product(s) .................................. 79 
6.1.2 
Preparation, Handling, and Storage .......................................... 79 
6.1.3 
Packaging, Labelling, and Shipment .......................................... 79 


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6.2 
Blinding ............................................................................................... 80 
6.3 
Method of Assigning Treatment ....................................................... 81 
6.4 
Dose and Administration ................................................................... 81 
6.4.1 
Dose Modification ........................................................................ 82 
6.4.2 
Intervention After the End of the Study .................................... 83 
6.5 
Precautions and/or Lifestyle Considerations................................... 83 
6.6 
Prior Medication ................................................................................ 83 
6.7 
Concomitant Medication and Procedures ....................................... 83 
6.8 
Overdose ............................................................................................. 85 
6.9 
Compliance ......................................................................................... 86 
6.10 
Accountability .................................................................................... 86 
7 
ADVERSE EVENTS .............................................................................. 88 
7.1 
Definitions ........................................................................................... 88 
7.1.1 
Adverse Events ............................................................................. 88 
7.1.2 
Serious Adverse Events ............................................................... 88 
7.1.3 
Suspected Unexpected Serious Adverse Reactions ................... 89 
7.1.4 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments .................................................................................. 89 
7.1.5 
Adverse Events of Special Interest ............................................. 89 
7.2 
Assessment of Adverse Events .......................................................... 90 
7.2.1 
Severity.......................................................................................... 90 
7.2.2 
Causality ....................................................................................... 91 
7.3 
Documenting and Reporting Adverse Events ................................. 91 
7.4 
Reporting of Serious Adverse Events ............................................... 92 
7.5 
Adverse Event and Serious Adverse Event Follow-up ................... 92 
7.6 
Safety Reporting Oversight ............................................................... 93 
8 
STATISTICS ........................................................................................... 94 
8.1 
General Procedures ........................................................................... 94 
8.2 
Analysis Populations .......................................................................... 94 
8.3 
Sample Size ......................................................................................... 95 
8.4 
Statistical Methods ............................................................................. 95 
8.4.1 
Analysis of Efficacy ...................................................................... 95 
8.4.1.1 
Primary Endpoint Analysis ................................................... 95 
8.4.1.2 
Multiplicity ............................................................................. 96 
8.4.1.3 
Sensitivity Analysis ................................................................ 97 
8.4.1.4 
Supplementary Analysis ........................................................ 97 
8.4.1.5 
Secondary Endpoints ............................................................. 97 
8.4.1.6 
Exploratory Endpoints .......................................................... 97 
8.4.2 
Analysis of Safety ......................................................................... 97 
8.4.3 
Demographic and Baseline Characteristics ............................... 98 
8.4.4 
Pharmacokinetic Analysis ........................................................... 98 
8.4.5 
Handling of Missing Values ........................................................ 98 
9 
ETHICS AND RESPONSIBILITIES ................................................... 99 
9.1 
Good Clinical Practice ....................................................................... 99 
9.2 
Institutional Review Board/Independent Ethics Committee ......... 99 
9.3 
Informed Consent .............................................................................. 99 
9.4 
Adjudication Committee and Independent Data Monitoring 
Committee ......................................................................................... 101 
9.4.1 
Adjudication Committee ........................................................... 101 


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9.4.2 
Independent Data Monitoring Committee .............................. 102 
9.5 
Financing and Insurance ................................................................. 102 
9.5.1 
Contractual and Financial Details ............................................ 102 
9.5.2 
Insurance, Indemnity, and Compensation............................... 102 
9.5.3 
Financial Disclosure ................................................................... 102 
10 RECORDS MANAGEMENT.............................................................. 103 
10.1 
Source Documentation..................................................................... 104 
10.2 
Case Report Form Completion and Data Management ............... 104 
10.3 
Study Files and Record Retention .................................................. 105 
11 AUDITING AND MONITORING ...................................................... 106 
11.1 
Risk and Quality Tolerance Limits ................................................ 106 
11.2 
Protocol Adherence and Deviations ............................................... 106 
12 AMENDMENTS ................................................................................... 108 
13 STUDY REPORT AND PUBLICATIONS ........................................ 109 
14 STUDY START AND TERMINATION ............................................ 110 
15 CONFIDENTIALITY .......................................................................... 111 
16 REFERENCES ..................................................................................... 112 
17 APPENDICES ....................................................................................... 116 
17.1 
APPENDIX I – Study Administrative Structure .......................... 116 
17.2 
APPENDIX II – Detection and Management of Suspected or 
Confirmed Cases of Drug-Induced Liver Injury .......................... 118 
17.2.1 
Criteria for Close Monitoring of Liver Biochemistry and IMP 
Action .......................................................................................... 118 
17.2.2 
Close Monitoring ........................................................................ 121 
17.3 
APPENDIX III – MELD Score ....................................................... 124 
17.4 
APPENDIX IV – West Haven Criteria and Clinical Description 125 
17.5 
APPENDIX V – Child-Pugh Classification of Severity of Cirrhosis
............................................................................................................ 126 
LIST OF TABLES 
Table 1 
Schedule of Assessments .................................................................... 24 
Table 2 
Investigational Medicinal Product Kits ........................................... 82 
LIST OF FIGURES 
Figure 1 
Study Schematic ................................................................................. 23 
Figure 2 
Triggers to Recheck and Interrupt Drug in Patients With ALT 
≤3×ULN at Baseline and No Symptoms ......................................... 120 
Figure 3 
Triggers to Interrupt Drug in Patients With ALT ≤3×ULN at 
Baseline, and if (+) Symptoms or Abnormal INR or Bilirubin ... 121 


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LIST OF ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibodies 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
C3M 
a peptide of helical collagen Type III degradation 
C4 
7α-OH-4-cholesten-3-one 
CCL4 
carbon tetrachloride 
CFR 
Code of Federal Regulations 
CKD-EPI 
chronic kidney disease epidemiology collaboration 
CRO 
Contract Research Organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DILI 
drug-induced liver toxicity 
EAPA 
Europe, Asia-Pacific, and Africa 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDISH 
evaluation of drug-induced serious hepatoxicity 
eGFR 
estimated glomerular filtration rate 
ELF 
Enhanced Liver Fibrosis 
EMA 
European Medicines Agency 
EoS 
End of Study 
EoT 
End-of-Treatment 
EQ 
EuroQol 
EQ-5D 
EuroQol 5 dimension 
EudraCT 
EU Drug Regulating Authorities Clinical Trials 


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FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
HBsAg 
hepatitis B surface antigen 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
hsCRP 
high sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IQR/med 
interquartile range over median ratio 
IRB 
Institutional Review Board 
IXRS 
interactive voice response system/interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
MMRM 
Mixed model repeated measures 
MoA 
mechanism of action 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
No observed adverse effect level 
NOX 
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 
OAT 
organic anion transporter 
OCA 
obeticholic acid 
OD 
once daily 
PBC 
primary biliary cholangitis 
PBC-40 
primary biliary cholangitis 40 questionnaire 


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PGIC 
Patient’s Global Impression of Change 
PGIS 
Patient’s Global Impression of Severity  
PIIINP 
amino-terminal propeptide of Type III procollagen 
PK 
pharmacokinetic(s) 
PPS 
Per Protocol Set 
PRO-C3 
released N-terminal propeptide of Type III collagen 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QTL 
quality tolerance limit 
RBC 
red blood cell 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
sDILI 
suspected drug-induced liver injury 
SOC 
system organ class 
T4 
thyroxine 4 
TEAE 
treatment-emergent adverse event 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
TLR4 
Toll-like receptor 4 
tmax 
time to maximum concentration 
TSH 
thyroid-stimulating hormone 
UDCA 
ursodeoxycholic acid 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WBC 
white blood cell 
WI-NRS 
Worst Itch Numerical Rating Scale 


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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Primary Biliary Cholangitis 
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a 
liver disease caused by autoimmune (T-cell-mediated) attack on the small to medium 
intralobular bile ducts (Selmi et al 2011, Beuers et al 2015). A continuous assault on 
the bile duct epithelial cells leads to their gradual destruction and eventual 
disappearance (ie, 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 (Kaplan and 
Gershwin 2005, Lindor et al 2009). The reasons for the autoimmune attack are not well 
understood but may involve environmental triggers in genetically-susceptible 
individuals. 
The reported prevalence of PBC ranges from 20 to 400 cases per million of the 
population with some geographical differences (Sood et al 2004, Peters et al 2007). 
PBC is more common in women than men (9:1 ratio) and is mostly diagnosed between 
the ages of 30 and 60 years (Myers et al 2009, Hirschfield et al 2013). 
Up to 60% of patients with PBC are asymptomatic at diagnosis. In these cases, PBC is 
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 
(Balasubramaniam et al 1990, Poupon 2010, Levy et al 2023). 
Common laboratory test abnormalities in patients with PBC include elevated alkaline 
phosphatase (ALP), antimitochondrial antibodies (AMA), antinuclear antibodies, and 
hyperlipidemia. Other findings may include elevations in serum aminotransferases and 
bilirubin. Complications of PBC include cirrhosis, hepatocellular carcinoma, metabolic 
bone disease, and malabsorption (EASL 2017). 
PBC is often associated (codiagnosed) with other autoimmune disorders including: 
Sjogren syndrome, autoimmune thyroid disease (Hashimoto’s thyroiditis) and 
rheumatoid arthritis (EASL 2017). 
1.1.1.1 
Management and Treatment of Primary Biliary Cholangitis 
Management of patients with PBC consists of treatment of the underlying disease and 
management of its symptoms and complications, including pruritus, fatigue, 
xanthomata, hypercholesterolemia, vitamin deficiencies, anemia, malabsorption, 
osteoporosis, etc. (EASL 2017). 
PBC is a progressive disease in most patients. The only widely accepted standard of 
care treatment is ursodeoxycholic acid (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 targeted treatment for the autoimmune injury to biliary 
epithelial 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 13 to 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 
(Selmi et al 2011, Lindor et al 2009; EASL 2017; Lindor et al 2020), and can delay 
histologic progression (Sood et al 2004, Kaplan and Gershwin 2005, Peters et al 2007) 
and improve long-term survival (Myers et al 2009, Hirschfield et al 2013). However, 
UDCA is not a uniformly effective drug; there is little benefit to symptoms, and 
approximately 40% of PBC patients have a suboptimal response to UDCA 
(Corpechot et al 2008, Rudic et al 2012). 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 been approved by the FDA and 
EMA for treatment of PBC (Invernizzi et al 2015). 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. 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 anticholestatic effect was 
associated with a reduction in hepatocellular damage, as shown by decreases in 
aspartate aminotransferase (AST) and alanine aminotransferase (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 normal 
(ULN) reference range (Nevens et al 2016). 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 approved 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 (Dyson et al 2015, Hirschfield et al 2016). Also, 
there is a need to address symptomatic relief in patients with PBC eg, fatigue and 
pruritus (Nevens et al 2023). 


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1.1.2 
Setanaxib (Investigational Medicinal Product) 
Setanaxib (formerly GKT137831) is a first-in-class inhibitor of the human protein 
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) Isoforms 1 
and 4. It is a small organic molecule of low molecular weight and a member of the 
pyrazolopyridine dione chemical class. 
The NOX family is a set of transmembrane proteins (Bedard and Krause 2007). 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 modulate multiple signaling 
pathways by oxidizing regulatory cysteine residues in target proteins. ROS can also 
cause other types of posttranslational 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 fibrotic and 
inflammatory disorders (Krause and Bedard 2008, Paik et al 2014, Liang et al 2016, 
Teixeira et al 2016). Importantly, studies have revealed that liver tissue expression of 
NOX1 and/or NOX4 is consistently elevated in patients with fibrotic liver diseases 
(Bettaieb et al 2015, Lan et al 2015). 
Setanaxib is being investigated in several fibrotic and inflammatory disorders, 
including PBC. Setanaxib’s mechanism of action (MoA) differs from that of 
anticholestatic agents, which are marketed (UDCA, OCA), in late-stage development 
(seladelpar, elafibranor), or increasingly used off-label (bezafibrate, fenofibrate). 
Specifically, setanaxib possesses broad antifibrotic and anti-inflammatory effects but 
does not modulate bile acid metabolism. Phase 2 results indicated that through this 
novel MoA, setanaxib achieves further reductions in markers of cholestatic injury 
(ALP, gamma glutamyl transpeptidase GGT]), improves markers of liver fibrosis (liver 
stiffness, PRO-C3/C3M), and improves quality of life (fatigue and its social and 
emotional impact). These therapeutic benefits were substantially greater in patients 
with elevated liver stiffness at Baseline, a population at risk of disease progression. 
Compounds with novel MoAs are needed, particularly in patients at higher risk or in 
patients not responding or not tolerating anticholestatic therapies. 
1.1.3 
Nonclinical Studies 
In Vitro and In Vivo Pharmacology 
Detailed summaries for all studies are given in the Investigator’s Brochure (IB). 
A set of in vitro and in vivo pharmacology studies have been conducted with setanaxib 
to support its proposed use as a NOX1/4 enzyme inhibitor for the treatment of fibrotic 
and inflammatory disorders including PBC. Investigation of potential effects against a 
broad range of receptors and enzymes confirmed that setanaxib demonstrated no 
significant off-target activity, except for significant inhibition of human recombinant 


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15-lipoxygenase-2. However, a review of available literature did not detect a safety 
concern. 
In in vitro studies in isolated cells, setanaxib 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 (transforming growth factor beta 1), PDGF 
(platelet-derived growth factor), toll-like receptor 4 (TLR4), hedgehog, and angiotensin 
II (Lan et al 2015). As a result, setanaxib markedly reduced the induction of markers of 
myofibroblast activation, including αSMA (smooth muscle actin alpha), fibronectin, 
and procollagen I (Aoyama et al 2012, Jiang et al 2012). 
These direct antifibrogenic effects translate into antifibrotic activity in multiple in vivo 
models of liver fibrosis. Specifically, setanaxib attenuated the development of liver 
fibrosis induced by experimental cholestasis (in the bile duct ligation and MDR2 
[multiple drug resistance 2]-/-, mouse models). Setanaxib also prevented liver fibrosis 
in models of nonalcoholic steatohepatitis (NASH) (in the STAM [stelic animal model] 
and fast food diet models [Jiang et al 2012, Teixeira et al 2014, Bettaieb et al 2015]) 
and in toxic hepatitis (in carbon tetrachloride [CCL4]-induced liver injury 
[Aoyama et al 2012]). Reduced in vivo fibrogenesis was associated with a marked 
reduction in markers of myofibroblast activation. 
In addition, setanaxib has shown potent anti-inflammatory effects in a number of 
biological settings, including metabolic and cholestatic liver injury. Specifically, 
setanaxib prevented the induction of adhesion molecules, cytokines, and chemokines 
in CCL4-induced liver injury and fast food diet-induced NASH (Bettaieb et al 2015). 
These effects on innate immunity resulted in a profound reduction of macrophage 
infiltration. Available data suggest that these anti-inflammatory effects are mediated 
through reduced activation of multiple pathways, including TLR4 and NF-κB (nuclear 
factor kappa B) (Paik et al 2014). In these studies, reduced liver inflammation was 
associated with a reduction in plasma levels of liver transaminases. 
In Vivo and In Vitro Safety Pharmacology and Toxicology 
To support clinical development of setanaxib via oral administration a series of safety 
pharmacology studies and a toxicity program designed in accordance with guidelines 
provided by the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) were conducted with setanaxib. This 
included a standard battery of genotoxicity studies and repeat dose toxicity studies in 
the rat and dog of up to 26 weeks and 39 weeks duration, respectively. 
Setanaxib was shown to be devoid of in vitro and in vivo genotoxicity and there are no 
relevant effects on fertility or embryonic/fetal development. 
The no observed adverse effect level (NOAEL) in rats was established at 
1000 mg/kg/day, the highest dose tested. The dog was the more sensitive species, and 
the NOAEL was established at 150 mg/kg/day in the 26-week dog study and 
300 mg/kg/day in the pivotal 39-week dog study. Treatment-related effects in the dog 
studies were confined to electrocardiogram (ECG) changes, decreased thyroid hormone 


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levels, which in some animals correlated to thyroid follicular hypertrophy, and effects 
on the erythrocyte and reticulocyte counts indicative of effects on bone marrow. 
Cardiac disorders: Setanaxib and its main active metabolite GKT138184 had no effect 
on the hERG channel, with an IC50 of >300 μM. There was no significant inhibition of 
INa or ICa with 100 μM of setanaxib or GKT138184. IKs was inhibited 60% by 100 μM 
setanaxib and not significantly inhibited by 100 μM of the metabolite, GKT138184. 
Setanaxib and GKT138184 have no significant inhibitory activity on the IKr cardiac ion 
channel at 300 μM. 
In dog studies, the chronic administration of setanaxib in the 500/300 mg/kg dose group 
was associated with reversible QT prolongation and atrioventricular-block events. 
Cardiovascular effects of setanaxib were examined in conscious dogs using radio 
telemetry. No effects of setanaxib at doses of up to 1000 mg/kg were observed on blood 
pressure, heart rate, RR, QRS, and PR intervals or on R wave height, compared to the 
vehicle-treated group. Significant, but limited, increases in QT interval were observed 
at 3 to 4 hours postdose in dogs receiving doses of 100 mg/kg or above in this conscious 
dog using telemetry study. QT/QTc intervals were evaluated at several time points in 
the 13-, 26- and 39-week dog studies. There were no indications of any ECG changes 
in the 13-week or 39-week dog studies, in contrast to the 26-week study where variable 
changes in QTc intervals were limited to the earlier timepoints in the highest setanaxib 
dose group only (500/300 mg/kg). 
The variability of the changes in QT in time and in relation to dose and the lack of 
consistency within and between animals, the absence of treatment-related ECG 
alterations at both the NOAEL of 150 mg/kg/day and the highest tolerated dose of 
300 mg/kg/day in the 26-week dog study, at the NOAEL of 300 mg/kg in the 39-week 
dog study, or at any of the doses tested in the already completed clinical studies, did 
not provide definitive information that setanaxib could prolong QT in a way that 
indicated a definitive risk to humans. 
Thyroid disorders: Findings related to the thyroid, ie, decreased thyroxine (T4) and 
increased thyroid-stimulating hormone (TSH), in some cases correlating with thyroid 
hypertrophy, seen in early toxicology studies in dogs were not replicated in the chronic 
toxicity studies, even though higher exposures were attained. No thyroid follicular cell 
hypertrophy or changes in thyroid hormones were observed at any dose level up to a 
dose of 300 mg/kg/day in either the 26-week or 39-week dog studies. 
Bone marrow disorders: In dog toxicology studies, the administration of setanaxib in 
the ≥500/300 mg/kg dose group was associated with a reduction in erythroid precursors 
in the bone marrow, and reduced reticulocyte and red blood cell (RBC) counts in 
peripheral blood, leading to severe aplastic anemia in 1 dog, which required euthanasia. 
By Week 5, ie, prior to the dose reduction from 500 to 300 mg/kg/day in the 26-week 
dog study, a marked decrease in reticulocyte count (∼90% decrease compared with 
pretest) was detected for 1 female dog. As per protocol, no further hematologic 
monitoring was conducted until Week 13, at which time reticulocyte counts remained 
decreased and red cell parameters were markedly decreased. This time course indicates 
that setanaxib affected erythroid progenitors in 1 dog during the initial dosing period 
with 500 mg/kg. These findings may be due to a direct effect of setanaxib on erythroid 


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progenitors because setanaxib was found to be cytotoxic in vitro to hematopoietic 
BFU-E (burst-forming unit-erythroid) progenitor cells derived from canine bone 
marrow mononuclear cells. This effect was observed only at concentrations greater than 
10 μM. 
In addition, minor and reversible changes in total plasma bilirubin and other liver 
function tests were observed but were never associated with signs of hepatocellular 
injury or liver pathologies and as such were not considered to be adverse. 
1.1.4 
Clinical Studies 
To date, 6 Phase 1 studies in healthy subjects (GSN000108, GSN000109, GSN000198, 
GSN000199, GSN000299, GSN000310), 2 Phase 2 studies (1 in patients with PBC 
[GSN000300], 1 in patients with Type 2 diabetes and albuminuria [GSN000200]) have 
been completed. A Sponsor-led study with setanaxib in patients with recurrent or 
metastatic squamous cell carcinoma of the head and neck (GSN000400) is ongoing. 
Ongoing Investigator-initiated studies are evaluating setanaxib in patients with Type 1 
diabetes and micro-albuminuria (Study GSN000241), and in patients with idiopathic 
pulmonary fibrosis (Study GSN000341/Protocol No. IRB-300003198). 
Pharmacokinetics 
The Phase 1 studies have characterized the clinical pharmacokinetics (PK), safety and 
tolerability profile of single and multiple ascending doses of setanaxib and the main 
active metabolite GKT138184 in healthy subjects. 
No safety signals or dose-limiting toxicities have been identified up to a maximum 
single 1800 mg dose or repeated 800 mg twice daily (BID) dose (total daily dose of 
1600 mg) for 10 consecutive days. 
Potential food and drug interactions have been evaluated. Study GSN000310 assessed 
the effect of repeated setanaxib administration on the PK of selected cytochrome (CYP) 
450 isoenzyme CYP2C9, CYP2C19 and CYP3A4 and transporter substrates, including 
for OAT1 and OAT3 (organic anion transporters). 
Both setanaxib and its main active metabolite (GKT138184) exhibit approximate dose 
proportional PK across the dose ranges studied. Following both single and multiple 
dose administration of setanaxib across all doses studied, the main active metabolite 
exposure is consistently approximately 20% of the corresponding parent exposure. The 
PK for setanaxib and GKT138184 are similar. 
Setanaxib is rapidly absorbed after oral administration (time to maximum concentration 
[tmax] between 0.5 and 3 h post dosing), with a tendency for later tmax for both capsules 
and tablets when setanaxib is administered under fed conditions. Setanaxib dosed in the 
fasted state is typified by higher inter-subject variability in maximum concentration and 
area under the curve (AUC). Following single-dose administration of setanaxib tablets, 
estimates of setanaxib elimination half-life ranged from approximately 8 to 14 h, and 9 
to 12 h for the main active metabolite GKT138184. Modest accumulation of both 
setanaxib and GKT138184 were observed on repeated BID administration of the tablet 


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formulation (for 1200 and 1600 mg total daily doses), with steady state Day 8 exposures 
ranging from 2 to 30% higher than corresponding exposures on Day 1. 
The main routes of the primary metabolism of setanaxib appear to be 
uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 to GKT289993 (N-
glucuronide) and via CYP3A4, principally to the main active metabolite GKT138184 
(product of demethylation). Therefore, strong inhibitors and inducers of CYP3A4 and 
UGT1A9 may affect the plasma exposures of setanaxib. 
Setanaxib has been shown to be a weak inhibitor of CYP2C9 and CYP2C19 at the 
800 mg BID dose in healthy subjects, increasing the AUC of sensitive probe substrates 
by 45% and 60%, respectively. 
Setanaxib has been shown to be a weak inhibitor of OAT3 at the 800 mg BID dose in 
healthy subjects, increasing the AUC of a sensitive probe substrate by 33%. 
Efficacy in Patients with PBC (Protocol GSN000300) 
This completed Phase 2 proof of concept study was an international double-blind, 
randomized, placebo-controlled clinical study to assess the efficacy and safety of oral 
setanaxib in patients with PBC, persistently elevated ALP, and elevated levels of GGT 
who were receiving UDCA. The primary efficacy endpoint was defined as the percent 
GGT reduction from Baseline to Week 24. Secondary efficacy endpoints included ALP 
changes, liver stiffness measured by transient elastography (FibroScan®) and quality of 
life. Statistical significance for all endpoints at Week 24 was set at p<0.047 for the first 
dose level tested and 0.023 for the 2nd dose level tested, according to the Hochberg 
adjustment method for multiple analyses. A total of 111 eligible patients were 
randomized to setanaxib (400 mg once daily [OD] or 400 mg BID) or placebo 
according to 1:1:1 randomization ratio for a total of 24 weeks. 
At Week 24, GGT reductions were -8% for placebo, -5% for setanaxib 400 mg OD, 
and -19% for setanaxib 400 mg BID. These changes did not achieve statistical 
significance at Week 24, although statistical significance had been achieved at the 
6-week interim efficacy analysis (p<0.01 for setanaxib 400 mg BID versus placebo). 
For the 400 mg BID dose, the mean percent change from Baseline in serum GGT was 
maintained at around -19% from Week 12 to Week 24. 
A statistically significant reduction in overall treatment effect was also observed for 
ALP levels (p=0.002) over the course of the Double-blind Treatment Period. At 
Week 24, setanaxib 400 mg BID achieved meaningful reductions in ALP. Changes 
were -3% for placebo, −10% for setanaxib 400 mg OD, and -13% for setanaxib 400 mg 
BID (p<0.049 versus placebo). There was a statistically significant change in ALP 
versus Baseline for the setanaxib 400 mg BID of -16% observed at 6 weeks. No changes 
were observed for total bilirubin (+11% for placebo, +5% for 400 mg OD, and +15% 
for setanaxib 400 mg BID). On the composite endpoint of serum ALP <1.67xULN, 
ALP decrease >15%, and total bilirubin <ULN, the response rates at Week 24 were 5% 
for placebo, 18% for setanaxib 400 mg OD, and 25% for setanaxib 400 mg BID. 
Median percent changes in valid liver stiffness measurements in the intention-to-treat 
analysis set were +4.1% for placebo, +1.4% for setanaxib 400 mg OD, and −4.9% for 


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setanaxib 400 mg BID. Patients with advanced liver fibrosis at Baseline (predefined 
population of patients with liver stiffness ≥9.6 kPa), experienced greater absolute 
reductions in median liver stiffness from Baseline following 24 weeks of setanaxib 400 
mg BID (–3.0 kPa) compared with modest reductions following 24 weeks of setanaxib 
400 mg OD (−1.0 kPa) or placebo treatment (−0.7 kPa), corresponding to mean 
percentage reductions of −16%, −5%, and +4%, respectively (p=0.11 for setanaxib 400 
mg BID versus placebo). 
The posthoc analyses of the percent change from Baseline to Week 24 in serum GGT 
and ALP by Baseline liver stiffness subgroup showed that patients with elevated liver 
stiffness at Baseline who received the setanaxib 400 mg BID dose achieved greater 
mean reductions in serum GGT and ALP at Week 24 (−32.4% and −24.3%, 
respectively) than those with normal or marginally elevated liver stiffness at Baseline 
(−12.9% and −8.7%, respectively). 
At Week 24, patients treated with setanaxib 400 mg BID reported greater mean 
(standard error of mean) absolute reductions from Baseline in PBC-40 fatigue domain 
score (–3.6 [1.3]) versus those receiving setanaxib 400 mg OD (–0.8 [1.0]) or placebo 
(0.6 [0.9]). Similar observations were made across all PBC-40 domains except itch. In 
the setanaxib 400 mg BID arm, patients with moderate to severe fatigue at Baseline had 
a greater reduction in mean fatigue score at Week 24 (–5.8 [2.1]) versus those with mild 
fatigue (–0.6 [0.9]); results were similar across all domains. Reduced fatigue was 
correlated with emotional, social, symptom, and cognitive improvements. 
The analysis of the percent change from Baseline to Week 24 in PBC-40 questionnaire 
showed a statistically significant improvement for the 400 mg BID dose (versus 
placebo) in the fatigue, social, and emotional domains (p-values equal to 0.027, 0.003, 
and 0.031, respectively). 
The analysis of the percent change from Baseline to Week 24 in pruritus score (using a 
visual analogue scale [VAS]) showed a statistically significant reduction for the 400 mg 
OD dose (p-value=0.004) versus placebo. For the 400 mg BID dose, the difference 
versus placebo is not statistically significant (p-value=0.103). 
Safety 
In patients with PBC, setanaxib exhibited a favorable safety profile throughout the 24-
week Double-blind Treatment Period. No dropouts or treatment interruptions due to 
pruritus or fatigue were reported. Only 2 serious adverse events (SAEs) were reported, 
a case of Grade 1 urinary infection requiring hospitalization in the placebo group and a 
case of multiple bone fractures related to a traffic accident in the setanaxib 400 mg BID 
group. Both cases were deemed unrelated to study drug by the Investigators. A review 
of adverse events (AEs), safety laboratory results, vital signs, physical examination, 
and ECG did not identify any safety signals associated with setanaxib at 400 mg OD or 
400 mg BID. 
The safety signals identified in toxicology studies (see Section 1.1.3) have not been 
detected in the completed clinical studies to date. Specifically, there was no evidence 
of drug effect on thyroid function, bone marrow function, or cardiac conduction: 


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Thyroid disorders: In clinical studies of setanaxib completed to date, there has been 
no evidence of thyroid disorders related to setanaxib exposure. 
Bone marrow disorders: In clinical studies of setanaxib completed to date, there has 
been no evidence of bone marrow toxicity related to setanaxib exposure. 
Cardiac disorders: In clinical studies of setanaxib completed to date, there has been 
no evidence of clinically relevant changes in ECGs associated with setanaxib, including 
QT prolongation.  
In this ongoing study, TRANSFORM GSN000350 (data cutoff of 21 August 2023), 
there was 1 SAE of QTc prolongation that occurred in a patient with atrial fibrillation. 
The investigational medicinal product (IMP) was discontinued and the patient remained 
asymptomatic throughout the event duration. 
Liver disorders: In clinical studies of setanaxib completed to date, there have been 
no cases of hepatic disorders related to setanaxib exposure. 
In the ongoing TRANSFORM GSN000350 study (data cutoff of 21 August 2023), there 
have been 4 SAEs in 4 patients associated with mild elevation in liver blood test results 
that were considered possibly related to the IMP. These 4 SAEs of elevated liver blood 
test results were the only SAEs of hepatic disorders that were considered related to the 
IMP in the entire setanaxib clinical program to date. All 4 patients with elevated liver 
blood test results discontinued IMP and remained asymptomatic throughout the period 
of the abnormal liver laboratory results. 
For further details, refer to the IB. 
1.2 
Study Rationale 
PBC is a chronic disease and without effective treatment it is often progressive, leading 
to cirrhosis and liver failure, resulting in liver transplantation or death (EASL 2017). 
This study is being conducted in order to determine the effect of setanaxib on 
biochemical response based on ALP and fatigue in patients with PBC, elevated liver 
stiffness, and intolerance or inadequate response to UDCA. Intolerance to UDCA is 
defined as patients unable to tolerate the full-labeled dose of UDCA in PBC 
(13-15 mg/kg) due to frequently reported gastrointestinal symptoms such as diarrhea 
and abdominal pain. 
This study will assess the decrease in ALP with daily doses of 1200 mg and 1600 mg 
versus placebo, whereas the previous PBC setanaxib Phase 2 study (GSN000300) 
investigated daily doses of 400 mg and 800 mg versus placebo. 
Since the initial study design, there has been a significant evolution in the management 
of patients with PBC. In particular, the use of second-line therapies such as OCA 
(Ocaliva) and fibrates (eg, bezafibrate) has expanded, and a significant proportion of 
patients who are intolerant or nonresponders to UDCA are able to receive dual or triple 
therapy (ie, UDCA plus OCA and/or a fibrate). As a consequence, there appears to have 
been a general reduction in the level of disease activity observed in patients being 


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considered for enrolment in the study (allowing for patients on dual or triple therapy), 
as judged by lower levels of ALP. This has likely decreased the available study 
population and consequently the rate of enrolment of patients into the study.  
Based on the observed low enrolment rate, Calliditas does not consider it feasible to 
complete the study in its current format within a reasonable timeframe. It is nevertheless 
acknowledged that there is preliminary evidence of beneficial effects of setanaxib on 
important clinical aspects of PBC, including ALP, fatigue and related social and 
cognitive manifestations (Invernizzi et al 2023). Despite the evolution in the 
therapeutic approach to PBC, there still remain significant unmet needs, in particular 
with respect to quality of life outcomes such as fatigue, as this is typically unaffected 
by existing therapies (Jones et al 2023).  
Calliditas has therefore decided to amend the protocol changing the study from the 
current Phase 2b/3 study to a 24-week Phase 2b study of 60 to 70 patients to enable an 
earlier assessment of the safety and efficacy of setanaxib with the two doses (1600  mg 
and 1200 mg) versus placebo. With this amended design there is no longer a need for 
an interim analysis for the assessment of futility and dose selection for a Phase 3 
portion, as this is removed. Consequently, the 52-week Extension Phase Treatment 
Period has been removed. 
Given the revision to a Phase 2b study, it is of scientific relevance to focus on an 
individual endpoint only. Therefore, rather than the originally planned composite 
endpoint consisting of change in ALP and total bilirubin, the primary endpoint has been 
amended to evaluate the individual endpoint of change in ALP. The secondary 
endpoints of change in fatigue and liver stiffness are retained, as is the composite 
endpoint of changes in markers of cholestasis. 
The reduced duration of study treatment from 52 weeks to 24 weeks in combination 
with the change from a composite primary endpoint to an individual primary endpoint 
(change in ALP) with fatigue as a secondary endpoint is supported by the preliminary 
evidence obtained in the Phase 2 study in patients with PBC (GSN000300) as detailed 
in Section 1.1.4. This study showed statistically significant and clinically meaningful 
changes in the above mentioned endpoints after 24 weeks of treatment. This is in line 
with a retrospective investigation, which concluded that measuring ALP at 6 months is 
of clinical relevance (Murillo Perez et al 2023). 
As consequence of the change in primary endpoint, the assumptions for the sample size 
have been revisited: with approximately 16 evaluable patients per arm (48 patients 
overall), there will be >80% power to detect a >25% reduction in ALP in setanaxib-
treated patients versus a 2.5% reduction in the placebo arm with a 2-sided p<0.05. For 
the secondary endpoint of change in fatigue, there will be >80% power to detect a 20% 
reduction in fatigue versus a 2.5% increase in the placebo arm. A dropout rate of 
approximately 25% leads to a target sample size of 66 patients (22 per arm). A range 
of approximately 60 to 70 patients allows for variability in the assumed dropout rate.  
In combination, the revision of treatment duration, primary endpoint, and sample size 
has statistical validity and an acceptable probability of detecting clinically meaningful 
changes in ALP and fatigue. During the analysis, the benefit-risk profile of each 


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setanaxib dose will be assessed and compared to determine the optimal dose for further 
development.  
Given the changes to endpoints, study duration, and statistical analysis of the study, the 
study will no longer support a direct application for approval in PBC. Rather, the final 
analysis will permit an assessment of the development pathway for setanaxib in PBC, 
which will potentially focus on quality of life outcomes such as fatigue. The amended 
study no longer has an adaptive component and no part of it can be considered Phase 3 
in development stage. The description of the study is therefore amended from 
Phase 2b/3 to Phase 2b. Given that the revisions may allow the 2 doses of setanaxib to 
be distinguished, it is considered feasible that only 1 additional study may be required 
for regulatory approval. It should be noted that patients, Investigators, and the Sponsor 
have remained blind to randomized treatment and no unblinded data have been 
reviewed prior to this amendment. 
Details regarding the rationale for setanaxib dose selection are provided in 
Section 3.2.1. 
1.3 
Benefit/Risk Assessment 
Potential Benefits 
Patients included in this study will have PBC with elevated liver stiffness, despite 
treatment with first-line and potentially second-line treatments for PBC. Participation 
in this study provides the patient with a potential opportunity to take setanaxib, which 
is being evaluated for efficacy in this clinical study. Patients included in the study will 
have a 2/3 chance of receiving setanaxib. While NOX1/4 inhibition represents an 
attractive therapeutic strategy in patients with PBC, therapeutic benefits in patients with 
PBC have yet to be demonstrated. 
During this study patients will undergo the regular medical evaluations and assessments 
for PBC, as part of the study procedures. 
Potential Risks 
As summarized in Section 1.1.3 and Section 1.1.4, setanaxib has been extensively 
investigated in nonclinical and clinical studies. 
In the completed Phase 1 and Phase 2 studies, the safety profile of setanaxib has been 
shown to be favorable, with no clinical safety signal and no dose-limiting toxicity 
identified (see Section 1.1.4). The safety signals identified in the toxicology studies 
(thyroid function, ECG abnormalities, hematological changes) have been carefully 
monitored in all clinical studies completed to date. No treatment-related clinical or 
pathological findings have been observed, irrespective of dose, treatment duration or 
type of clinical study. 
The doses of setanaxib under investigation in this study are 1200 mg/day and 
1600 mg/day. The highest dose regimen to be evaluated in this study constitutes a dose 
doubling compared to the previous study in patients with PBC where there were no 
safety signals of concern (see the setanaxib dose rationale and justification of safety 


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margins in Section 3.2.1). Due to the higher setanaxib doses being evaluated in the 
current study, there is a potential risk of new safety signals that have not been observed 
to date in the previous clinical studies. Patients included in this study will undergo 
regular safety assessments. In addition, given the findings from the toxicology studies 
(see Section 1.1.3), and the characteristics of the disease, appropriate exclusion criteria 
and safety endpoints for regular monitoring have been built into this study as 
precautions. 
• 
Thyroid disorders (hypothyroidism): Patients with TSH levels >ULN at Screening 
will be excluded from this clinical study. The levels of TSH and free T4 will be 
regularly monitored during the study. In the case of TSH ≥10 mIU/L, IMP 
administration will be interrupted while the patient undergoes evaluation for 
hypothyroidism. 
• 
Bone marrow disorders (anemia): Patients with a history of bone marrow disorder, 
including aplastic anemia, or any current marked anemia defined as hemoglobin 
<10.0 g/dL will be excluded from the study. Reticulocyte counts will be regularly 
monitored during the study. In case of Common Terminology Criteria for Adverse 
Events (CTCAE) Grade ≥2 anemia, IMP administration will be interrupted while 
the patient undergoes further evaluation. 
• 
Cardiac disorders: Patients with certain cardiac conduction abnormalities as well as 
patients with a second- or third-degree atrioventricular block will be excluded from 
the study. Patients included in the study will undergo regular monitoring for 
evidence of cardiac disorders by 12-lead ECGs. If the patient develops a QT 
prolongation (QTc Fridericia interval >450 milliseconds for males and 
>470 milliseconds for females), or an increase in QTc greater than 60 milliseconds 
from Baseline, whichever comes first, or if the patient develops other severe cardiac 
conditions per the Investigator’s judgment, the IMP will be discontinued. 
• 
Liver disorders (DILI): Patients with total bilirubin >2×ULN and/or plasma ALT 
and/or AST >3×ULN will be excluded from the study. Liver biochemistry tests will 
be regularly monitored during the study. As noted in Appendix II, if prespecified 
levels of AST, ALT, total bilirubin, or international normalized ratio (INR) are met 
during the study, IMP administration will be interrupted while the patient undergoes 
further evaluation. 
Drug-induced liver injury (DILI), anemia, and hypothyroidism will be AEs of special 
interest ([AESIs], see Section 7.1.5) in this study and will be reported within 24 hours 
of the Investigator becoming aware of the event. 
An Adjudication Committee will remain blinded to patient treatment assignment and 
will adjudicate the AESIs and the adverse clinical outcomes (see Section 5.4). An 
unblinded Independent Data Monitoring Committee (IDMC) will oversee the safety of 
participating patients. The IDMC will regularly review an aggregated list of events 
adjudicated by the Adjudication Committee (see Section 9.4). 
The medications being taken by a patient will be carefully evaluated by the Investigator 
before the patient is enrolled into the study, and concomitant medications will be 


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recorded throughout the study. The main routes of the primary metabolism of setanaxib 
appear to be UGT1A9 to GKT289993 (N-glucuronide) and via CYP3A4, principally to 
the main active metabolite GKT138184 (product of demethylation). Therefore, strong 
inhibitors and inducers of UGT1A9 or CYP3A4 may affect the plasma exposures of 
setanaxib. Setanaxib is a weak inhibitor of CYP2C9, CYP2C19 and OAT3. 
In vitro, setanaxib inhibited breast cancer resistance protein (BCRP) and MDR1 
(P-glycoprotein) and also suggests that setanaxib is an inducer of CYP2B6. 
Therefore, setanaxib may increase the plasma concentration of drugs which are 
primarily eliminated through these enzymes and transporters. Caution should be 
exercised during concomitant use of the drug with setanaxib. Based on a literature 
search, and nonclinical and clinical safety data, it is the Sponsor’s position that 
setanaxib does not have immunosuppressive properties. All approved COVID-19 
vaccines are allowed in setanaxib studies. It is important that the COVID-19 
vaccinations are not delayed. 
At least one-third of patients included in this study will not receive setanaxib. 
Therefore, there is a risk of disease progression without the possibility of trying any 
other new potential treatments for PBC. 
More detailed information about the known and expected benefits, risks, and reasonably 
expected AEs of setanaxib can be found in the IB. 
Considering the measures taken to minimize risk to the patients participating in this 
study, the potential risks identified in association with setanaxib are justified by the 
anticipated benefits that may be afforded to patients with PBC. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective and Endpoint 
Primary Objective  
Primary Endpoint 
• To evaluate the effect of setanaxib on 
ALP at Week 24 in patients with PBC 
and with elevated liver stiffness and 
intolerance or inadequate response to 
UDCA 
• Change 
in 
ALP 
at 
Week 24 
compared to Baseline 
Information about the corresponding estimand is provided in Section 8.4.1.1. 
2.2 
Secondary Objectives and Endpoints 
Secondary Objective 
Secondary Endpoint 
• To evaluate the effect of setanaxib on 
fatigue at Week 24 
• Change in fatigue at Week 24 
compared to Baseline, as assessed by 
○ the Patient-Reported Outcomes 
Measurement 
Information 
System (PROMIS) short form-
Fatigue 7b Daily  
○ the Patient’s Global Impression of 
Severity (PGIS) fatigue 
○ the Patient’s Global Impression of 
Change (PGIC) fatigue  
○ the PBC-40 questionnaire 
 
(PBC-40) fatigue domain 
• To evaluate the effect of setanaxib on 
liver stiffness at Week 24 
• Change in liver stiffness at Week 24 
compared to Screening, as assessed 
by 
transient 
elastography 
(FibroScan®) 
• To evaluate the effect of setanaxib on 
ALP, fatigue, and liver stiffness at 
Week 24, where setanaxib doses are 
combined 
• Change in ALP at Week 24 compared 
to Baseline, where setanaxib doses 
are combined 
○ Change in fatigue at Week 24 
compared to Baseline, as assessed 
by the PROMIS short form-
Fatigue 7b Daily, the PGIS 
fatigue , the PGIC fatigue, and the 
PBC-40 fatigue domain, where 
setanaxib doses are combined 
○ Change in liver stiffness at 
Week 24 compared to Screening, 
as 
assessed 
by 
transient 
elastography (FibroScan®), where 
setanaxib doses are combined 


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• To evaluate the effect of setanaxib on 
pruritus at Week 24 
• Change in pruritus at Week 24 
compared to Baseline, as assessed by 
the Worst Itch Numerical Rating 
Scale (WI-NRS), the PBC-40 itch 
domain, and the PGIS and the PGIC 
pruritus 
• To evaluate the effect of setanaxib on 
markers of cholestasis at Week 24 
• Changes in markers of cholestasis as 
assessed by proportion of patients at 
Week 24 with: 
○ ALP reduction to <1.67×ULN 
and total bilirubin ≤1×ULN and a 
≥15% or ≥30% or ≥40% or ≥70% 
ALP reduction from Baseline, 
respectively 
○ ALP reduction to <1.5×ULN and 
total bilirubin ≤1×ULN and a 
≥40% 
ALP 
reduction 
from 
Baseline 
○ ALP <1×ULN and total bilirubin 
≤1×ULN 
○ Total bilirubin <0.6×ULN 
• To 
evaluate 
the 
safety 
and 
tolerability of setanaxib over a 
24-week Treatment Period 
• AEs. Monitoring for AEs at all visits 
• AESIs: 
○ DILI 
○ Anemia 
○ Hypothyroidism 
• Laboratory tests: 
○ Hematology 
○ Biochemistry 
○ Urinalysis 
○ Thyroid function 
• Vital signs 
• 12-lead ECGs: clinically significant 
abnormalities 


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2.3 
Exploratory Objectives and Endpoints 
Exploratory Objectives 
Exploratory Endpoints 
• To evaluate the effect of setanaxib 
over a 24-week Treatment Period on 
markers of liver fibrosis, cholestasis, 
bile acid metabolism, and liver 
function 
• Changes in markers of liver fibrosis, 
as assessed by the Enhanced Liver 
Fibrosis 
(ELF) 
score, 
PRO-C3 
(released N-terminal propeptide of 
Type III collagen), C3M (a peptide of 
helical 
collagen 
Type III 
degradation), and PRO-C3/C3M ratio 
over 24 weeks compared to Baseline 
• Changes in total and conjugated 
bilirubin over 24 weeks compared to 
Baseline 
• Changes in markers of bile acid 
metabolism, as assessed by total bile 
acids, C4 (C4=7α-OH-4-cholesten-3-
one), 
fibroblast 
growth 
factor 
(FGF)19, and FGF21 over 24 weeks 
compared to Baseline 
• Changes in markers of liver function 
over 24 weeks compared to Baseline, 
as assessed by: 
○ Serum fibrinogen, albumin, and 
INR 
○ ALT, AST, GGT, high sensitivity 
C-reactive protein (hsCRP), and 
immunoglobulin M 
(IgM) 
indicating liver inflammation and 
injury 
• To evaluate the effect of setanaxib on 
adverse clinical outcomes 
• Assessment over 24 weeks of: 
○ All-cause mortality 
○ Proportion of patients requiring a 
liver transplant (transplant list 
inclusion) 
○ Proportion of patients with a 
Model for End Stage Liver 
Disease (MELD) score of ≥15 
○ Proportion of patients with new 
onset 
of 
variceal/portal 
hypertension bleed and/or hepatic 
encephalopathy 
(West Haven 
criteria), spontaneous bacterial 
peritonitis, and ascites requiring 
treatment 


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Exploratory Objectives 
Exploratory Endpoints 
• To further evaluate the effect of 
setanaxib 
on 
patient-reported 
outcomes 
• Change over 24 weeks compared to 
Baseline in: 
○ Social isolation symptoms, as 
assessed by the PBC-40 social 
domain 
○ Overall health-related quality of 
life, 
as 
assessed 
by 
the 
PROMIS-29 questionnaire 
○ EuroQol five-dimensional (EQ-
5D) Utility Index 
• To determine the predose plasma 
levels of setanaxib and its metabolite 
GKT138184 
• Predose plasma concentrations of 
setanaxib and GKT138184 over 
24 weeks 


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3 STUDY PLAN 
3.1 
Overall Study Design and Plan 
This study is a randomized, placebo-controlled, double-blind, parallel-group, 
multicenter, Phase 2b study assessing oral setanaxib administered as an add-on therapy 
in patients with PBC, elevated liver stiffness, and intolerance or inadequate response to 
UDCA. The safety and efficacy of 1200 mg/day and 1600 mg/day setanaxib will be 
assessed against matching placebo over 24 weeks of treatment. It is planned to enroll 
approximately 60 to 70 patients at 80 to 130 investigational centers in North America, 
Europe, Israel, Australia, and New Zealand. 
The study design is outlined in Figure 1 (Study Schematic), and the visit schedule and 
planned assessments at each visit are detailed in Table 1. 
The study will consist of a 4-week Screening Period, a 24-week Double-blind 
Treatment Period, and a 4-week Follow-up Period. The total duration of the study for 
patients remaining in the study until their final follow-up 
assessment 
(End-of-Treatment [EoT] Visit 30 days after the last IMP dose) will be approximately 
32 weeks (approximately 8 months). 
The Investigator will obtain signed informed consent from the patient before any study 
procedures are performed. For further details regarding the informed consent process, 
see Section 9.3. Patients will be assessed for eligibility during the Screening Period. 
All patients will attend Screening Visit 1. If liver biochemistry (see Footnote i of 
Table 1) and/or serum pregnancy (see Footnote l of Table 1) retests are required, 
patients will attend Screening Visit 2. Screening Visit 1 and, if required, Screening 
Visit 2 should be completed within 4 weeks prior to Randomization. If required, 
Screening Visit 2 should be conducted by Day -4. 
At a subset of study sites that accept referral patients or where sparse transient 
elastography (FibroScan®) assessments are standard of care, a pre-Screening visit 
including local laboratory liver function tests and transient elastography can be 
performed to assess patient eligibility. The Investigator will then obtain signed pre-
screening consent. Data obtained at a pre-Screening visit cannot be re-used for 
screening. Full standard screening must be repeated for patient enrollment. 
Eligible patients will be randomized to oral setanaxib 1200 mg/day, 1600 mg/day, or 
placebo, according to a 1:1:1 randomization ratio, stratified by Screening serum 
ALP < or ≥3.0×ULN. See Section 6.3 for further details on the method of assigning 
patients to the treatment groups, and see Section 6.4 for further details on the dose and 
administration of setanaxib and placebo. 
Baseline assessments will be performed on Day 1 (Visit 3). Post-Baseline assessments 
will be performed at Weeks 2 (Visit 4), 4 (Visit 5), 8 (Visit 6), 12 (Visit 7), and 
24 (Visit 8). In addition, study patients will be contacted by phone by the study site 
staff at Weeks 16 and 20. 


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Special Note: Patients who are following the previous protocol schedule (protocol 
version 4) and are already beyond Week 24 should permanently discontinue IMP as 
soon as possible and have an EoT Visit 30 days after their last dose. 
Following permanent IMP discontinuation at any time during the study, patients will 
undergo an EoT Visit 30 days after their last dose. If IMP is permanently discontinued, 
the study assessments should continue until completion of the Week 24 Visit (Visit 8). 
If it is not feasible to complete all the visits, every possible effort should be made to 
complete the Week 24 Visit. 
The Investigator, the site personnel, the Sponsor and their representatives involved in 
monitoring and conducting the study, and the patients will be blinded to treatment 
assignments until the database is locked and the study is unblinded for analysis (see 
Section 6.2). Also see Section 6.2 for details on access to the treatment codes in the 
event of emergency unblinding. 
If applicable, patients will continue UDCA, OCA, and bezafibrate or fenofibrate 
treatment at a stable dose during the Double-blind Treatment Period. Patients should 
not start additional treatments for PBC after Randomization. All medications will be 
recorded in the electronic Case Report Form (eCRF). 
Throughout the study, particular attention will be given to the detection and 
management of AESIs, suspected cases of DILI (see Section 5.3.2.1 and Appendix II), 
potential cases of bone marrow toxicity (see Section 5.3.2.2), and potential cases of 
hypothyroidism (see Section 5.3.2.3). 
The IDMC will oversee the safety of participating patients (see Section 9.4.2). The role 
and responsibilities of the IDMC will be outlined in an IDMC Charter. An Adjudication 
Committee, who will remain blinded to patient treatment assignment, will adjudicate 
the AESIs and the adverse clinical outcomes (see Section 9.4.1). The roles and 
responsibilities of the Adjudication Committee will be outlined in an Adjudication 
Charter. 
3.2 
Discussion of Study Design 
This study will be randomized, placebo-controlled, and double-blinded. Study 
randomization will prevent bias in treatment allocation. In addition, stratification by 
Screening serum ALP will help to ensure that the treatment groups are balanced in 
terms of population characteristics, thereby minimizing factors that could confound the 
interpretation of study results. The double-blinding of the study with regard to setanaxib 
and placebo treatment assignments will minimize bias in the assessment of treatment 
effect. Although Investigators are blinded to treatment assignments, the Investigators 
will review the laboratory reports, which will include ALP, the primary endpoint 
parameter, and bilirubin. It is acknowledged that access to the values might essentially 
unblind the Investigators to the treatment assignment of their patients. However, 
knowledge of ALP and bilirubin is required to inform the appropriate medical 
management of the patient from a safety perspective. 
The patients included in this study will have PBC with elevated liver stiffness, 
despite treatment with first-line, and potentially second-line, treatments for PBC. 


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All patients included in this study will continue treatment on their stable prescriptional 
dose of UDCA, unless the patient is intolerant to UDCA. Second-line therapies for PBC 
are also permitted for patients who have been on a stable dose for >3 months prior to 
Screening. Therefore, setanaxib or placebo will be given as add-on therapy to first 
and/or second-line therapies. Due to the lack of alternative effective treatments for this 
population of patients with PBC, a placebo-controlled study design is most appropriate. 
The doses of setanaxib under investigation in this study are 1200 mg/day and 
1600 mg/day. The highest dose regimen to be evaluated in this study constitutes a dose 
doubling compared to the previous study in patients with PBC where there were no 
safety signals of concern. Please refer to Section 3.2.1 for the setanaxib dose rationale 
and justification of safety margins. 
Management of patients with PBC includes monitoring of laboratory parameters 
(including ALP, bilirubin, AST, albumin, and platelet count) and elastography 
(EASL 2017). Abnormally high ALP levels typically occur in patients with PBC, and 
ALP values are associated with disease progression (EASL 2017). Bilirubin is a 
prognostic marker of a poor outcome in patients with PBC and is generally elevated at 
late stages of the disease (EASL 2017). Patients included in this study will have an ALP 
level ≥1.67×ULN and a total bilirubin level of ≤2×ULN at Screening. If the total 
bilirubin elevation is >ULN at Screening, the albumin level must be within the 
reference range. 
This Phase 2b study has as the primary endpoint change in ALP (%), with daily doses 
of 1200 mg and 1600 mg versus placebo, whereas the previous PBC setanaxib Phase 2 
study (GSN000300) investigated daily doses of 400 mg and 800 mg versus placebo. A 
central laboratory analyzes the levels of ALP and other laboratory parameters in order 
to standardize the analysis methodology and minimize sources of error from samples 
taken at the different study sites. 
The feasibility to conduct a study within an acceptable time frame under an adaptive 
Phase 2b/3Phase 2b study design, has proved challenging. This is considered to be 
related to new and more frequently used treatment options, which the study (all protocol 
versions) allows for, such as OCA and off-label use of bezafibrates. One consequence 
of this is that fewer patients than anticipated are meeting the inclusion criteria of ALP 
≥1.67×ULN or liver stiffness ≥8.0 kPa. Therefore, the study design is revised to a 
Phase 2b study, with the primary objective to assess the decrease in ALP. Please also 
see Section 1.2. 
Patients included in this study will have an EoT Visit 30 days after the last dose of IMP. 
Cholestasis often manifests with symptoms including fatigue and pruritus, which are 
significant causes of impaired quality of life (EASL 2017). In this study, fatigue and 
pruritus will be assessed as secondary endpoints. A structured approach to quantify 
fatigue and pruritus will be undertaken through the completion of validated 
questionnaires. 
Safety is being assessed in this study as a secondary endpoint. The safety assessments 
included in this study are standard. 


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3.2.1 
Setanaxib Dose Rationale and Justification of Safety Margins 
Given the experience of nonclinical and clinical data, the present study is designed to 
show efficiency in a safely conducted study. 
In the completed Phase 1 and Phase 2 studies, the safety profile of setanaxib has been 
shown to be favorable, with no clinical safety signal and no dose-limiting toxicity 
identified. 
The previous clinical study in patients with PBC (GSN000300) evaluated setanaxib 
400 mg BID for 24 weeks. This dosing regimen was considered safe and well tolerated, 
but the observed clinical efficacy was considered insufficient. Therefore, there is an 
interest in studying higher doses up to 800 mg BID for 24 weeks. 
The highest dose regimen to be evaluated in this study constitutes a dose doubling 
compared to the previous study in patients with PBC where there were no safety signals 
of concern. Although the expected exposures will be around the defined NOAEL for 
both the parent (setanaxib) and the main active metabolite (GKT138184), all the 
NOAEL defining toxicology signals can and will be monitored and were not observed 
neither in the healthy volunteers at 800 mg BID for 8 days or patients at 400 mg BID 
for 24 weeks. 
For the proposed maximal dose (setanaxib 800 mg BID [total daily dose 1600 mg]), 
toxicology studies in the dog, the most sensitive species, provide a safety margin of ≥1, 
when the combined concentration of setanaxib and its main active metabolite 
(GKT138184) is considered. The safety margin for setanaxib alone is also ≥1. However, 
for the main active metabolite GKT138184, the safety margin is calculated to be 0.7. 
Refer to the Setanaxib Investigator Brochure for further details on the safety margins. 
Given the findings from the toxicology studies and the characteristics of the disease, 
appropriate exclusion criteria and safety endpoints for regular monitoring have been 
built into this study, as precautions. Please refer to Section 1.3 for further details. 
3.3 
End of Study 
A patient is considered to have completed the study if he/she has completed all study 
visits. 
The end of the study is defined as the date of the last visit or last procedure of the last 
patient in the study. 


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4 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, 
also known as protocol waivers or exemptions, is not permitted. 
4.1 
Inclusion Criteria 
The following inclusion criteria must be met for a patient to be eligible for inclusion in 
the study: 
1. Male or female patient aged ≥18 years, inclusive at the time of informed consent. 
2. Willing and able to give written informed consent and to comply with the 
requirements of the study. 
3. Definite or probable PBC diagnosis as demonstrated by the presence of ≥2 of the 
following 3 diagnostic factors: 
a. Documented history of elevated ALP levels ≥1.67×ULN of the local reference 
range. 
b. Documented history of positive AMA titer or positive PBC-specific antibodies 
(anti-GP210 or anti-SP100 or antibodies against the major M2 components 
[PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]). 
c. Historical liver biopsy consistent with PBC. 
4. Serum ALP ≥1.67×ULN at Screening. 
One repeat blood sampling (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who 
do not meet this inclusion criterion at Screening Visit 1. If this inclusion criterion 
is then met at Screening Visit 2, the patient may be eligible for the study. 
5. Liver stiffness measured by transient elastography (FibroScan®) of ≥8.0 kPa and an 
interquartile range over median ratio (IQR/med) of ≤30% at Screening, are taken 
with the results expressed in kilopascals [kPa]). 
One repeat liver stiffness measurement can be performed within the Screening 
Period at the discretion of the Investigator for patients who do not meet the inclusion 
criterion at the initial screening assessment. If the inclusion criterion is then met, 
the patient may be eligible for the study. 
6. UDCA prescriptional dose use for the past 6 months (at a stable dose for >3 months 
prior to Screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to 
Screening). Intolerance to UDCA is defined as patients unable to tolerate the full-
labeled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported 
gastrointestinal symptoms such as diarrhea and abdominal pain. 


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7. For patients receiving OCA, fenofibrate, or bezafibrate treatment for at least 
6 months and stable dose for >3 months prior to Screening. 
8. For patients intolerant to OCA, OCA must have been discontinued >3 months prior 
to Screening. 
9. For patients previously treated with bezafibrate or fenofibrate, and these agents 
were discontinued prior to Screening, they must have been discontinued >3 months 
prior to Screening. 
10. Female patients 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 up to 90 days after the last dose of IMP. 
a. For the purposes of this study, women of childbearing potential are defined as 
“Fertile, following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy.” 
b. Postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In female patients who are not using hormonal 
contraception or hormonal replacement therapy but with suspected menopause 
and less than 12 months of amenorrhea, a high follicle-stimulating hormone 
(FSH) level in the postmenopausal range will be required at Screening to 
confirm a postmenopausal state. Confirmation with more than one FSH 
measurement is required. 
c. Highly effective contraception is defined as methods that can achieve a failure 
rate of less than 1% per year when used consistently and correctly. These 
methods are: 
(1) Combined 
(estrogen 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, 
or transdermal) 
(2) Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
(3) Intrauterine device 
(4) Intrauterine hormone-releasing system 
(5) Bilateral tubal occlusion 
(6) Vasectomized partner 
(7) Sexual abstinence (refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments). The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient.  


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Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception).  
Female condom and male condom should not be used together. 
11. Female patients of childbearing potential must have a negative serum pregnancy 
test at Screening and a negative urine pregnancy test at Randomization/Baseline 
before dosing. 
12. Male patients with female partners of childbearing potential must be willing to use 
a condom and require their partner to use a highly effective contraceptive method 
(as defined in the list in item 10c). This requirement begins at the time of informed 
consent and ends 90 days after receiving the last dose of IMP. 
13. Male patients must be willing not to donate sperm, and female study patients must 
be willing not to donate eggs, from Baseline until 90 days after the last dose of IMP. 
4.2 
Exclusion Criteria 
A patient who meets any of the following exclusion criteria will not be eligible for 
inclusion in the study: 
1. A positive pregnancy test or breastfeeding for female patients. 
2. Any historical or current hepatic decompensation event defined as variceal/portal 
hypertension bleed and/or hepatic encephalopathy, spontaneous bacterial 
peritonitis, ascites requiring treatment, or liver transplantation list inclusion. 
3. History of liver transplantation, current placement on a liver transplant list or 
current MELD score of ≥12 unless the patient is on anticoagulant therapy, or a 
Child-Pugh Score of ≥6. 
4. Cirrhosis with complications, including history or presence of hepatocellular 
carcinoma. 
5. Total bilirubin >2×ULN. In case of total bilirubin elevation >ULN the Screening 
serum albumin must be within the reference range. 
One repeat blood sampling (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who 
meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not 
met at Screening Visit 2, the patient may be eligible for the study. 
6. Plasma ALT >3×ULN and/or AST >3×ULN. 
One repeat blood sampling (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who 
meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not 
met at Screening Visit 2, the patient may be eligible for the study. 


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7. INR >1.2 unless patient is on anticoagulant therapy. 
One repeat blood sampling (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who 
meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not 
met at Screening Visit 2, the patient may be eligible for the study. 
8. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, as calculated by 
the central laboratory using the chronic kidney disease epidemiology collaboration 
(CKD-EPI) equation. 
9. TSH >ULN at Screening. 
One repeat blood sampling (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who 
meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not 
met at Screening Visit 2, the patient may be eligible for the study. 
10. Competing etiology for liver disease (eg, hepatitis C, as defined by positive hepatitis 
C virus antibody and positive hepatitis C RNA [unless effectively cured of 
hepatitis C (HCV antibody positive and negative HCV RNA) with a sustained 
virologic response for at least 6 months prior to Screening], active hepatitis B 
[HBsAg positive], NASH, alcoholic liver disease, autoimmune hepatitis, 
autoimmune hepatitis-PBC overlap syndrome, primary sclerosing cholangitis, 
Gilbert’s Syndrome). 
11. Medical conditions that could cause nonhepatic increases in ALP (eg, Paget's 
disease). 
12. Known history of HIV infection. If the anti-HIV antibody test is positive, HIV RNA 
negativity has to be confirmed by the central laboratory. 
13. Surgery (eg, stomach bypass) or medical condition that might significantly affect 
absorption of medicines (as judged by the Investigator). 
14. Positive urine drug screen (if not due to prescriptional use of a concomitant 
medication, as confirmed by the Investigator) at Screening. Patients on stable 
methadone or buprenorphine maintenance treatment for at least 6 months prior to 
Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol 
products are not allowed. 
15. Patients receiving prohibited medications within 3 months of Screening Visit 1 as 
specified in Section 6.6 and 6.7. 
16. Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 
5 half-lives of the IMP (if known) (whichever is longer) or current enrollment in an 
interventional clinical study. 


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17. Evidence of any of the following cardiac conduction abnormalities: A QTc 
Fridericia interval >450 milliseconds for males or >470 milliseconds for females, 
as calculated by the central reader. Patients with a second- or third-degree 
atrioventricular block are to be excluded. 
18. History of a malignancy within 5 years of Screening with the following exceptions: 
a. Adequately treated carcinoma in situ of the cervix 
b. Adequately treated basal or squamous cell cancer or other localized 
nonmelanoma skin cancer. 
19. The occurrence of any acute infection requiring systemic antibiotic therapy within 
the 2 weeks prior to Screening Visit 1. 
20. A history of bone marrow disorder including aplastic anemia, or any current marked 
anemia defined as hemoglobin <10.0 g/dL. 
21. Prior treatment with setanaxib or participation in a previous setanaxib clinical study. 
22. Unstable cardiovascular disease as defined by any of the following: 
a. Unstable angina within 6 months prior to Screening 
b. Myocardial infarction, coronary artery bypass graft surgery, or coronary 
angioplasty within 6 months prior to Screening 
c. Cerebrovascular accident within 6 months prior to Screening 
d. New York Heart Association Class III or IV heart failure 
23. Presence of any laboratory abnormality or condition that, in the opinion of the 
Investigator, could interfere with or compromise a patient’s treatment, assessment, 
or compliance with the protocol and/or study procedures. 
24. Any other condition which, in the opinion of the Investigator, constitutes a risk or 
contraindication for the participation of the patient in the study, or that could 
interfere with the study objectives, conduct, or evaluation. 
25.  Hypersensitivity or intolerance to setanaxib or to any of its excipients or placebo 
compounds. 
4.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study 
but who do not meet one or more criterion required for participation and are not 
subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients, to meet the 
Consolidated Standards of Reporting Trials publishing requirements, and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE. 


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Note that one repeat blood sampling (with analysis by the central laboratory) can be 
performed at Screening Visit 2 for patients who do not meet the serum ALP inclusion 
criterion and/or who meet the INR, TSH, total bilirubin and/or ALT/AST exclusion 
criteria at Screening Visit 1 at the Investigator’s discretion, if the Investigator believes 
that the result was spurious, confounded, or not in line with the historical values of the 
patient. In these cases, the repeat assessment is allowed without the patient being 
considered a screen failure. Screening Period extensions of up to 7 days may be 
considered on a case-by-case basis, if agreed by the Investigator and Medical Monitor. 
Patients who are screen failures may undergo full rescreening once at the discretion of 
the Investigator if there is a reasonable expectation that the patient is potentially eligible 
for the study. In these cases, the rescreened patient should be assigned a new unique 
screening number. A second full rescreening at the discretion of the Investigator if there 
is a reasonable expectation and rationale provided that the patient is potentially eligible 
for the study can be done if agreed by the Medical Monitor. Again, the rescreened 
patient should be assigned a new unique screening number. 
4.4 
Premature Discontinuation 
4.4.1 
Premature Discontinuation of Investigational Medicinal Product 
Patients should discontinue the IMP if any of the following occurs: 
1. The patient withdraws his/her consent to participate in the study. 
2. The patient develops an illness that would interfere with his/her continued 
participation in the study, at the Investigator’s discretion. 
3. The patient is noncompliant with study procedures or medication, which in the 
opinion of the Investigator, impacts patient safety and/or the integrity of the study 
results. 
4. The patient takes prohibited medication that warrants the IMP discontinuation at 
the discretion of the Investigator. The introduction of any standard of care PBC 
treatment (OCA, fenofibrate, or bezafibrate) is allowed, but warrants IMP 
discontinuation (see Section 6.7). Dose modifications of concomitant PBC 
treatments initiated before Randomization do not require IMP discontinuation. 
5. The patient is confirmed to be pregnant. 
6. The Sponsor or regulatory agency requests withdrawal of the patient. 
7. The patient has suspected drug-induced liver injury (sDILI) meeting Criteria C in 
Appendix II. 
8. The patient has CTCAE Grade ≥2 anemia AND the retest absolute reticulocyte 
count is below 50% of the Baseline value, IMP will not be resumed and will be 
permanently discontinued. 


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9. The patient has a retest TSH level of ≥10 mIU/L if overt biological hypothyroidism 
is confirmed (ie, TSH ≥10 mIU/L and reduced free T4) (see Section 5.3.2.3). 
10. The patient has one or more adverse clinical outcome listed in Section 5.4. 
11. The patient has a severe cardiac condition per the Investigator’s judgment, QT 
prolongation (QTc Fridericia interval >450 milliseconds for males and 
>470 milliseconds for females), or an increase in QTc greater than 60 milliseconds 
from Baseline, whichever comes first. 
Patients who permanently discontinue IMP prior to completion of the Week 24 Visit 
(Visit 8) will have an EoT Visit 30 days after the last IMP dose, after which every 
possible effort should be made to complete the Week 24 study assessments (Visit 8) 
(see Table 1). 
Patients who discontinue IMP prematurely will not be replaced. 
4.4.2 
Premature Discontinuation from the Study 
Participation in the study is strictly voluntary. A patient has the right to withdraw from 
the study at any time for any reason, without any reprisal. 
The Investigator has the right to terminate participation of a patient for any of the 
following reasons: 
• Violation of the protocol jeopardizing patient safety and/or integrity of study results 
• Any other reason relating to the patient's safety 
• Any other reason relating to the integrity of the study data 
Investigators should make every effort to discuss with the study monitor/Sponsor 
before discontinuing a patient from the study; it should be considered if IMP 
discontinuation, with completion of the Week 24 Visit (Visit 8) may be appropriate (see 
Section 4.4.1). 
If a patient is withdrawn from the study, the study monitor/Sponsor will be informed 
immediately. If there is a medical reason for withdrawal, the patient will remain under 
the supervision of the Investigator until satisfactory health has returned. 
If the patient withdraws consent for disclosure of further information, the Sponsor may 
retain and continue to use any collected data before such a withdrawal of consent. If a 
patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
Although a patient is not obliged to give his/her reason(s) for withdrawing prematurely 
from a study, the Investigator should make a reasonable effort to ascertain the reason(s), 
while fully respecting the patient's rights. 


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At the time of premature study discontinuation, the Investigator should make every 
effort to ensure the patient completes the assessments indicated at the EoT Visit, which 
will be the End of Study (EoS) Visit for the patient; see Table 1. 
Patients who prematurely discontinue from the study cannot subsequently rejoin the 
study. 
For details on the discontinuation of study sites or the study as a whole, see Section 14. 
4.4.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon 
as possible, counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue 
in the study. 
• Before a patient is deemed lost to follow-up, the Investigator (or designee) must 
make every effort to regain contact with the patient (where possible, at least 2 phone 
calls and, if necessary, a certified letter to the patient’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
patient’s medical notes. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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5 DESCRIPTION OF STUDY ASSESSMENTS 
Refer to Table 1 for the schedule of assessments. 
Patients will be asked to fast from 10 pm on the day prior to study visits until after the 
study procedures have been completed. Patients will be reminded to bring the IMP and 
their PBC medications with them to each study visit. On visit days, patients will take 
their morning doses of IMP and their usual PBC medications with food (or up to 
30 minutes after eating a meal) after the study procedures have been completed. In cases 
where the FibroScan® assessment is carried out on a different day than the study visit, 
refer to Section 5.2.2 for fasting and IMP instructions. 
In general, the assessments at the site visits will be conducted in the following order: 
• Patient-reported outcomes (see Section 5.2.3 for the order of patient-reported 
outcomes assessments) 
• AEs/concomitant medications recording 
• Physical examinations/vital signs/ECGs 
• Laboratory assessments/FibroScan® 
• Dispense IMP 
• Patient takes morning dose of IMP with food (or up to 30 minutes after eating a 
meal), as well as any morning doses of their usual medications for PBC 
(see Section 6.7) 
5.1 
Demographics and Other Screening Assessments 
All patients will attend Screening Visit 1. If serum pregnancy (see Footnote l of 
Table 1) retests are required, patients will attend Screening Visit 2. Screening Visit 2 is 
also performed at the discretion of the Investigator to retest liver stiffness, liver 
biochemistry and/or TSH when eligibility criteria are not met at Screening Visit 1 (see 
Footnotes h and i of Table 1). Screening Visit 1 and, if required, Screening Visit 2 
should be completed within 4 weeks prior to Randomization. If required, Screening 
Visit 2 should be conducted by Day -4. Screening Period extensions of up to 7 days 
may be considered on a case-by-case basis, if agreed by the Investigator and Medical 
Monitor. 
Demographics will be collected as described in Section 5.1.2. The assessment of 
medical history is described in Section 5.1.1. 
Safety assessments, including laboratory assessments, which are also part of the 
screening assessments are described in Section 5.3. The eGFR will be calculated as 
described in Section 5.1.3. 
The screening assessment of liver stiffness by transient elastography (FibroScan®) will 
be assessed as described in Section 5.2.2. 


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Prior medications will be assessed at Screening, as described in Section 6.6. 
5.1.1 
Medical History 
Relevant medical history, including any ongoing illnesses, will be recorded in the 
eCRF, with the start date and stop date (if applicable) of the illness/condition. 
Any prestudy procedures will be recorded in the eCRF as part of the medical history 
assessment. 
5.1.2 
Demographics 
Demographic data, including year of birth/age, sex, and race, will be recorded in the 
eCRF. 
5.1.3 
Estimated Glomerular Filtration Rate 
The CKD-EPI formula for adults will be used to calculate eGFR (mL/min/1.73 m2) 
from the biochemistry and demographic data collected at Screening Visit 1. The eGFR 
will be calculated by the central laboratory according to the equation included in the 
central laboratory manual. 
5.1.4 
Child-Pugh Score 
The Child-Pugh Score will be calculated from the total bilirubin, serum albumin, and 
INR central laboratory test results from blood samples collected at Screening Visit 1, 
together with the clinical criteria of hepatic encephalopathy and ascites. In case 
retesting of liver function tests, TSH, and INR are performed at Screening Visit 2, 
then the Screening Visit 2 results are used for calculating the Child-Pugh Score. The 
formulas to calculate the Child-Pugh Score are provided in Appendix V. 
5.2 
Efficacy Assessments 
5.2.1 
Biochemical Response 
Liver biochemistry blood samples for the assessment of biochemical response (based 
on ALP and total bilirubin levels) will be collected as described in Section 5.3.2. 
Biochemical response will be assessed at each post-Baseline visit for which a liver 
biochemistry blood sample is collected. 
5.2.2 
Liver Stiffness, Transient Elastography (FibroScan®) 
Transient elastography (FibroScan®) will be used to assess the degree of liver stiffness. 
The assessments will be conducted by a health professional trained, qualified, and 
experienced in the use of FibroScan® and in accordance with the manufacturer’s manual 
and the study specific site operations manual. 
FibroScan® will be carried out in the morning in fasting state, and hence predose, with 
fasting from 10 pm on the day prior to the study visit. For assessments carried out on a 
different day than the study visit, FibroScan® assessments can be performed on any day 


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during the specified visit windows predose or postdose but always after a 3-hour 
fasting. 
During the Screening Period, the FibroScan® assessment can be performed on any day 
between 28 and 4 days prior to the Randomization/Baseline actual visit, after a 3-hour 
fasting. One repeat liver stiffness measurement can be performed within the Screening 
Period at the discretion of the Investigator for patients who do not meet the inclusion 
criterion at the initial screening assessment. If the inclusion criterion is then met, the 
patient may be eligible for the study. The FibroScan Screening assessment meeting the 
inclusion criterion will serve as the Baseline value. 
It is recommended that the patient’s FibroScan® assessment is done by the same person 
using the same type of probe at each study visit. The results from FibroScan® 
assessments will be expressed in kPa. FibroScan® images will be read locally. 
Investigators will printout the results of the FibroScan® assessments and file the 
printouts in the patient notes. The results, the FibroScan® software version and probe 
used will be recorded in the eCRF. 
Both non-SmartExam and SmartExam software versions can be used. Every effort 
should be made to not mix the use of non-SmartExam and SmartExam versions for the 
assessments in individual patients. FibroScan® acquisition files from SmartExam 
assessments should be downloaded from the FibroScan® and stored in accordance with 
the Study Operational Manual. Those files will be used to a posteriori compute the liver 
stiffness values obtained without SmartExam algorithm. 
Patients eligible for the study are required to have liver stiffness of ≥8.0 kPa and an 
IQR/med of ≤30% at Screening. At each subsequent FibroScan® assessment an 
IQR/med of ≤30% for liver stiffness measurement is required (Boursier et al 2013; 
Corpechot et al 2022). 
5.2.3 
Patient-reported Outcomes 
Patient-reported outcome questionnaires will be completed on paper at time points 
specified in Table 1. The Sponsor or designee will provide the questionnaires to the 
study sites. Site staff should refer to the site operation manual for guidance on the 
administration of the patient-reported outcomes. The completed questionnaires will be 
maintained at the study site as source documents. The results will be transcribed into 
the eCRF by site personnel. The eCRF entry guidelines include questionnaire-specific 
instructions on how to manage any ambiguous responses to individual items. 
• 
Fatigue will be assessed using the PROMIS short form-Fatigue 7b Daily 
(Section 5.2.3.1), and the PGIS fatigue, PGIC fatigue (Section 5.2.3.5) and the 
PBC-40 fatigue domain (Section 5.2.3.1). 
• 
Pruritus will be assessed using the WI-NRS (Section 5.2.3.3), the PBC-40 itch 
domain (Section 5.2.3.1), and the PGIS and PGIC pruritus (Section 5.2.3.5). 
• 
Social isolation symptoms will be assessed using the PBC-40 social domain 
(Section 5.2.3.1). 


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• 
Health-related quality of life will be assessed using PROMIS-29 (Section 5.2.3.4) 
• 
Health utility data will be computed using the EQ-5D Utility Index 
(Section 5.2.3.6). 
The patient-reported outcome questionnaires PBC-40, PROMIS-29, and EQ-5D are 
completed at the site. The completion of questionnaires at the site visits should be 
performed before any of the other study procedures, including the collection of blood 
for laboratory assessments. At study site visits, the patient will be asked to read and 
complete the questionnaires independently. The patient will be given sufficient time to 
complete the assessments. If a patient is unable to read, the site staff will administer the 
questionnaires by reading aloud the content of the questionnaires to the patient and 
recording the patient’s verbal response. The questionnaires will be administered in the 
following order: 
• 
PBC-40 
• 
PROMIS-29 
• EQ-5D 
The patient questionnaires PROMIS short form-Fatigue 7b Daily and WI-NRS are 
completed at home every evening for 7 days prior to the site visits. PGIS and PGIC for 
fatigue and pruritus, respectively, are completed at home in the evening prior to the site 
visits (ie, Day 7 of each of the diary completion weeks). The questionnaires are 
provided as booklets where the questionnaires are placed in the order specified below. 
Detailed completion instructions are included in the booklets. 
• 
PROMIS short form-Fatigue 7b Daily 
• 
WI-NRS 
• 
PGIS fatigue 
• 
PGIC fatigue  
• 
PGIS pruritus 
• 
PGIC pruritus 
5.2.3.1 
Primary Biliary Cholangitis-40 Questionnaire 
The PBC-40 is a disease-specific health-related quality of life measure validated for use 
in patients with PBC (Jacoby et al 2005). The questionnaire comprises 40 questions in 
6 domains related to fatigue, emotional, social, and cognitive function, general 
symptoms, and itch, and 3 additional questions related to general health and well-being. 
Patients will be asked to select his/her most appropriate response for all questions 
applying a 1-week recall period. 


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5.2.3.2 
Patient-Reported Outcomes Measurement Information System Short 
Form-Fatigue 7b Daily 
The PROMIS short form-Fatigue 7b Daily is a generic fatigue scale designed to 
measure daily fatigue. The instrument comprises 7 items and is completed daily using 
a recall period of ‘since waking up’. This measure will be completed at home by the 
patient via daily diary over 7 consecutive days prior to the study visits. 
5.2.3.3 
Worst Itch Numerical Rating Scale 
The 11-point WI-NRS will be completed at home and collected via daily diary over 
7 days prior to the visits. 
5.2.3.4 
Patient-Reported Outcomes Measurement Information System 
Questionnaire 
The PROMIS-29 Profile (v2.1) comprises 7 domains (anxiety, depression, fatigue, pain 
interference, physical function, sleep disturbance, and ability to participate in social 
roles and activities) and a single pain intensity item (Cella et al 2010). Each of the 
7 domains contains 4 items. Patients will be asked to respond to each question or 
statement by marking the box underneath the most appropriate response. 
5.2.3.5 
Patient’s Global Impression of Severity and Patient’s Global 
Impression of Change Fatigue and Pruritus 
PGIS and PGIC fatigue and PGIS and PGIC pruritus will be recorded at the times 
indicated in Table 1. 
5.2.3.6 
EuroQoL 5-Dimension Utility Index 
The 5-level version of the EQ-5D (EQ-5D-5L) comprises a descriptive system with 
5 dimensions 
(mobility, 
self-care, 
usual 
activities, 
pain/discomfort, 
and 
anxiety/depression) and the EQ-VAS (Herdman et al 2011; EuroQoL Research 
foundation 2019). 
Each of the 5 dimensions in the descriptive system has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The 
patient will be asked to indicate his/her health by ticking the box next to the most 
appropriate statement in each of the 5 dimensions. This decision results in a 1-digit 
number that expresses the level selected for that dimension. The digits for the 
5 dimensions will be combined into a 5-digit number that describes the patient’s health 
state. 
The EQ-VAS is a vertical VAS numbered from 0 to 100, where 0=The worst health 
you can imagine, and 100=The best health you can imagine. The patient will be asked 
to mark an X on the scale to indicate how his/her health is today, and to write the 
number he/she marked on the scale in the box next to the scale. 


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5.2.4 
Laboratory Markers of Liver Fibrosis, Cholestasis, and Liver Function 
5.2.4.1 
Liver Fibrosis 
Blood samples for the assessment of ELF score, which is based on tissue inhibitor of 
metalloproteinase 1 (TIMP-1), amino-terminal propeptide of Type III procollagen 
(PIIINP), and hyaluronic acid, will be collected as described in Section 5.3.2. 
These blood samples will also be used for the assessment of the other PBC-related 
biomarkers PRO-C3 and C3M. 
5.2.4.2 
Cholestasis and Bile Acid Metabolism 
The liver biochemistry blood sample, collected as described in Section 5.3.2, will be 
used for the assessment of markers of cholestasis based on ALP levels and total 
bilirubin. 
Blood samples for the assessment of markers of bile acid metabolism, based on total 
bile acids, C4, FGF19, and FGF21, will be collected as described in Section 5.3.2. 
5.2.4.3 
Liver Function 
The biochemistry blood sample, collected as described in Section 5.3.2, will be used 
for the assessment of serum fibrinogen and albumin levels; the hematology blood 
sample will be used for the assessment of INR; and the liver biochemistry sample will 
be used for the assessment of total and conjugated bilirubin, ALP, ALT, AST, and GGT. 
The MELD score will be calculated based on the results from the liver biochemistry 
(total bilirubin), biochemistry (creatinine, and sodium if MELD score >11), and 
hematology (INR) blood samples (see Appendix III). The MELD score is provided by 
the central laboratory. 
Blood samples for the assessment of hsCRP and IgM will be collected as described in 
Section 5.3.2. 
5.3 
Safety Assessments 
5.3.1 
Adverse Events 
AEs will be followed, recorded, and reported in line with the procedures described in 
Section 7. AESIs are defined in Section 7.1.5. 
Particular attention will be given to the detection and management of potential bone 
marrow toxicity (Section 5.3.2.1), cases of DILI (Section 5.3.2.2), and potential cases 
of hypothyroidism (see Section 5.3.2.3). In the event that a patient has any clinical signs 
or symptoms that are, in the opinion of the Investigator, consistent with hepatitis (such 
as right upper quadrant discomfort, fever, fatigue, nausea, vomiting, jaundice, rash, or 
eosinophilia >5%) or drug-induced hepatoxicity, please refer to Appendix II. 


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5.3.2 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory, unless otherwise 
specified. The central laboratory will analyze the samples or send them to reference 
laboratory(ies) for analysis, as indicated in the central laboratory manual. Laboratory 
assessments of PK and sampling for future biomarker and genetic research are 
described in Section 5.5, Section 5.6, and Section 5.7, respectively. 
Blood and urine samples will be collected predose under fasting conditions (see 
Section 5) at the times indicated in Table 1. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples. The blood volumes to 
be collected per patient during the study will be provided in the ICF and/or in the central 
laboratory manual. For further details, refer to the central laboratory manual. 
Sampling for the analysis of clinical laboratory parameters will be performed before 
the administration of IMP. 
The following parameters will be assessed: 
Liver biochemistry: ALP, ALT, AST, total and conjugated bilirubin, and GGT 
One repeat blood sampling for ALP, total bilirubin and/or ALT/AST (with analysis by 
the central laboratory) can be performed at the discretion of the Investigator at 
Screening Visit 2 for patients who do not meet an inclusionary laboratory value at 
Screening Visit 1. 
Note that biochemical response is assessed based on the liver biochemistry sample 
(Section 5.2.1). 
ELF score and other PBC-related biomarkers: TIMP-1, PIIINP, and hyaluronic acid 
for calculation of the ELF score; and the other PBC-related biomarkers PRO-C3 and 
C3M 
Other markers of liver function: hsCRP and IgM 
Markers of bile acid metabolism: Total bile acids, C4, FGF19, FGF21 
Autoantibodies: AMA titer, PBC-specific antibodies (anti-GP210, anti-SP100, 
antibodies against major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase 
complex]) 
A sample for the assessment of autoantibodies will be collected at Screening Visit 1 
only. Central laboratory results will not be used to confirm patient eligibility at 
Baseline. 
Viral serology: HIV antibodies (1 and 2) and, if positive for HIV antibodies, HIV 
RNA; hepatitis B surface antigen and hepatitis C virus antibody and, if positive for 
HCV antibody, HCV RNA 


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A sample for the assessment of viral serology will be collected at Screening Visit 1 
only. 
Pregnancy test (serum): See Section 5.3.3. 
Hematology: hematocrit, hemoglobin, absolute and relative reticulocyte counts, 
RBC count, white blood cell (WBC) count, differential WBC count, platelet count, 
absolute neutrophil count, mean cell volume, and INR 
One repeat blood sampling for INR (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who do 
not meet the inclusionary laboratory value at Screening Visit 1. 
Biochemistry: glucose, total protein, albumin, fibrinogen, creatinine, urea, 
total cholesterol, triglycerides, sodium, potassium, and chloride 
Serum creatinine data will be used to calculate eGFR at Screening Visit 1 
(see Section 5.1.3). 
Thyroid function: TSH and free T4 
One repeat blood sampling for TSH (with analysis by the central laboratory) can be 
performed at the discretion of the Investigator at Screening Visit 2 for patients who do 
not meet the inclusionary laboratory value at Screening Visit 1. 
Drug screen (urine): a urine screen for amphetamines, cocaine or opiates (ie, heroin 
and morphine) will be performed at Screening. Patients on stable methadone or 
buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 
may be included in the study. Patients with a positive urine drug screen due to 
prescription opioid-based medication are eligible if the prescription and diagnosis are 
reviewed and approved by the Investigator. Patients with a positive urine drug screen, 
if not due to prescriptional use of a concomitant medication, as confirmed by the 
Investigator, will be excluded from the study. Medicinal cannabis and cannabidiol 
products are not allowed. 
Urinalysis: quantitative test for urine pH and protein; qualitative tests for glucose, 
ketones, bilirubin, blood, and microscopic examination of the sediment 
Pregnancy test (urine): See Section 5.3.3. 
Refer to the central laboratory manual for details regarding the collection, processing, 
and shipping of the blood and urine samples. 
The Investigator must review the laboratory report and assess results for clinical 
significance, including ALP values, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the eCRF. Refer to 
Section 7.1.4. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those that are not associated with 
the underlying disease, unless judged by the Investigator to be more severe than 
expected for the patient’s condition. 


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All laboratory tests with values considered clinically significantly abnormal during the 
patient’s participation in the study or within 30 days after the last dose of IMP, 
whichever is later, should be repeated until the values return to normal, to Baseline 
levels, or have stabilized and are no longer clinically significant, as determined by the 
Investigator or Medical Monitor. 
If such values do not return to normal/Baseline within a period of time judged 
reasonable by the Investigator, then the etiology should be identified, and the Sponsor 
(or designee) notified. 
If required due to COVID-19-related restrictions, laboratory samples to follow-up 
an AE, including the retests for DILI (see Appendix II), absolute reticulocyte count 
(see Section 5.3.2.2), or TSH and free T4 (see Section 5.3.2.3), may be collected by a 
qualified healthcare professional at a location other than the study site. For other 
circumstances pertaining to patient safety during COVID-19-related restrictions, 
follow-up with the Sponsor (or designee). 
Laboratory samples taken to follow-up an AE, including, absolute reticulocyte 
count, or TSH and free T4 noted above, may be tested locally so that the results are 
communicated to the Investigator’s site promptly. If required due to COVID-19-related 
restrictions, the results of local safety laboratory tests may be provided to the 
Investigator by phone. Local laboratory results will not be entered into the eCRF. 
However, where unscheduled central laboratory confirmation is not possible for 
protocol-specified retests for evaluation of anemia, or hypothyroidism, the retest results 
may be requested. 
For cases of suspected DILI (Appendix II), the retesting as well as close monitoring 
will be done by central laboratory only. 
5.3.2.1 
Suspected Drug-induced Liver Injury 
During the study, the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether the patient meets 
DILI criteria at any point during the study. 
In the event that a patient has any of the following laboratory results, please refer to 
Appendix II for details regarding the detection and management of suspected or 
confirmed cases of DILI, including instructions for retesting, close monitoring, and 
action to take regarding the IMP: 
• AST or ALT ≥3×ULN 
• AST or ALT >2×Baseline 
• Total bilirubin >2×ULN 
• INR >1.5 (except for patients on anticoagulant therapy). 
Baseline values for liver tests (ALT and AST) are determined by averaging the values 
obtained at Screening and Baseline/Day 1 to determine the arithmetic mean. 


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Details of the IMP stopping criteria relating to suspected or confirmed DILI are 
provided in Section 4.4 and Appendix II. 
Any suspected or confirmed DILI events meeting the criteria for an AESI, as defined 
in Section 7.1.5, will be reported to the Sponsor (or designee) following the same 
procedure as for SAEs (see Section 7.4). 
5.3.2.2 
Detection and Management of Potential Bone Marrow Toxicity 
Particular attention will be given to the detection and management of potential cases of 
bone marrow toxicity. In case of Grade ≥2 severity anemia, the Investigator will instruct 
the patient to interrupt IMP administration and to return to the study center within 
7 days so that the absolute reticulocyte count can be retested. If the retest value is below 
50% of the Baseline value, IMP will not be resumed and will be permanently 
discontinued. IMP administration will be resumed, only if the retest value for the 
absolute reticulocyte count is ≥50% of the Baseline value and a Grade ≤1 of anemia, 
and an alternative cause for the anemia can be documented. The patient will continue 
to be closely monitored (at least weekly) until normalization of the reticulocyte count, 
ie, return to Baseline values. 
Anemia will be reported to the Sponsor (or designee) as an AESI, as defined in 
Section 7.1.5, following the same procedure as for SAEs (Section 7.4). 
5.3.2.3 
Detection and Management of Hypothyroidism 
Particular attention will be given to the detection and management of potential cases of 
hypothyroidism. In case of TSH ≥10 mIU/L, based on the regular TSH laboratory 
follow-up and/or based on unscheduled TSH test due to change of the thyroid hormone 
replacement dose for patients on thyroid hormone replacement therapy, or initiation of 
thyroid hormone replacement therapy, the Investigator will instruct the patient to 
interrupt IMP administration and to return to the study center within 5 days so that TSH 
and free T4 values can be retested at the central laboratory. If the retest value is 
≥10 mIU/L with reduced free T4, IMP will not be resumed. If hypothyroidism is not 
confirmed (ie, central laboratory TSH <10 mIU/L and normal free T4), IMP 
administration will be resumed as per protocol. The patient will continue to be closely 
monitored by at least their clinical status and TSH/free T4 levels (at least weekly) until 
normalization of the TSH and free T4 values, ie, return to Baseline values. 
Hypothyroidism will be reported to the Sponsor (or designee) as an AESI, as defined 
in Section 7.1.5, following the same procedure as for SAEs (Section 7.4). 
5.3.3 
Pregnancy 
All patients are required to meet the requirements relating to pregnancy and use of 
contraception described in the inclusion and exclusion criteria (see Section 4.1 and 
Section 4.2, respectively). 
For female patients who are considered postmenopausal but have less than 12 months 
of amenorrhea and who are not on concomitant estrogen replacement therapy, a high 


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FSH level in the postmenopausal range will be required at Screening. Confirmation 
with more than one FSH measurement is required. 
Serum (beta human chorionic gonadotrophin) or urine pregnancy tests will be 
performed for female patients of childbearing potential at the time points indicated in 
Table 1. 
Female patients of childbearing potential must have a serum pregnancy test at 
Screening Visit 1. The blood sample for the serum pregnancy test must be taken within 
7 days of Day 1. Therefore, if Screening Visit 1 is performed more than 7 days prior to 
Day 1, the serum pregnancy test must be repeated at Screening Visit 2 within 7 days of 
Day 1. The result must be negative for the patient to be eligible for the study. If the test 
result is positive, the patient must be excluded from the study. The serum pregnancy 
tests will be analyzed by the central laboratory. A negative urine pregnancy test result 
is required at Randomization/Baseline before dosing. Urine pregnancy tests will be 
analyzed locally. 
Monitoring for pregnancies in female patients and the partners of male patients will 
continue from the patient’s inclusion in the study until 30 days after the last dose of 
IMP. Male patients will be required to inform the Investigator if their partner becomes 
pregnant during the study and up to 30 days after the last dose of IMP. The Investigator 
should inform the Sponsor (or designee) within 24 hours of learning of the pregnancy 
or partner pregnancy by completing and submitting a pregnancy report form (refer to 
the SAE contact information at the beginning of this protocol) to the Sponsor 
(or designee). 
If a patient becomes pregnant, she will permanently discontinue IMP and attend an EoT 
Visit 30 days after the last dose of IMP, after which the patient will be encouraged to 
continue study assessments until completion of the Week 24 Visit (Visit 8). Any 
pregnant patient and the fetus will be closely followed-up throughout the duration of 
the pregnancy to determine the outcome (including spontaneous miscarriage, elective 
termination, normal birth, or congenital abnormality). The Investigator will ask the 
patient to provide informed consent to record information on the health of the baby. 
Generally, follow-up will be required for no longer than 6 to 8 weeks beyond the 
estimated delivery date. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, 
fetal death, stillbirth, congenital abnormalities, ectopic pregnancy) will be considered 
SAEs. 
For any male study patient’s partner who becomes pregnant, the Investigator will 
attempt to collect pregnancy information on the male patient’s partner while the male 
patient is in this study until 30 days after the last dose of IMP. The Investigator will 
record pregnancy information on the appropriate form and submit it to the Sponsor (or 
designee) within 24 hours of learning of the partner’s pregnancy. The Investigator will 
obtain informed consent from the female partner to collect information about the 
pregnancy and its outcome. Information on the status of the mother and child will be 


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forwarded to the Sponsor (or designee). Generally, the follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. Abnormal pregnancy outcomes (eg, spontaneous abortion, 
fetal death, stillbirth, congenital abnormalities, ectopic pregnancy) will be considered 
SAEs. 
5.3.4 
Breastfeeding 
Breastfeeding women will be excluded from the study. 
5.3.5 
Vital Signs 
Vital signs will be measured as outlined in Table 1 with the patient in a sitting position 
after 5 minutes’ rest and will include pulse rate, systolic blood pressure (SBP), and 
diastolic blood pressure (DBP). Body temperature will be measured at Screening 
Visit 1 according to local standard of care. Method of temperature measurement will 
be recorded in the patient notes and in the eCRF. 
5.3.6 
12-lead Electrocardiogram 
An ECG device with a built-in printer will be provided by Clario and will be used for 
all study ECG assessments. Triplicate 12-lead ECGs will be obtained as outlined in 
Table 1. 
The ECGs will be conducted in the supine position after 5 minutes’ rest. At each time 
point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The 
full set of triplicates should be completed in less than 4 minutes. 
The ECG tracing printout should be signed and dated by the person who made the 
interpretation locally (for purposes of patient safety management); the tracing printout 
will be archived at the study site. The machines will provide heart rate, PR, QRS, QT, 
QTc intervals, and abnormal findings. 
Electrocardiograms obtained throughout the study will be electronically transferred for 
central reading. 
The central reader will analyze the patient’s ECG results. The ECG analysis from the 
central reading, including HR (bpm), RR, QT, QRS, QTc Bazett, and QTc Fridericia 
intervals (milliseconds), and interpretation (abnormalities, rhythm, conduction), will be 
sent to the study site. The mean QTc Fridericia interval calculated by the central reader 
and based on triplicate ECGs, will be used for the assessment of eligibility. 
If there is any evidence of the cardiac conditions or abnormalities as described in 
Section 4.4.1, IMP is to be permanently discontinued. 
Further details regarding the ECG assessments are provided in the site operations 
manual or manual provided by the vendor. 


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5.3.7 
Physical Examination, Including Height and Body Weight 
Patients will undergo complete physical examinations and symptoms-directed physical 
examinations, as indicated in Table 1. 
The complete physical examination will include assessments of the standard physical 
examination items, including general appearance, skin, eyes, ears, nose, throat, head 
and neck, heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, 
neurological, and other body systems, if applicable, for describing the status of the 
patient’s health. 
Body weight and height (height at Screening Visit 1 only) will also be measured and 
recorded. The patient should be dressed in light clothing, without shoes. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Any new abnormalities or worsening of existing abnormalities that are 
associated with signs and/or symptoms (except for PBC-related pre-existing conditions 
[see Section 7.3]) should be reported as AEs or SAEs, as appropriate (see 
Section 7.1.4). 
5.4 
Adverse Clinical Outcomes 
The following adverse clinical outcomes will be captured during the study: 
• All-cause mortality 
• Patients requiring a liver transplant (transplant list inclusion) 
• MELD score of ≥15 (confirmed at repeat testing at least 14 days apart), as calculated 
by the central laboratory, according to the formulas in Appendix III 
The MELD score will be calculated based on the results from the liver biochemistry 
(total bilirubin), biochemistry (creatinine, and sodium if MELD score >11), and 
hematology (INR) blood samples, collected as described in Section 5.3.2. 
• Variceal bleed 
• Portal hypertension bleed 
• Hepatic encephalopathy (West Haven criteria), see Appendix IV 
• Spontaneous bacterial peritonitis 
• Uncontrolled ascites requiring treatment 
In the event of any of these outcomes, IMP will be permanently discontinued, as noted 
in Section 4.4.1, and the patient may continue study visits. 
Investigators will record the AEs in the Adverse Event page of the eCRF and will 
indicate on the Adverse Event page if it meets the criteria for an SAE. If the event meets 


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the criteria of an SAE, it will be reported using the paper safety report form within 
24 hours of becoming aware of the event. 
The adverse clinical outcomes will be adjudicated by the Adjudication Committee (see 
Section 9.4.1). 
Investigators will indicate on the eCRF Adverse Event page if the event meets the 
criteria for adjudication. If the event meets the criteria for adjudication, the Investigator 
will then complete the Adjudication Event eCRF. 
Please refer to the Investigator adjudication manual for further information. 
5.5 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of setanaxib 
and GKT138184 at the visits specified in Table 1. The PK blood volumes to be 
collected during the study will be provided in the ICF and/or in the central laboratory 
manual. Samples will be collected predose in the morning. 
Instructions for the collection and handling of biological samples will be provided by 
the Sponsor (or designee) and will be included in the central laboratory manual. The 
actual date and time that each sample is collected will be recorded. 
The measurement of plasma setanaxib and GKT138184 concentrations will be 
performed by a central laboratory. 
5.6 
Future Biomarker Research 
Patients will have the option to accept or decline additional blood sampling for future 
biomarker research. 
Patients who consent to future biomarker research will have a blood sample collected 
at Baseline and Week 24. The optional biomarker blood volumes to be collected during 
the study will be provided in the ICF and/or in the central laboratory manual. 
The blood samples will be used for analyses of biomarkers related to liver fibrosis 
and/or PBC. The biomarker analyses results may be used to explore potential 
relationship with setanaxib response and/or disease progression data obtained in this 
study. 
The results of the biomarker analyses will be reported separately from the clinical study 
report (CSR) and individual biomarker analysis results will not be reported to the 
Investigator or the Site. 
Details on processes for collection, shipment and destruction of the samples can be 
found in the central laboratory manual. 


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5.7 
Future Genetic Research 
Where local regulations and Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC)allow, a blood sample for DNA isolation will be collected at Baseline 
from patients who have consented to participate in the genetic analysis component of 
the study. The blood volume of this optional sample will be provided in the ICF and/or 
in the central laboratory manual. Participation is optional. Patients who do not wish to 
participate in the genetic research may still participate in the study. 
DNA samples will be used for research related to setanaxib and/or PBC and related 
diseases. They may also be used to develop tests/assays, including diagnostic tests 
related to setanaxib and/or IMPs of this drug class and PBC. The genetic research may 
consist of the analysis of one or more candidate gene(s) or the analysis of genetic 
markers throughout the genome or analysis of the entire genome. 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to setanaxib or IMPs of this class to understand study disease 
or related conditions. 
The results of genetic analyses will be reported separately from the CSR and will not 
be communicated to study sites. 
The Sponsor or designee will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
Details on processes for collection, shipment, and destruction of these samples can be 
found in the central laboratory manual. 


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6 TREATMENTS 
6.1 
Investigational Product(s) 
6.1.1 
Description of Investigational Product(s) 
 
Test Product 
 
IMP/non-IMP: 
IMP 
Name: 
Setanaxib  
Doses:  
• Setanaxib 1200 mg/day group 
• Setanaxib 1600 mg/day group 
Mode of administration: 
Oral film-coated tablets 
Setanaxib film-coated tablets will contain 400 mg 
setanaxib per tablet formulated with excipients. 
Manufacturer: 
Aptuit 
Via Alessandro Fleming, 4 
37135 Verona VR 
Italy 
 
Placebo 
 
Substance: 
Matching placebo film-coated tablets, containing only 
excipients, will be provided. The placebo film-coated 
tablets will be visually identical to setanaxib film-coated 
tablets in order to maintain the blind. 
Doses:  
Not applicable 
Mode of administration: 
Matching oral tablets 
Manufacturer: 
Aptuit 
Via Alessandro Fleming, 4 
37135 Verona VR 
Italy 
6.1.2 
Preparation, Handling, and Storage 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at 
the site. The bottles containing setanaxib and placebo film-coated tablets will be stored 
under controlled conditions according to the storage requirements described on the 
label(s). The IMP is to be stored at room temperature or below. The film-coated tablets 
must not be frozen or stored above 25ºC or 77ºF. The Investigator (or designee) will 
instruct the patients to store the IMP in accordance with the instructions on the label(s). 
6.1.3 
Packaging, Labelling, and Shipment 
Setanaxib and placebo will be packaged and labeled in accordance with all applicable 
regulatory requirements and Good Manufacturing Practice guidelines. 


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Setanaxib and placebo will be provided in high-density polyethylene (HDPE) bottles 
containing: 
• Setanaxib 400 mg film-coated tablets for morning dosing 
• Matching placebo film-coated tablets for morning dosing 
• Setanaxib 400 mg film-coated tablets for evening dosing 
• Matching placebo film-coated tablets for evening dosing. 
Each bottle will contain 70 film-coated tablets. 
The packaging of the placebo will be the same as the IMP in order to maintain the blind. 
Setanaxib and placebo will be shipped and stored under controlled conditions according 
to the storage requirements. The IMP must be stored at room temperature or below (the 
film-coated tablets must not be frozen or stored above 25ºC or 77ºF). 
Refer to the pharmacy manual for full details for packaging, labelling, and shipment of 
the IMP. 
Almac UK will label and package the IMP bottles and will supply the IMP to local 
depots/study sites on behalf of the Sponsor (or designee). 
6.2 
Blinding 
This study is double-blinded. The Investigator, the site personnel, the Sponsor and their 
representatives involved in monitoring and conducting the study, the Adjudication 
Committee, and the patients will be blinded to treatment assignments. 
Randomization data will be kept strictly confidential, accessible only to authorized staff 
and the IDMC until the time of unblinding. Authorized staff may include the 
randomization statistician, who will store the master randomization list in a secure 
system, an unblinded statistician, and unblinded programmers, who will provide the 
IDMC with unblinded data for review in accordance with the procedures described in 
the IDMC Charter. The randomization will be performed by the external interactive 
voice response system/interactive web response system (IXRS) provider, Almac. The 
blinded statistician supporting the study will have no access to the unblinded 
randomization schedule. All authorized unblinded staff must be documented. 
The setanaxib and placebo film-coated tablets are visually identical in order to maintain 
the blind. Setanaxib and placebo bottles will be coded and labeled in a manner that 
protects blinding. The coding system will permit rapid identification of the product (in 
case of medical emergencies), that does not permit undetectable breaking of the blind. 
Breaking of the blind is only allowed in the case of an emergency, when knowledge of 
the IMP is essential for the clinical management of the patient. In such emergency 
situations, the responsibility to break the treatment code resides solely with the 
Investigator. The Investigator will have immediate access to break the blind through 


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IXRS. The Investigator must contact the Sponsor within 1 working day after the event, 
without revealing to the Sponsor (or contract research organization [CRO]) the results 
of the code break, except to the designated global patient safety representative. The 
Investigator must document the date of unblinding and the reason. 
Emergency unblinding will be organized through IXRS. The Investigator must record 
the date of unblinding and the reason. All breaks of the blind must be adequately 
documented. 
If an SAE is reported, the designated global patient safety representative may unblind 
the treatment assignment for the individual patient through IXRS in order to meet 
regulatory reporting requirements. 
Although Investigators are blinded to treatment assignments, the Investigators will 
review the laboratory reports, which will include ALP and bilirubin values. This is 
required to ensure the appropriate medical management of the patient from a safety 
perspective. 
6.3 
Method of Assigning Treatment 
Each patient will have a unique screening number obtained from the IXRS. This will 
be assigned at Screening Visit 1. If a patient is rescreened (see Section 4.3), the 
rescreened patient should be assigned a new unique screening number. The Investigator 
will keep a record (the patient screening log) of patients who enter Screening. 
Once the patient has been successfully screened and the Investigator has determined 
that the patient is eligible, the patient will be confirmed as enrolled within the IXRS. 
Randomization will be performed via a centralized IXRS. 
The randomization codes will be prepared by the randomization statistician. 
The randomization statistician will store the master randomization list in a secure 
system. 
If a patient withdraws from study participation, his/her unique identification number(s) 
cannot be re-used for another patient. 
On Day 1, eligible patients will be assigned to setanaxib 1200 mg/day, setanaxib 
1600 mg/day, or placebo according to a 1:1:1 randomization ratio, stratified by 
Screening serum ALP < or ≥3.0×ULN. Each patient will receive a unique 
randomization number when he/she is assigned IMP. Patients will be allocated to IMP 
according to the randomization code. 
6.4 
Dose and Administration 
Patients will be assigned to IMP as described in Section 6.3. 
At each dispensing visit (Table 1), patients will receive kit(s) comprising 4 bottles (see 
Table 2). Each bottle contains 70 film-coated tablets. Patients will be dispensed 1 or 


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2 IMP kits at dispensing visits, as described in the site operations manual, to ensure that 
the patient has sufficient IMP to last until the next scheduled visit. 
Table 2 
Investigational Medicinal Product Kits 
IMP 
Bottles for morning dosing 
Bottles for evening dosing 
Bottle 1 
Bottle 2 
Bottle 3 
Bottle 4 
Setanaxib 1200 mg/day 
Setanaxib  
400 mg tablets 
Setanaxib  
400 mg tablets 
Setanaxib  
400 mg tablets 
Placebo 
tablets 
Setanaxib 1600 mg/day 
Setanaxib  
400 mg tablets 
Setanaxib  
400 mg tablets 
Setanaxib  
400 mg tablets 
Setanaxib  
400 mg tablets 
Placebo 
Placebo 
tablets 
Placebo 
tablets 
Placebo 
tablets 
Placebo 
tablets 
Patients will take 4 tablets per day, 1 tablet from each bottle. Two tablets will be taken 
in the morning and 2 tablets will be taken in the evening (see Table 2), for 24 weeks. 
• Patients allocated to setanaxib 1200 mg/day will self-administer 2 tablets of 
setanaxib 400 mg in the morning, 1 tablet of setanaxib 400 mg in the evening, and 
1 tablet of placebo in the evening. 
• Patients allocated to setanaxib 1600 mg/day will self-administer 2 tablets of 
setanaxib 400 mg in the morning and 2 tablets of setanaxib 400 mg in the evening. 
• Patients allocated to placebo will self-administer 2 placebo tablets in the morning 
and 2 placebo tablets in the evening. 
Patients will be instructed not to take their morning IMP dose on visit days until after 
the study assessments have been completed. 
The tablets should be taken orally with food or up to 30 minutes after eating a meal. 
Each tablet should be taken separately and swallowed whole with water. The patients 
will be instructed to distribute their morning and evening doses as even as possible. 
For BID administration, the dosage interval should be at least 4 hours. A missed 
morning dose can therefore be taken up until 4 hours prior to the evening dose. Patients 
will be provided with a patient IMP dosing card. Patients will be instructed to record 
the date and time of each tablet that they take on the dosing card straight after they have 
taken the tablet. 
Patients will be reminded to bring the IMP (including any empty bottles and packaging) 
and the patient IMP dosing card with them to each study visit. 
The IMP dosing card will be considered as a source document. Site personnel will 
record the date and time of the IMP dose prior to PK Visits in the eCRF. 
6.4.1 
Dose Modification 
No dose modifications are permitted on a patient-basis in this study. Dose interruptions 
are required in case of DILI, anemia, and hypothyroidism, when the events meet the 


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criteria as defined in Appendix II, Section 5.3.2.2, and Section 5.3.2.3, respectively. 
Events that require permanent discontinuation of IMP are listed in Section 4.4.1. 
6.4.2 
Intervention After the End of the Study 
Continued access to IMP is not planned beyond the completion of the study. 
6.5 
Precautions and/or Lifestyle Considerations 
Patients will be asked to fast from 10 pm on the day prior to study visits until after the 
study procedures have been completed. In cases where the FibroScan® assessments are 
carried out on a different day than the study visit, refer to Section 5.2.2 for fasting 
instructions. 
6.6 
Prior Medication 
The requirements regarding prior use of UDCA and second-line therapies for PBC, 
including OCA, fenofibrate, or bezafibrate, are provided in the inclusion criteria 
(Section 4.1). The recording requirements for prior medications are included in 
Section 6.7. 
Prohibited Medications 
The following medications are prohibited within 3 months of Screening Visit 1, and 
during the study: oral and systemic corticosteroids, colchicine, mycophenolate mofetil, 
azathioprine, methotrexate, sulfasalazine, leflunomide, cyclophosphamide, valproate, 
or isoniazid. Note: nonsystemic corticosteroids, ie, topical/nasal/inhaled/other 
corticosteroids are allowed provided used in recommended doses, and up to 7 days of 
low doses up to up to 10 mg prednisone or equivalent of oral/parenteral corticosteroids 
are allowed. 
Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 
5 half-lives of the IMP (if known) (whichever is longer) is prohibited, as is current 
enrollment in another interventional clinical study. 
6.7 
Concomitant Medication and Procedures 
The use of a UDCA at a prescriptional dose is required during the study, unless the 
patient is intolerant to UDCA (see Inclusion Criterion 6). Second-line therapies for 
PBC, including OCA, fenofibrate, or bezafibrate, are also permitted during the study. 
For patients receiving these agents, all efforts should be made to maintain the dose of 
UDCA, OCA, and fenofibrate or bezafibrate stable during the Double-blind Treatment 
Period. The reasons for considering a dose change should be clearly documented in the 
study documentation. Patients should not start additional treatments for PBC after 
Randomization. If PBC treatments are started it will lead to IMP discontinuation. Dose 
modifications of concomitant PBC treatments initiated before Randomization do not 
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Patients will be instructed not to take their usual PBC medications on visit days until 
after the study assessments have been completed. Patients will be reminded to bring 
their medications for PBC with them to each study visit. 
Regarding COVID-19 vaccination, as setanaxib does not have immunosuppressive 
properties based on nonclinical and clinical safety data, the Sponsor considers that study 
patients may undergo COVID-19 vaccination during the study. 
Concomitant Medications to be Used with Caution 
Setanaxib has been shown to be a weak inhibitor of OAT3, CYP2C9 and CYP2C19 in 
a clinical study. In addition, setanaxib inhibited BCRP and P-glycoprotein in vitro. This 
may result in increased exposures of applicable concomitant medications, and hence 
caution should be exercised with use of: 
• Medications that are primarily eliminated through OAT3 
• Sensitive CYP2C9 and CYP2C19 substrates that have a narrow therapeutic range 
such as warfarin and phenytoin (CYP2C9) and S-mephenytoin (CYP2C19) 
• Sensitive substrates of BCRP and P-glycoprotein such as digoxin 
In vitro data suggests that setanaxib is an inducer of CYP2B6. This may result in 
decreased exposures and therefore reduced efficacy of applicable concomitant 
medications, and hence caution should be exercised with use of: 
• Sensitive CYP2B6 substrates, such as tamoxifen, valproic acid, and 
cyclophosphamide 
Prohibited Concomitant Medications 
The prohibited (prior) medications and devices listed in Section 6.6 are also prohibited 
during the Double-blind Treatment Period. 
In addition, the following medications are prohibited during the Double-blind 
Treatment Period: 
• Potent 
CYP3A4 
inhibitors 
(itraconazole, 
lopinavir/itonavir, 
telaprevir, 
clarithromycin, ritonavir, ketoconazole, indinavir/ritonavir, conivaptan, and 
voriconazole) 
• Potent UGT1A9 inhibitors and inducers: such as belumosudil, cannabidiol, 
cannabinol, 
deferasirox, 
diflunisal, 
eltrombopag, 
fosphenytoin/phenytoin, 
isavuconazole, medical cannabis, mefenamic acid, methylene blue, morniflumate, 
niflumic acid, perampanel, regorafenib, rifampicin, sorafenib, umifenovir) 
If patients receive a prohibited medication, Investigators should consider if IMP 
administration should be temporarily interrupted or permanently discontinued. 
Additionally, if a patient has taken a prohibited medication (eg, short-term antifungal 
therapy) and the Investigator learns about it later, this might not lead to the permanent 


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discontinuation of IMP. In this case, there should be no signs of drug-drug interaction 
and continuation of IMP administration will be left to the Investigator’s discretion. 
Medication Recording Requirements 
Prior and concomitant medications taken for PBC, including UDCA, OCA, fenofibrate 
or bezafibrate, will be recorded up to the end of the EoT Visit in the appropriate section 
of the eCRF. 
All other medication (including vaccines, over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) taken from 3 months (90 days) before Screening 
Visit 1 until the end of the EoT Visit will also be recorded in the appropriate section of 
the eCRF. 
The following details must be recorded in the eCRF: 
• Medication name, ideally the generic name 
• Reason for use 
• Start and end date of administration 
• The dose and frequency of administration 
In addition, the following details of medications taken for PBC, will be recorded in the 
eCRF: 
• Prior use of OCA (yes/no), fenofibrate (yes/no), bezafibrate (yes/no) 
• Reason for dose change (only concomitant medications taken for PBC) 
• Reason for discontinuing prior or concomitant medications taken for PBC 
The Medical Monitor should be contacted if there are any questions regarding prior or 
concomitant medication or procedures. 
6.8 
Overdose 
For this study, a single intake of 5 or more setanaxib tablets and/or a total daily dose of 
7 or more tablets will be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose with setanaxib. 
Decisions regarding dose interruptions will be made by the Investigator based on the 
clinical evaluation of the patient. 
In the event of an overdose, patients should be closely observed/hospitalized for close 
observation and appropriate symptomatic/supportive medical care and be followed 
until resolution/stabilization of any clinical issues. 


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Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved setanaxib) must be communicated to the Sponsor (or a specified designee) 
using the overdose report form within 24 hours of becoming aware of its occurrence. 
Any overdose associated with clinical symptoms will be recorded as an AE or SAE, as 
appropriate. Note that an overdose without clinical symptoms will not be recorded as 
an AE or SAE, even if the patient was hospitalized for observation. Details of any signs 
or symptoms and their management should be recorded, including details of any 
treatments administered for the overdose. All overdoses with clinical symptoms 
meeting the SAE criteria must be reported as described in Section 7.4. 
6.9 
Compliance 
The Investigator (or designee) will explain the correct use of the IMP to each patient 
and will check that each patient is following the instructions properly. Patients will 
document the IMP doses that they take on a patient IMP dosing card. 
Compliance will be assessed at each visit by counting the returned tablets and will be 
documented in the source documents and eCRF. Any deviation from the correct use of 
the IMP will be recorded in the eCRF. 
A record of the number of IMP tablets dispensed to and taken by each patient will be 
maintained and reconciled with IMP and compliance records. The IMP start and stop 
dates, including dates for IMP interruptions, will also be recorded in the eCRF. 
6.10 
Accountability 
The IMP must not be used for any purpose other than that defined in this protocol. 
All supplies of IMP will be accounted for in accordance with Good Clinical Practice 
(GCP). 
The pharmacist (or designee) should maintain accurate records of all IMP supplies 
received during the study. These records should include the dates and amounts of IMP 
that were received at the site, dispensed, and destroyed or returned to the Sponsor (or 
designee). The records should include dates, quantities, batch/serial numbers, 
expiration dates (if applicable), and the unique code numbers assigned to the IMP and 
study patients. If errors or damage in the IMP shipments occur, the Investigator should 
contact the Sponsor (or its designee) immediately. Copies of the IMP accountability 
records will be provided by each Investigator for inclusion in the trial master file. The 
study monitor will periodically check the supplies of IMP held by the Investigator or 
pharmacist to verify accountability of the IMP used. 
The Investigator (or designee) will dispense the IMP only to the identified patients in 
this study, according to the procedures described in this study protocol. Details of IMP 
dispensed to patients, will be recorded in the eCRF. Investigators should maintain 
records that document adequately that the patients were provided the doses specified 
by the protocol and reconcile all IMP received from the Sponsor (or designee). 
After the end of the study, all unused IMP and all medication containers should be 
destroyed at the study center or returned to the drug depot for destruction, as instructed 


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in the pharmacy manual. In either instance, complete documentation will be returned 
to the Sponsor (or designee). The IMP resupply will be managed by the IXRS. 


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7 ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
7.1.2 
Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• Results in death (Investigators should identify 1 SAE that is the leading cause of 
death). 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event that may not result in death, be life-threatening, or 
require hospitalization. The event will be considered an SAE when, based upon 
appropriate medical and scientific judgment, the event may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such events include intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
Definition of Terms 
Life-threatening: an AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred, i.e,, it does not include a reaction that, if it had occurred 
in a more severe form, might have caused death. For example, drug-induced hepatitis 
that resolved without evidence of hepatic failure would not be considered life-
threatening even though drug-induced hepatitis can be fatal. It does not include an AE 
or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. 
Hospitalization for elective surgery, or for procedures planned prior to the patient 
providing informed consent, or routine clinical procedures that are not the result of an 


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AE (eg, elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'nonserious' according to the 
usual criteria. 
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Disability/incapacity: an AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient’s ability to carry out normal life 
functions. 
7.1.3 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction is defined as an untoward and 
unintended response to a study drug, which is not listed in the applicable product 
information (eg, IB for an unapproved IMP or the SmPC [Summary of Product 
Characteristics] for an authorized medicinal product), and meets one of the following 
serious criteria: results in death, is life-threatening, requires hospitalization or 
prolongation of an existing hospitalization, results in persistent or significant disability 
or incapacity, is a congenital anomaly or birth defect, or is an important medical event 
that may not result in death, be life-threatening, or require hospitalization; and is 
assessed as causally related to the IMP. For suspected unexpected serious adverse 
reactions, the blind will be broken for safety reporting purposes. 
7.1.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities without clinical significance should not be recorded as AEs 
or SAEs. However, clinically significant laboratory abnormalities as per the 
Investigator’s assessment (eg, clinical chemistry, hematology, and urinalysis 
abnormalities) that require medical or surgical intervention or lead to IMP interruption 
or discontinuation must be recorded as an AE or SAE, as applicable. In addition, 
laboratory or other abnormal assessments (eg, in ECGs, X-rays, or vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. Any worsening 
of existing abnormalities that are associated with signs and/or symptoms (except for 
PBCrelated- pre-existing conditions [see Section 7.3]) should be reported as AEs or 
SAEs, as appropriate. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (eg, anemia) as the AE or SAE, not the laboratory result (ie, 
decreased hemoglobin). 
For specific information on handling of clinical laboratory abnormalities, see 
Section 5.3.2. 
7.1.5 
Adverse Events of Special Interest 
The AESIs for this study are DILI, anemia, and hypothyroidism. 


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AESIs of DILI will be defined as any DILI event that meets the criteria in A, B, or C 
of Appendix II. Please refer to Section 5.3.2.1 and Appendix II for details regarding the 
detection and management of cases of DILI. 
AESIs of anemia will be defined as CTCAE Grade ≥2 anemia AND absolute 
reticulocyte counts of <50% of the Baseline value, which is confirmed by repeat testing. 
Please refer to Section 5.3.2.2 for details regarding the detection and management of 
potential cases of bone marrow toxicity. 
AESIs of hypothyroidism will be defined as TSH levels of ≥10 mIU/L, which is 
confirmed by repeat testing at the central laboratory (ie, TSH ≥10 mIU/L and reduced 
free T4). Please refer to Section 5.3.2.3 for details regarding the detection and 
management of hypothyroidism. The AESI should be reported by the investigative site 
to the ICON Drug Safety Center within 24 hours of learning about the event by 
completing the paper safety report form and sending it via email or fax. The 
documentation and processing of AESIs is further detailed in the Investigator Site File. 
The AESIs will be adjudicated by the Adjudication Committee (see Section 9.4.1). 
Investigators will indicate on the relevant Adverse Event eCRF page if the event meets 
the criteria for an AESI. If the event meets the criteria for an AESI, the Investigator will 
inform the Sponsor (or designee) of the AESI utilizing the safety report form (refer to 
the SAE contact information at the beginning of this protocol) and will then complete 
the Adjudication Event eCRF. 
Please refer to the Investigator adjudication manual for further information. 
7.2 
Assessment of Adverse Events 
7.2.1 
Severity 
The terms serious and severe are not synonymous. The general term “severe” is often 
used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache). This is 
NOT the same as serious, which is usually associated with events that pose a threat to 
a patient’s life or ability to function (see Section 7.1.2). A severe AE (classified as 
Grade 3) does not necessarily need to be considered serious. For example, a WBC count 
of 1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be 
considered serious. Seriousness (not intensity) serves as a guide for defining regulatory 
reporting obligations. 
Investigators will grade all AEs by severity using CTCAE (version 4.03). 
If an AE is not listed in the CTCAE criteria, a corresponding grading is to be performed 
by the Investigator based on his/her best medical judgment as follows: 
• Mild (Grade 1): asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 


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• Moderate (Grade 2): minimal, local, or noninvasive intervention indicated; 
limited age-appropriate instrumental activities of daily living (ADL) 
• Severe (Grade 3): medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or limiting 
self-care ADL 
• Life-threatening (Grade 4): life-threatening consequences; urgent intervention 
indicated 
• Death (Grade 5): death related to an AE 
7.2.2 
Causality 
Investigators are required to systematically assess the causal relationship between the 
AEs and SAEs and the exposure to the IMP using the following definitions: 
Related: 
• The AE has a reasonable possibility of an association with the product because: 
○ The AE follows a reasonable temporal sequence to IMP administration and 
cannot be reasonably explained by the patient’s clinical state or other risk 
factors (eg, disease under study, concurrent diseases, or concomitant 
medications). 
○ The AE follows a reasonable temporal sequence to IMP administration, and it 
is a known reaction to the drug under study or a related chemical group or is 
predicted by known pharmacology or nonclinical safety. 
Not Related: 
• The AE does not follow a reasonable sequence from IMP administration, or it can 
be reasonably explained by the patient’s clinical state or other factors (eg, disease 
under study, concurrent diseases, and concomitant medications). 
7.3 
Documenting and Reporting Adverse Events 
Reporting of AEs will begin when the patient has provided informed consent and will 
continue up to 30 days after the last IMP administration. 
Occurrence of AEs may be volunteered spontaneously by the patient; discovered as a 
result of general, nonleading verbal questioning by the study staff; or determined by 
physical examination or other safety assessments. All AEs will be monitored and 
recorded in the eCRF throughout the entire study. Note that worsening of PBC-related 
pre-existing conditions will not be reported as AEs. Worsening of other existing 
abnormalities that are associated with signs and/or symptoms should be reported as AEs 
(or SAEs), as appropriate. 


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For all AEs, the Investigator must pursue and obtain adequate information (a 
description of the event, severity, time of occurrence, including whether the AE onset 
was before, during, or after the IMP administration if the AE started on a dosing day, 
duration, and any action, eg, treatment/follow-up tests). The outcome of the event 
should be provided along with the Investigator’s assessment of the relationship to the 
IMP. The Investigator must also assess whether the event meets the criteria for 
classification as an SAE. 
It is the Investigator’s responsibility to review all documentation (eg, hospital notes, 
laboratory reports, and diagnostic reports) related to an AE. Wherever possible, 
the Investigator’s diagnosis, not the individual signs and symptoms, will be 
documented as the AE. 
Investigators are not obligated to actively seek AEs or SAEs after the patient’s 
conclusion of study participation. However, if the Investigator learns of any SAE, 
including death, at any time after a patient has been discharged from the study, and 
he/she considers the event to be reasonably related to the IMP or study participation, 
the Investigator must promptly notify the Sponsor (or designee). 
7.4 
Reporting of Serious Adverse Events 
For SAEs with an onset inside the reporting period (ie, onset after provision of informed 
consent and up to 30 days after the last IMP administration), the Investigator must 
immediately, without undue delay but under no circumstances no later than 24 hours 
after becoming aware of the event, inform the Sponsor (or designee) of the SAE 
utilizing the safety report form (refer to the SAE contact information at the beginning 
of this protocol). 
The Investigator is obliged to respond to any request for follow-up information 
(eg, additional information, event outcome, final evaluation, or other records where 
needed) or to any question the Sponsor (or designee) may have concerning the SAE 
within the same timelines as those noted above for initial reports. This is necessary to 
ensure prompt assessment of the event by the Sponsor (or designee) and, as applicable, 
to allow the Sponsor to meet strict regulatory timelines associated with expedited 
reporting obligations for events of this nature. 
7.5 
Adverse Event and Serious Adverse Event Follow-up 
During the study (and after the patient’s participation in the study has ended), all AEs 
and SAEs should be followed proactively by the Investigator until the event resolves or 
the condition stabilizes to a level acceptable to the Investigator, until the event is 
otherwise explained, or until the patient is lost to follow-up. At the time the patient’s 
study participation ends, all ongoing AEs and SAEs should be evaluated for resolution. 
New or updated information will be recorded in the originally completed eCRF and the 
Investigator will submit any updated SAE/AESI information to the Sponsor (or 
designee) within the same timelines as those noted above for initial reports after receipt 
of the information. 


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7.6 
Safety Reporting Oversight 
In accordance with ICH GCP, the Sponsor (or designee) will inform Investigators of 
“findings that could affect adversely the safety of patients, impact the conduct of the 
study, or alter the IEC/IRB’s approval/favorable opinion to continue the trial.” 
The Sponsor (or designee) has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of an IMP under clinical 
investigation. The Sponsor (or designee) will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, 
and Investigators. To support compliance with these requirements, the Investigator 
must provide requested information in a timely manner. 
An Investigator who receives an Investigator safety report describing SAEs or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor 
(or designee) will file it along with the IB and will notify the IRB/IEC, if appropriate, 
according to local requirements. 


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8 STATISTICS 
8.1 
General Procedures 
With the exception of the unblinded statistician and programmers supporting the 
IDMC, all personnel involved with the analysis of the study will remain blinded until 
database lock and identification of protocol deviations. Analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) by the Sponsor or its representatives. 
A detailed description of all statistical analyses to be performed for this study and any 
deviations from the analysis detailed in the protocol will be outlined in the Statistical 
Analysis Plan (SAP). A first version of the SAP will be prepared prior to the inclusion 
of the first study patient and the SAP will be approved prior to database lock. 
All data will be presented by treatment group. Descriptive statistics (number of 
observations, mean, SD, median, minimum, and maximum) will be provided for 
continuous variables, and counts and percentages will be presented for categorical 
variables. 
For the primary endpoint of change in ALP (%), Baseline is defined as the last 
nonmissing measurement prior to the first administration of study drug, or, if multiple 
pretreatment measurements are available, the arithmetic mean of the last (up to) 
3 measurements preceding the first administration of study drug. This includes 
unscheduled and screening visits. For rescreened patients, the value associated with 
their screen failure record will not be considered for Baseline. If a patient has a 
Screening Visit 2 due to a retest for ALP, the last nonmissing measurement prior to the 
first administration of study drug will be used as Baseline for the efficacy analyses. 
For other endpoints, Baseline will be defined as the last nonmissing measurement 
before or on the date of first administration of IMP, unless otherwise stated in the SAP. 
The primary analysis will include data collected over a 24-week Double-blind 
Treatment Period. Any data collected after Week 24 (and a 4-week Follow-up Period) 
will be listed and, where sufficient data are available, may be summarized. 
8.2 
Analysis Populations 
The Full Analysis Set (FAS) will include all patients who are randomized to a treatment 
group and receive at least 1 tablet of IMP or placebo and have at least 1 post-Baseline 
value for the primary endpoint. This analysis set will be the primary set used for all 
efficacy analyses, along with the summary of disposition, demographics, and Baseline 
characteristics. Patients will be analyzed according to the treatment group they were 
randomized to regardless of the actual treatment received. 
The Safety Analysis Set will include all randomized patients who receive at least 
1 tablet of IMP or placebo. Patients will be analyzed according to the treatment they 
actually received. This analysis set will be used for summaries of safety data. 
For supplementary analysis purposes, primary and secondary efficacy analyses will be 
repeated utilizing a Per Protocol Set (PPS), including all patients who do not have any 


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major protocol deviations that would potentially affect the efficacy of the study drug. 
Major protocol deviations and any other reasons for exclusion from the PPS will be 
defined in the SAP and this analysis set will be finalized in a blinded manner prior to 
database lock. The PPS will be analyzed as actually treated. 
The PK Analysis Set will include all patients who receive at least 1 dose of setanaxib 
and have at least 1 measured concentration at a scheduled PK time point postdose. 
Patients may be excluded if they have an important AEs or protocol deviations that may 
impact PK. 
8.3 
Sample Size 
The primary efficacy endpoint is the change in ALP (%) over 24 weeks. 
It is planned to enroll approximately 60 to 70 patients. Patients will be randomized and 
allocated to placebo, setanaxib 1200 mg/day, or setanaxib 1600 mg/day according to a 
1:1:1 randomization ratio. 
This study is designed to detect a >25% reduction in ALP in setanaxib-treated patients 
versus a 2.5% reduction in the placebo arm with an overall 2-sided p<0.05. Standard 
deviations are assumed to be 19% and 24%, respectively, based on the Phase 2a study 
with setanaxib and the Phase 3 POISE study with Ocaliva. With approximately 
16 evaluable patients per arm (48 patients overall) and using a Hochberg step-up test to 
control alpha across 2 dose comparisons versus placebo, this study has 88.2% global 
power to detect at least 1 treatment arm as significantly different from placebo and 
68.3% power to detect both treatment arms as statistically significant. Also, for the 
secondary endpoint of change in fatigue, there will be >80% power to detect a 20% 
reduction in fatigue versus a 2.5% increase in the placebo arm. 
An assumed dropout rate of approximately 25% leads to a target sample size of 
66 enrolled patients (22 per arm). A range of approximately 60 to 70 enrolled patients 
allows for variability in the assumed dropout rate. 
8.4 
Statistical Methods 
8.4.1 
Analysis of Efficacy 
Efficacy data will be presented and analyzed using the FAS and a supplementary 
analysis will be performed using the PPS. 
8.4.1.1 
Primary Endpoint Analysis 
The primary endpoint is listed in Section 2.1. 
For the primary efficacy analysis, each setanaxib treatment group (1600 mg and 
1200 mg) will be compared with placebo. The primary estimand is to assess the change 
in ALP (%) over 24 weeks in patients with PBC, elevated liver stiffness, and intolerance 
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The following intercurrent events will be considered and further detailed in the SAP. 
Patients who start additional PBC-related medication(s) after Randomization will have 
their IMP discontinued (Section 6.7). These patients will be included in the analysis, 
but efficacy data collected after the start of the new therapy will be excluded. PBC-
related medication(s) will be identified through blinded medical review prior to 
database lock. For all other patients who discontinue from treatment prior to Week 24 
but return for the Week 24 Visit (Visit 8), the Week 24 result will be used regardless of 
the occurrence of the intercurrent event. Patients with missing results will have their 
values imputed based on observed data. Further details will be defined in the SAP. 
The primary endpoint will be evaluated using a mixed model for repeated measures 
(MMRM) with log(ALP) – log(Baseline) as response with log(Baseline) as a 
continuous covariate, ALP stratification (<3.0×ULN or ≥3.0×ULN), treatment and visit 
as categorical covariates and treatment by visit as interaction term. All ALP data 
captured at Weeks 2, 4, 8, 12, and 24 will be included in the model. The relative mean 
change from Baseline at Week 24 will be estimated and corresponding 2-sided 95% 
confidence intervals will be calculated. The relative mean change and confidence 
interval will also be converted to the percentage scale, for presentation purposes. 
An unstructured covariance matrix will be used to model the within-patient correlation 
of data. The Kenward-Roger’s degrees-of-freedom adjustment will be used. Restricted 
maximum likelihood will be used to obtain parameter estimates. The least squares 
means will be estimated by visit along with the associated 95% confidence intervals 
and p-values with the analysis taken from the estimate at 24 weeks. In the case of 
insufficient patients at either level of the stratification, the stratification factor will be 
removed from the model. 
Model assumptions of the MMRM will be assessed using residual plots (such as q-q 
plots, histograms, box plots, and scatter plots). If the model above does not converge, 
heterogeneous Toeplitz covariance structure will be used instead of the unstructured 
covariance matrix. If convergence still does not meet, the Toeplitz structure then will 
be used. 
8.4.1.2 
Multiplicity 
The null hypothesis is no difference in change in ALP (%) between setanaxib and 
placebo over 24 weeks. The alternative hypothesis is that setanaxib demonstrates a 
difference in change in ALP (%) over placebo. 
In order to control the study-wise error rate, that is, the probability of rejecting the true 
null hypothesis for the primary endpoint at 1-sided 0.025, a Hochberg step-up 
procedure will be applied to adjust for 2 dose comparisons versus placebo. 
For the analysis of secondary and exploratory endpoints, “nominal” p-values will be 
presented and will not be considered as part of the study-wise control of type I error. 
This is considered appropriate for an exploratory Phase 2b study. 


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8.4.1.3 
Sensitivity Analysis 
Sensitivity analyses to test the intercurrent strategy and the assumption of missing at 
random for the MMRM model will be defined in the SAP. 
In the case of outliers in the ALP data, a further sensitivity analysis will utilize robust 
regression; this will be defined in the SAP. 
8.4.1.4 
Supplementary Analysis 
The primary and secondary efficacy analyses will be repeated using the PPS, as defined 
in Section 8.2. 
8.4.1.5 
Secondary Endpoints 
The secondary efficacy endpoints, as appropriate, will be analyzed using the same 
approach as the primary analysis. 
As additional secondary endpoints, the 2 setanaxib dose arms will be combined for the 
analysis of change in ALP (%), change in fatigue, and change in liver stiffness and will 
be analyzed per the primary endpoint. 
8.4.1.6 
Exploratory Endpoints 
The exploratory endpoints are listed in Section 2.3. 
The analyses of the exploratory endpoints will be defined in the SAP. 
8.4.2 
Analysis of Safety 
The safety endpoints are listed in Section 2.2. 
The Safety Analysis Set will be used for the analysis of safety data (AEs, including 
AESIs, clinical laboratory tests, vital signs, 12-lead ECGs, and physical examination). 
AEs that occur, having been absent before the date and time of the first dose of the IMP, 
or have worsened in severity or seriousness after initiating the IMP until 30 days after 
the date and time of last dose of IMP will be classified as treatment-emergent AEs 
(TEAEs). The number of TEAEs and number and percentage of patients experiencing 
TEAEs will be summarized by treatment group, severity, and relation to IMP. TEAEs 
will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class (SOC) and preferred term. All AEs will be listed by patient. 
SAEs will be listed by patients and summarized by treatment group, MedDRA SOC, 
and preferred term. Summaries will also be presented by severity and relationship to 
IMP. 
Laboratory data (hematology, serum chemistry, and urinalysis) will be converted to 
Système International units for reporting and processing purposes. Absolute values and 
changes from Baseline will be presented descriptively. Laboratory data outside 
study-specific reference ranges will be listed. 


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Abnormal laboratory values will be listed by patient and summaries of the incidence 
and frequency by treatment group, scheduled visit, severity, and relationship to IMP 
will be presented. Shift tables of CTCAE (version 4.03) graded labs will be presented. 
WBC and reticulocyte counts will be expressed in absolute values. Differential count 
will be expressed as both absolute count and percentage of WBCs. Evaluation of drug-
induced serious hepatotoxicity (eDISH) analysis will be conducted in order to explore 
potential liver toxicity signals by treatment group. 
Vital signs and ECG parameters will be presented descriptively. Vital signs including 
pulse rate, SBP, and DBP and 12-lead ECG data will be summarized by treatment group 
and listed by patient. 
A summary of abnormal physical examination findings by treatment group and 
scheduled visit will be presented. 
8.4.3 
Demographic and Baseline Characteristics 
Demographic characteristics (including age, sex, ethnicity, and race) and Baseline 
characteristics (including height, weight, and disease characteristics) will be presented 
descriptively, overall and by treatment group. 
Discrepancies between randomization stratification information (obtained from IXRS) 
and strata formed based on Screening factors collected on eCRFs will be tabulated and 
listed. 
8.4.4 
Pharmacokinetic Analysis 
The PK Analysis Set will be used for PK Analyses. 
Plasma concentrations of setanaxib and GKT138184, along with blood sampling dates 
and actual blood sampling time relative to previous dosing time, will be listed by 
patient, dose group (ie, actual treatment), and nominal sampling time. Samples with 
time deviation from nominal time will be identified and listed. Plasma concentrations 
of setanaxib and GKT138184 will be summarized with descriptive statistics by actual 
treatment and nominal sampling time, and dose normalized, as appropriate. The 
descriptive statistics will include N, mean, standard deviation, coefficient of variation, 
geometric mean, median, Q1, Q3, minimum, and maximum. Mean plasma setanaxib 
and GKT138184 concentrations (dose normalized as appropriate) versus study visit will 
be plotted as a box plot. 
8.4.5 
Handling of Missing Values 
If there are missing ALP or fatigue data, imputation methods will be utilized. These 
will be described in the SAP. 
Imputation for missing partial dates of AEs and concomitant medication will be 
specified in the SAP. 


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9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
This study will be conducted in accordance with the Note for Guidance on GCP ICH 
Harmonised Tripartite Guideline E6 (R1)/Integrated Addendum E6 (R2); US FDA 
Code of Federal Regulations (CFR) (Title 21 Parts 50, 56, 312), requirements for the 
conduct of clinical studies as provided in the EU Directive 2001/20/EC; the general 
guidelines indicated in the Declaration of Helsinki; and all applicable regulatory 
requirements. 
9.2 
Institutional Review Board/Independent Ethics Committee 
Before initiating a study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRBs/IECs for the study protocol/amendment(s), 
written ICF(s), any ICF updates, patient recruitment procedures (eg, advertisements), 
and any written information to be provided to patients and a statement from the 
IRBs/IECs that these comply with GCP requirements (if applicable). A current copy of 
the IB should be included as part of the written application to the IRB/IEC. 
The IRB/IEC approval(s) must identify the protocol version as well as the documents 
reviewed. Any amendments to the protocol will require IRB/IEC approval before the 
implementation of the changes made to the study, except for changes necessary to 
eliminate an immediate hazard to the study patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings, including 
adverse drug reactions that are both serious and unexpected, as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to the 
requirements of all applicable regulations 
• Promptly reporting deviations from, or changes to, the protocol to eliminate 
immediate hazards to the study patients 
9.3 
Informed Consent 
In obtaining and documenting informed consent, the Investigator should comply with 
the applicable regulatory requirement(s) and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. Prior to the beginning 
of the study, the Investigator should have the IRB/IEC's written approval/favorable 
opinion of the written ICF and any other written information to be provided to study 
patients. 


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• The Investigator or his/her representative will explain the purpose and nature of the 
study as well as possible adverse effects to the patient or his/her legally acceptable 
representative and answer all questions regarding the study. 
• Patients must be informed that their participation is voluntary, and consent can be 
withdrawn at any point. 
• Patients or their legally acceptable representative will be required to sign a 
statement of informed consent that meets the requirements of US FDA CFR Title 
21 Part 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements in the US, and the IRB/IEC or study site. 
• Prior to a patient’s participation in the study, the written ICF should be signed and 
personally dated by the patient or by the patient's legally acceptable representative, 
and by the person who conducted the informed consent discussion. 
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent 
was obtained. 
• The original copy of the signed ICF will be retained at the study site. 
• A copy of the ICF and any other written information must be provided to the patient 
or the patient’s legally acceptable representative. 
• If the ICF is revised, the revised ICF must have received the IRB/IEC's 
approval/favorable opinion in advance of its use. Patients must be informed of the 
changes to the ICF and must re-consent to the most current version during their 
participation in the study. The patient or the patient’s legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation 
in the study. The communication of this information should be documented. 
In addition, patients will be required to document agreement for optional future genetic 
research. The patients will be informed about its purpose, confidentiality of test results, 
and will be asked for their authorization to perform the test. If the patient does not 
consent to the blood sample for future genetic testing, they may still participate in the 
study but will not have a blood sample taken for the future genetic testing. 
Patients will also be required to document agreement for optional future biomarker 
research. The Investigator (or authorized designee) will explain to each patient the 
objectives of the future biomarker research and will be asked for their authorization to 
collect the blood samples. Patients will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage 
period. If the patient does not consent to the blood samples for future biomarker 
research, they may still participate in the study but will not have the blood samples 
taken for the future biomarker research. 


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Patients will be required to document agreement for the use of remaining mandatory 
PK back-up samples for optional exploratory research. The Investigator (or authorized 
designee) will explain to each patient the objectives of the exploratory research. 
The samples will be used for research related to setanaxib and/or PBC and related 
diseases. They may also be used to develop tests/assays, including diagnostic tests 
related to setanaxib and/or IMPs of this drug class and PBC. The research may include 
genetic research and may consist of the analysis of one or more candidate gene(s) or 
the analysis of genetic markers throughout the genome or analysis of the entire genome. 
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period. A separate signature 
will be required to document a patient's agreement to allow any remaining PK back-up 
samples to be used for exploratory research. Patients who decline to participate in this 
optional research will not provide this separate signature. 
If a patient is unable to read or if a legally acceptable representative is unable to read, 
an impartial witness should be present during the entire informed consent discussion. 
The witness should sign and personally date the ICF after: 
• The written ICF and any other written information to be provided to patients is read 
and explained to the patient or the patient’s legally acceptable representative 
• The patient or the patient’s legally acceptable representative has orally consented 
to the patient’s participation in the study 
• The patient or the patient’s legally acceptable representative has signed and 
personally dated the ICF, if they are capable of doing so 
By signing the ICF, the witness attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the 
patient or the patient's legally acceptable representative, and that informed consent was 
freely given by the patient or the patient’s legally acceptable representative. 
9.4 
Adjudication Committee and Independent Data Monitoring Committee 
9.4.1 
Adjudication Committee 
The Adjudication Committee, who will remain blinded to patient treatment assignment, 
will adjudicate the AESIs (DILI, anemia, and hypothyroidism), and the following 
adverse clinical outcomes, which will require permanent IMP discontinuation: all-cause 
mortality, transplant list inclusion, MELD score of ≥15 (confirmed at repeat testing at 
least 14 days apart), variceal bleed, portal hypertension bleed, hepatic encephalopathy, 
spontaneous bacterial peritonitis, and uncontrolled ascites requiring treatment. These 
events will be adjudicated as defined in an Adjudication Charter. 
Expert adjudication of cases will be conducted using the CIOMS/RUCAM (Council for 
International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment 
Method) score, as well as detection of Hy’s Law cases. Data from eDISH analysis will 
be provided to the Adjudication Committee. 


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An aggregated list of adjudicated events will be regularly provided to the IDMC for 
review. 
The roles and responsibilities of the Adjudication Committee will be outlined in the 
Adjudication Charter. 
9.4.2 
Independent Data Monitoring Committee 
The IDMC will oversee the safety of participating patients. 
The IDMC will regularly review an aggregated list of events adjudicated by the 
Adjudication Committee. The frequency of review will be specified in the IDMC 
Charter. 
An eDISH analysis will be conducted for each predefined IDMC meeting in order to 
explore potential liver toxicity signals at the study cohort level. 
The IDMC may recommend change(s) to the setanaxib dose regimen(s), or interruption 
or discontinuation of an active treatment group(s) based on the regular IDMC safety 
data reviews, as defined in the IDMC Charter. 
The IDMC will include independent consultants, including an unblinded statistician 
and physicians, and will be supported by an IDMC Specialist and programmers, as well 
as any other functions detailed in the IDMC Charter. 
The role and responsibilities of the IDMC will be outlined in the IDMC Charter. 
9.5 
Financing and Insurance 
9.5.1 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and 
the CRO and/or Sponsor (or designee) will sign a clinical trial agreement prior to the 
start of the study, outlining overall Sponsor and Investigator responsibilities in relation 
to the study. The contract should describe whether costs for pharmacy, laboratory, and 
other protocol-required services are being paid directly or indirectly. 
9.5.2 
Insurance, Indemnity, and Compensation 
The Sponsor will maintain an appropriate clinical study insurance policy. 
9.5.3 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 


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10 RECORDS MANAGEMENT 
All clinical study information should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation, and verification. This principle applies to 
all records referenced in this protocol, irrespective of the type of media used. 
An eCRF will be used to store and transmit patient information. Information from the 
medical records (progress notes) and other source documents is to be promptly entered 
into the appropriate section of the eCRF. The eCRF must be reviewed and electronically 
signed and dated by the Investigator on an ongoing basis. The Investigator is 
responsible for verifying that the data entries are accurate and correct by signing the 
eCRF. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by 
authorized site personnel (eg, Investigators and the Study Coordinator). The eCRF must 
be completed as soon as possible after any patient evaluation or communication. If data 
are to be changed due to erroneous input or other reason, an electronic audit trail will 
track these changes. The eCRFs and computers that store them must be accessible to 
study monitors and other regulatory auditors. 
During each study visit, a physician participating in the study will maintain progress 
notes in the patient’s medical records to document all significant observations. At a 
minimum, these notes are to contain: 
• The date of the visit and the corresponding day or visit in the study schedule 
• General condition and status remarks by the patient, including any significant 
medical findings. The severity, frequency, duration, and resolution of any reported 
AE, and the Investigator's assessment as to whether the reported AE is related to 
IMP 
• Changes (including dosages) in concomitant medications/therapies (including 
medical foods) or procedures 
• A general reference to the procedures completed 
• Protocol deviations identified that could potentially affect safety and/or study 
results 
• The signature or initials of all physicians making an entry in the medical record 
(progress notes) 
In addition, any contact with the patient via phone or other means that provides 
significant clinical information is to also be documented in the medical record 
(progress notes), as described above. 
Changes to information in the medical record (progress notes) and other source 
documents are to be initialed and dated on the day the change is made by the 
Investigator (or designee). If the reason for the change is not apparent, a brief 


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explanation for the change is to be written adjacent to the change. Changes to the eCRF 
will be electronically tracked. 
The ICON data management department will write a Data Management Plan, which 
will be finalized prior to performing any data validation. 
10.1 
Source Documentation 
Source documents contain the results of original observations and activities of a clinical 
investigation. They are the original records in which raw data are first recorded. Source 
documents include, but are not limited to, medical records (progress notes), ECG and 
computer printouts, screening logs, completed scales, quality of life questionnaires, and 
recorded data from automated instruments. 
The Investigator/site personnel should maintain adequate and accurate source 
documents and study records that include all pertinent observations on each of the site’s 
study patients. Source data should be attributable, legible, contemporaneous, original, 
accurate, and complete. Changes to source data should be traceable, should not obscure 
the original entry, and should be explained if necessary (eg, via an audit trail). 
All source documents from this study are to be maintained by the Investigator and made 
available for inspection by authorized persons. The Investigator will provide direct 
access to source documents/data for study-related monitoring, audits, IRB/IEC review, 
and regulatory inspections. The Sponsor should verify that each patient has consented, 
in writing, to direct access to his/her original medical records for study-related 
monitoring, audit, IRB/IEC review, and regulatory inspection. 
10.2 
Case Report Form Completion and Data Management 
An eCRF will be used to store and transmit patient information. The file structure and 
format for the eCRF will be provided by the Sponsor or its representative and should 
be handled in accordance with the instructions provided. 
The eCRF must be reviewed and electronically signed and dated by the Investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by 
authorized site personnel (eg, Investigators and the Study Coordinator). The eCRF must 
be completed as soon as possible after any patient evaluation or communication. If data 
are to be changed due to erroneous input or other reason, an electronic audit trail will 
track the changes. The eCRFs and computers that store them must be accessible to study 
monitors and other regulatory auditors. Changes to the eCRF will be electronically 
tracked. 
Data will be entered/loaded into a validated electronic database using a clinical data 
management system. Computerized data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency of the data. 


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10.3 
Study Files and Record Retention 
All data derived from the study will remain the property of the Sponsor. The Sponsor 
assumes accountability for actions delegated to other individuals, eg, the CRO. 
Records must be retained in accordance with the current ICH Guidelines on GCP. 
All essential study documents, including records of study patients, source documents, 
eCRFs, and the IMP inventory, must be kept on file. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of setanaxib. However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the Sponsor. The Sponsor is responsible for 
informing the Investigator when these documents no longer need to be retained. 
The Investigator is not to dispose of any records relevant to this study without written 
permission from the Sponsor and is to provide the Sponsor the opportunity to collect 
such records. The Investigator shall take responsibility for maintaining adequate and 
accurate source documents of all observations and data generated during this study, 
including hard copy source documents and electronic imaging files, as applicable. Such 
documentation is subject to inspection by the Sponsor, its representatives, and 
regulatory authorities. 
If an Investigator moves, withdraws from a study, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the Sponsor. 


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11 AUDITING AND MONITORING 
Sponsor-assigned monitors will conduct regular site visits to the investigational 
facilities for the purpose of monitoring various aspects of the study, such as verifying 
that the ICFs were signed and dated before any study-specific procedure was 
performed, assessing patient enrollment, compliance with protocol procedures, 
completeness and accuracy of data entered into the eCRFs, verification of eCRF data 
against original source documents, and occurrence of AEs. The Investigator must agree 
to Sponsor-authorized personnel having direct access to the clinical (or associated) files 
and clinical study supplies (dispensing and storage areas) to ensure compliance with 
applicable regulations, and the Investigator will assist with the Sponsor’s monitoring 
activities. 
Quality control will occur at each stage of data handling to ensure that all data are 
reliable and have been processed correctly. The Sponsor should ensure oversight of any 
study-related duties and functions carried out on its behalf, including study-related 
duties and functions that are subcontracted to another party by the Sponsor’s contracted 
CRO(s). 
The eCRFs should be completed in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
Details describing the strategy, responsibilities, and requirements of the study 
monitoring are provided in the study Medical Monitoring Plan. 
The purpose of an audit is to assess whether ethics, regulatory, and quality requirements 
are being fulfilled. The Sponsor or its representative may conduct audits at the 
investigative sites including, but not limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of eCRFs with source 
documents. Government regulatory authorities may also inspect the Investigator during 
or after the study. The Investigator (or designee) should contact the Sponsor/CRO 
immediately if this occurs. All medical records (progress notes) must be available for 
audit. The Investigator must agree to participate with audits conducted at a convenient 
time in a reasonable manner. 
11.1 
Risk and Quality Tolerance Limits 
Perceived risks and quality tolerance limits (QTLs) will be identified and documented 
in the Protocol Risk Evaluation Plan before the start of the study. 
The Sponsor will review risk control measures periodically to ascertain whether the 
implemented quality management activities remain effective and relevant. The quality 
management approach and any important deviations from the predefined QTLs 
(and remedial actions adopted) will be described in the CSR. 
11.2 
Protocol Adherence and Deviations 
The Investigator and site personnel should conduct the study in compliance with the 
protocol and should use continuous vigilance to identify and report protocol deviations. 


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A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol that may be on the part of the Investigator, the site 
personnel, or the patient. 
Important protocol deviations are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient's rights, safety, or well-being. For example, important 
protocol deviations may include enrolling patients in violation of key eligibility criteria 
designed to ensure a specific patient population or failing to collect data necessary to 
interpret primary endpoints, as this may compromise the scientific value of the study. 
The Investigator should not implement any deviation from the protocol without 
agreement from the Sponsor and prior review and approval from the IRB/IEC of an 
amendment, except where necessary to eliminate an immediate hazard to a study 
patient, or when the change involves only logistical or administrative aspects of the 
study, such as a change in a monitor or phone number. 
In the event of an important protocol deviation, the Investigator will discuss the 
deviation with the Sponsor’s Medical Monitor and will come to an agreement as to 
whether the patient should be withdrawn from the study due to the important protocol 
deviation. 


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12 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study 
patients, may be made only by the Sponsor. A protocol change intended to eliminate an 
apparent immediate hazard to patients should be implemented immediately. 
Any permanent change to the protocol must be handled as a protocol amendment. 
The written amendment must be submitted to the IRB/IEC, and the Investigator must 
await approval before implementing the changes. The Sponsor will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
The current version of the ICF will require similar modification if the IRB/IEC, 
Investigator, and/or Sponsor, judge the amendment to the protocol to substantially 
change the study design and/or increase the potential risk to the patient and/or impact 
the patient's involvement as a study patient. In such cases, the ICF will be renewed for 
enrolled patients before their continued participation in the study. 


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13 STUDY REPORT AND PUBLICATIONS 
This study will be registered on ClinicalTrials.gov in accordance with applicable laws 
or publication policy and may also be registered on other publicly accessible websites, 
such as EudraCT (EU Drug Regulating Authorities Clinical Trials), as necessary. 
Two CSRs will be prepared. The first CSR will contain all results from this study, 
except for the results of genetic analyses, which will be reported separately. The 
Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the CSRs according to the applicable regulatory requirements. The 
Sponsor should ensure that the CSRs meet the standards of the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). 
The publication policy of the Sponsor is discussed in the Investigator's clinical trial 
agreement. 


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14 STUDY START AND TERMINATION 
The study start date is the date on which the first patient provides informed consent. 
The end of the study is defined as the last patient’s last assessment. 
Both the Sponsor and the Investigator reserve the right to terminate the study or 
the participation in the study at an Investigator’s site at any time. In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given 
to the protection of the patients’ interests. 
If the study is prematurely terminated or suspended for any reason, 
the Sponsor/Investigator/site personnel should promptly inform the study patients and 
should assure appropriate therapy and follow-up for the patients. Where required by the 
applicable regulatory requirements, the IRB/IEC should be informed promptly and be 
provided with a detailed written explanation of the termination or suspension. 
If the Investigator terminates or suspends a study without prior agreement of the 
Sponsor, the Investigator should inform the site personnel. The Investigator/site 
personnel should promptly inform the Sponsor and the IRB/IEC. The Investigator/site 
personnel should also provide the Sponsor and the IRB/IEC a detailed written 
explanation of the termination or suspension. 


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15 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not 
be disclosed to any person or entity not directly involved with the study unless prior 
written consent is gained from the Sponsor. However, authorized regulatory officials, 
IRB/IEC personnel, the Sponsor and its authorized representatives are allowed full 
access to the records. 
All study patients must be informed that their personal study-related data will be used 
by the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the patient, who will be required to give consent for their data 
to be used as described in the ICF. The patients must be informed that their medical 
records may be examined by auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. In case of any data security breach, this will be reported to authorities in 
line with local requirements. 
Identification of patients and eCRFs shall be by unique patient identification numbers 
(such as screening or randomization numbers) only. All personal identifiers according 
to applicable regulations (eg, name, phone number) must be redacted permanently by 
the site personnel and replaced with the patient’s unique identification number in all 
records and data before transfer to the Sponsor (or designee). 
All personal details will be treated as confidential by the Investigator and staff at ICON. 


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16 REFERENCES 
Aoyama T, Paik YH, Watanabe S, et al. Nicotinamide Adenine Dinucleotide Phosphate 
Oxidase in Experimental Liver Fibrosis: GKT137831 as a Novel Potential Therapeutic 
Agent. Hepatology. 2012 Dec;56(6):2316-27. 
Balasubramaniam K, Grambsch PM, Wiesner RH, et al. Diminished Survival in 
Asymptomatic Primary Biliary Cirrhosis. A Prospective Study. Gastroenterology. 
1990 Jun; 98(6):1567-71. 
Bedard K and Krause KH. The NOX Family of ROS-generating NADPH Oxidases: 
Physiology and Pathophysiology. Physiol Rev. 2007 Jan;87(1):245-313. 
Bettaieb A, Jiang JX, Sasaki Y, et al. Hepatocyte Nicotinamide Adenine Dinucleotide 
Phosphate Reduced Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin 
Sensitivity During Development of Steatohepatitis in Mice. Gastroenterology. 
2015 Aug;149(2):468-80. 
Beuers U, Gershwin ME, Gish RG, et al. Changing Nomenclature for PBC: 
From “Cirrhosis” to “Cholangitis”. Hepatology. 2015 Nov;62(5):1620-2. 
Boursier J, Zarski JP, de Ledinghen V, et al. Determination of Reliability Criteria for 
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Hepatology. 
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Cella D, Riley W, Stone A, et al. Initial Adult Health Item Banks and First Wave 
Testing of Patient-Reported Outcomes Measurement System (PROMISTM) Network: 
2005-2008. J Clin Epidemiol. 2010 Nov;63(11):1179-94. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical Response to Ursodeoxycholic 
Acid and Long-term Prognosis in Primary Biliary Cirrhosis. Hepatology. 
2008 Sep;48(3):871-7. 
Corpechot C, Carrat F, Gaouar F, et al. Liver Stiffness Measurement by Vibration-
Controlled Transient Elastography Improves Outcome Prediction in Primary Biliary 
Cholangitis. J Hepatol. 2022; Article in press. 
Dyson JK, Hirschfield GM, Adams DH, et al. Novel Therapeutic Targets in Primary 
Biliary Cirrhosis. Nat Rev Gastroenterol Hepatol. 2015 Mar;12(3):147-58. 
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: 
The Diagnosis and Management of Patients with Primary Biliary Cholangitis. J 
Hepatol. 2017 Jul;67(1):145-72. 
EuroQol Research Foundation. EQ-5D-5L User Guide. 2019. Version 3.0 dated 
Sept 2019. Available at: https://euroqol.org/publications/user-guides/. Last Accessed 
on 21 Mar 2021. 


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Herdman M, Gudex C, and Lloyd A, et al. Development and Preliminary Testing of the 
New Five-level Version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. 
Hirschfield GM and Gershwin ME. The Immunobiology and Pathophysiology of 
Primary Biliary Cirrhosis. Annu Rev Pathol. 2013 Jan; 8:303-30. 
Hirschfield GM, Gershwin 2, Strauss R, et al; PURIFI Study Group. Ustekinumab for 
Patients with Primary Biliary Cholangitis who have an Inadequate Response to 
Ursodeoxycholic Acid: A Proof-of-concept Study. Hepatology. 2016 Jul;64(1):189-99. 
Invernizzi P, Carbone M, Jones D et al. Setanaxib, a first-in-class selective NADPH 
oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, 
phase 2 trial. Liver Int. 2023;43:1507-22.  
Invernizzi P, Pencek R, Marmon T, et al. Integrated Efficacy Summary for Obeticholic 
Acid in Subjects with Primary Biliary Cirrhosis. J Hepatology. 2015 Apr;62(2):S778. 
Jacoby A, Rannard A, Buck D, et al. Development, Validation and Evaluation of the 
PBC-40, a Disease Specific Health Related Quality of Life Measure for Primary Biliary 
Cirrhosis. Gut. 2005 Nov;54(11):1622-9. 
Jiang JX, Chen X, Serizawa N, et al. Liver Fibrosis and Hepatocyte Apoptosis are 
Attenuated by GKT137831, a Novel NOX4/NOX1 Inhibitor In Vivo. Free Radic Biol 
Med. 2012 Jul;53(2):289-96. 
Jones D, Carbone M, Invernizzi P, et al. Impact of setanaxib on quality of life outcomes 
in primary biliary cholangitis in a phase 2 randomized controlled trial. Hepatol 
Commun. 2023 Feb 20;7(3):e0057. 
Kaplan MM and Gershwin ME. Primary Biliary Cirrhosis. N Engl J Med. 
2005 Sep;353(12):1261-73. 
Krause KH and Bedard K. NOX Enzymes in Immuno-inflammatory Pathologies. 
Semin Immunopathol. 2008 Jul;30(3):193-4. 
Lan T, Kisseleva T, Brenner DA. Deficiency of NOX1 or NOX4 Prevents Liver 
Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell 
Activation. PLoS One. 2015 Jul;10(7):e0129743. 
Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary 
Cholangitis. Clin Gastroenterol Hepatol. 2023;21:2076–2087. 
Liang S, Kisseleva T, Brenner DA. The Role of NADPH Oxidases (NOXs) in Liver 
Fibrosis and the Activation of Myofibroblasts. Front Physiol. 2016 Feb 2;7:17. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary Biliary Cirrhosis. Hepatology. 
2009 Jul;50(1):291-308. 


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Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice 
Guidance From the American Association for the Study of Liver Diseases. Clin Liver 
Dis (Hoboken). 2020 Jan;15(1):1-2. 
Murillo Perez CF, Ioannou S, Hassanally I, et al. Optimizing therapy in primary biliary 
cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and 
predicts survival. Liver Int. 2023; 43:1497-1506. 
Myers RP, Shaheen AA, Fong A, et al. Epidemiology and Natural History of Primary 
Biliary Cirrhosis in a Canadian Health Region: a Population-based Study. Hepatology. 
2009 Dec;50(6):1884-92. 
Nevens F, Andreone P, Mazzella G, et al. for the POISE Study Group. 
A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl 
J Med 2016 Aug;375(7):631-43. 
Nevens F, Trauner M, Manns MP. Primary biliary cholangitis as a roadmap for the 
development of novel treatments for cholestatic liver diseases. J Hepatol. 2023 
Feb;78(2):430-41. 
Paik YH, Kim J, Aoyama T, et al. Role of NADPH Oxidases in Liver Fibrosis. 
Antioxid Redox Signal. 2014 Jun;20(17):2854-72. 
Peters MG, Di Bisceglie AM, Kowdley KV, et al. Differences Between Caucasian, 
African American, and Hispanic Patients with Primary Biliary Cirrhosis in the United 
States. Hepatology. 2007 Sep; 46(3):769-75. 
Poupon R. Primary Biliary Cirrhosis: a 2010 Update. J Hepatol. 2010 May; 52(5):745-
58. 
Rudic JS, Poropat G, Krstic MN, et al. Ursodeoxycholic acid for Primary Biliary 
Cirrhosis. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: 
CD000551. 
Selmi C, Bowlus CL, Gershwin ME, et al. Primary Biliary Cirrhosis. Lancet. 
2011 May;377(9777):1600-9. 
Sood S, Gow PJ, Christie JM, et al. Epidemiology of Primary Biliary Cirrhosis in 
Victoria, Australia: High Prevalence in Migrant Populations. Gastroenterology. 
2004 Aug;127:470-5. 
Teixeira G, Muzi C, Guerardel A, et al. (2014) The NADPH Oxidase (NOX) Inhibitor 
GKT137831 Alleviates Liver Inflammation and Fibrosis in a Mouse Model of 
Non-alcoholic Steatohepatitis (NASH). Keystone Symposia Conference. Fibrosis: 
From Bench to Bedside, Keystone. 
Teixeira G, Szyndralewiez C, Molango S, et al. Therapeutic Potential of NADPH 
Oxidase 1/4 Inhibitors. Br J Pharmacol. 2016 Jun;174(12):1647-69. 


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Vilstrup H, Amodio P, Bajaj J, et al. (2014) Hepatic encephalopathy in chronic liver 
disease: 2014 Practice Guideline by the American Association for the Study of Liver 
Diseases and the European Association for the Study of the Liver. Hepatology. 2014 
Aug;60(2):715-35. 
 


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17 APPENDICES 
17.1 
APPENDIX I – Study Administrative Structure 
Sponsor: 
Calliditas Therapeutics Suisse SA 
Chemin des Aulx 14 
1228 Plan-les-Ouates 
Switzerland 
The Sponsor assumes the responsibilities of the trial Sponsor for 
regulatory purposes and will provide for required insurance. 
Operationally 
Responsible for Study 
conduct, Including 
Certain Sponsor 
Obligations: 
The Sponsor is a controlled subsidiary of Calliditas Therapeutics AB,  
a Swedish corporation with its registered office and mailing address at 
PO Box 70351, SE-107 24 Stockholm, Sweden and its principal office and 
address for courier delivery at Kungsbron 1, SE11122 Stockholm, Sweden 
(“Calliditas” and, with its controlled affiliates, the “Calliditas Group”).  
As such, the Sponsor applies standard operating procedures relating to 
clinical development, medical affairs, manufacturing, quality assurance, 
quality control, and pharmacovigilance of the Calliditas Group. 
Certain Calliditas Group managers, including the Calliditas Group Chief 
Medical Officer, have been delegated responsibility by Sponsor for 
Sponsor’s activities within their functional areas. 
Sponsor’s medical 
expert: 
Chief Medical Officer 
c/o Calliditas Therapeutics AB 
Mailing address: PO Box 70351, SE-107 24 Stockholm, Sweden 
Principal office and address for courier delivery: Kungsbron 1, SE11122 
Stockholm, Sweden 
Phone:  
CRO: 
ICON plc 
Corporate Headquarters 
South County Business Park 
Leopardstown, Dublin 18  
Ireland 
Phone (IRL): +353 1 291 2000 
Phone (US): +1 215 616 3000  
Fax: +353 1 247 6260 
Medical Monitor(s) 
The names and contact details of the study Medical Monitor(s) will be 
provided in the Key Study Team Contact List. 
Central Laboratory: 
Cerba Research 
Industriepark-Zwijnaarde 3 
9052 Ghent 
Belgium 
Phone: Refer to the central laboratory manual 
Pharmacokinetics 
Laboratory 
Unilabs York Bioanalytical Solutions 
Cedar House 
Northminister Business Park 
Upper Poppleton 
York 
Y026 6QR 
UK 
PBC-Related Biomarker 
(PRO-C3 and C3M) 
Laboratory 
Nordic Biosciences 
Herlev Hovedgade 207 
DK-2730 Herlev 
Denmark 


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Central Reader for 
Electrocardiogram 
ERT Clinical 
Peterborough Business Park 
Lynch Wood 
Peterborough 
PE2 6FZ 
UK 
Central Reading for 
Imaging (MRE) 
Perspectum Ltd 
Gemini One 
5520 John Smith Drive 
Oxford 
OX4 2LL 
UK 
Central Pathologist 
Review (Liver Biopsy) 
Cerba Research 
Industriepark-Zwijnaarde 3 
9052 Ghent 
Belgium 
Setanaxib and placebo 
manufacturer: 
Aptuit 
Via Alessandro Fleming, 4 
37135 Verona VR 
Italy 
Setanaxib and placebo 
Distributor of Drug 
Supplies: 
Almac Clinical Services 
9 Charlestown Road 
Seagoe Industrial Estate 
Craigavon 
BT63 5PW 
UK 
IXRS 
Almac 
25 Fretz Road 
Souderton PA 18964 
US 
eCRF 
Medidata 
12 Hammersmith Grove, 9th Floor 
Hammersmith, London 
W6 7AP 
UK 
A log of the name and title of the Investigators who are responsible for conducting the 
study, and the address and phone numbers of the study sites will be maintained. 
The names and addresses of any other laboratories involved in the study (further to 
those stated above) will be provided in the laboratory manual. 
 
 


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17.2 
APPENDIX II – Detection and Management of Suspected or Confirmed 
Cases of Drug-Induced Liver Injury 
Particular attention will be given to the detection and management of suspected or 
confirmed cases of DILI. 
If any of the following laboratory results or clinical signs or symptoms are obtained 
during the study, the Investigator will instruct the patient to return to the study center 
within 24 to 48 hours of receipt of the laboratory test results to undergo a retest. 
• AST or ALT ≥3×ULN 
• AST or ALT >2×Baseline 
• Total bilirubin >2×ULN 
• INR >1.5 (except for patients on anticoagulant therapy) 
• Clinical signs or symptoms that are, in the opinion of the Investigator, consistent 
with hepatitis (such as right upper quadrant discomfort, fever, fatigue, nausea, 
vomiting, jaundice, rash, or eosinophilia >5%) or drug-induced hepatotoxicity. 
Isolated eosinophilia >5% without clinical signs or symptoms that are consistent 
with hepatitis or hepatotoxicity by the Investigator’s medical judgment, should not 
be considered suspected DILI (sDILI). Retesting of eosinophilia (>5%) will only 
be required in case this is observed in combination with at least one of the other 
criteria listed above. 
Baseline values for liver tests (ALT, AST, and total bilirubin) are determined by 
averaging the values obtained at Screening and Baseline/Day 1 to obtain the arithmetic 
mean. 
The results of the Test and Retest will be checked to determine if they meet the criteria 
in A or B, which are based on the patient’s ALT and AST levels at Baseline, or C 
below: 
17.2.1 
Criteria for Close Monitoring of Liver Biochemistry and IMP Action 
A) For patients with ALT and/or AST <ULN at study start (Baseline Values), unless 
an alternative cause for the combination of laboratory abnormalities is immediately 
apparent (and documented) at the time of the laboratory test elevations in the 
opinion of the Investigator, close monitoring for sDILI (as described in 
Appendix II, Section 17.2.2) will be performed in patients with any of the following 
criteria (all confirmed by repeat testing): 
a. ALT or AST >3×ULN  
b. Total bilirubin >2×ULN 
c. INR >1.5 (except for patients on anticoagulant therapy) 


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d. Clinical signs or symptoms that are, in the opinion of the Investigator, 
consistent with hepatitis (such as right upper quadrant discomfort, fever, 
fatigue, nausea, vomiting, jaundice, rash, or eosinophilia >5% provided the 
latter is in combination with any of the other criteria listed under A-a, b, c 
or d). 
B) For patients with ALT and/or AST between ≥ULN and <3×ULN at study start 
(Baseline Values), unless an alternative cause for the combination of laboratory 
abnormalities is immediately apparent at the time of the laboratory test elevations 
in the opinion of the Investigator (and documented), close observation for DILI 
(as described in Appendix II, Section 17.2.2) will be performed in patients with any 
of the following criteria (all confirmed by repeat testing): 
a. ALT or AST >2×Baseline at any time (see Figure 2 for illustration) 
b. Total bilirubin >2×ULN 
c. INR >1.5 (except for patients on anticoagulant therapy) 
d. Clinical signs or symptoms that are, in the opinion of the Investigator, 
consistent with hepatitis (such as right upper quadrant discomfort, fever, 
fatigue, nausea, vomiting, jaundice, rash, or eosinophilia >5% provided the 
latter is in combination with any of the other criteria listed under A-a, b, c 
or d). 
During the close monitoring period in A and B, IMP can be continued, unless: 
• The patient is symptomatic in addition to having elevated laboratory parameters 
• Close Monitoring is not possible 
• Criteria C of Appendix II (see below) are met and no other cause for laboratory 
abnormalities is clinically apparent and documented by the Investigator in the 
study documents 
• At the discretion of the Investigator 
C) For patients meeting any of the following events, IMP will be discontinued when 
no other cause for the combination of laboratory abnormalities is immediately 
apparent: 
a. ALT or AST >5×Baseline  
b. ALT or AST >10×ULN 
c. ALT or AST >3×Baseline (see Figure 3 for illustration) with 1 or more of 
the following: 
i. Total bilirubin >2×ULN 


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ii. Total bilirubin >1.5×Baseline and >ULN 
iii. INR >1.5 (except for patients on anticoagulant therapy) 
iv. Appearance of clinical signs or symptoms that are, in the opinion of 
the Investigator, consistent with drug-induced hepatotoxicity 
d. ALT or AST >Baseline with any 2 or more of the following: 
i. Total bilirubin >2×ULN or 1.5×Baseline 
ii. INR>1.5 (except for patients on anticoagulant therapy) 
iii. Appearance of clinical signs or symptoms that are, in the opinion of 
the Investigator, consistent with drug-induced hepatotoxicity 
If the above criteria in C are met, the Investigator will instruct the patient to discontinue 
IMP administration and return to the study center within 2 days of receipt of the 
laboratory test results to undergo a retest and additional investigations (ie, close 
monitoring) to assess for sDILI. IMP cannot be reintroduced. 
Any suspected or confirmed DILI event, defined as events meeting the criteria in A, B, 
or C above, will be closely monitored by the Investigator and the IDMC and reported 
to the Sponsor as an AESI following the same procedure as for SAEs. 
Figure 2 
Triggers to Recheck and Interrupt Drug in Patients With ALT 
≤3×ULN at Baseline and No Symptoms 
 
ALT=alanine aminotransferase; ULN=upper limit of normal 


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Figure 3 
Triggers to Interrupt Drug in Patients With ALT ≤3×ULN at 
Baseline, and if (+) Symptoms or Abnormal INR or Bilirubin 
 
ALT=alanine aminotransferase; ULN=upper limit of normal 
 
17.2.2 
Close Monitoring 
1. Monitor patient twice or 3 times weekly until liver biochemistries (ALT, AST, 
ALP, total bilirubin), and coagulation profile (INR) resolve, stabilize or return to 
within Baseline values. Additional tests (eg, conjugated bilirubin) should also be 
obtained, as appropriate, at the discretion of the Investigator. 
2. Monitor liver biochemistries and coagulation profile once a week or less according 
to the Investigator’s judgment if the abnormalities stabilize, resolve or return to 
within Baseline values, or IMP has been discontinued and the patient is 
asymptomatic. 
3. Close Monitoring can be stopped based on the Investigator’s clinical judgment once 
the abnormalities stabilize, resolve or return to within Baseline values; or when 
there is an alternative documented cause to explain the deterioration. 
4. Obtain a detailed history for symptoms assessment: appearance or worsening of 
clinical symptoms of hepatitis (such as right upper quadrant discomfort, fever, 
fatigue, nausea, vomiting, jaundice, rash, or eosinophilia >5%). If a patient is 
symptomatic in addition to having elevated laboratory parameters, the drug must be 
discontinued immediately, and a suspected DILI evaluation must be performed. 
5. Obtain a more detailed history of prior or concomitant diseases. 


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6. Obtain a history for concomitant medications, acetaminophen, dietary supplements, 
herbal remedies, other over-the-counter medications, recreational drug use, and 
special diets. 
7. If possible, quantify the alcohol consumption to assess for alcoholic hepatitis. 
8. Obtain a history of exposure to environmental chemical agents. 
9. 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 suspected DILI evaluation criteria in A, 
B, or C (laboratory analyses are performed at the central laboratory): 
Viral hepatitis serology including: 
1. Hepatitis A IgM antibody. 
2. Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 
3. Hepatitis C RNA. 
4. Hepatitis E IgM antibody. 
5. Cytomegalovirus IgM antibody. 
6. Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); however, IgM antibodies must be sent 
out as soon as possible. 
Follow-up signs and symptoms consistent with potential immune mediated injury and, 
if relevant, monitor until the abnormalities resolve and to EoT Visit. 
1. Fever, malaise, pruritus, etc.  
2. Rash.  
3. Edema.  
4. Lymphadenopathy. 
5. Hematological changes (leukopenia, anemia, thromobocytopenia, etc.), urinalysis, 
ECG etc. 
6. Other organ involvement, in addition to liver (kidney, heart, lungs, etc.). 
Other laboratory tests and assessments including: 
1. Serum Creatine phosphokinase and lactate dehydrogenase. 
2. Fractionate bilirubin, if total bilirubin >2×ULN. 


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3. A liver biopsy at the discretion of the Investigator. 
4. Assess for peripheral eosinophilia. Investigators are also encouraged to obtain a 
skin biopsy in subjects who have liver enzyme elevation together with eosinophilia. 
5. Assess for hypoxic/ischemic hepatopathy, and biliary tract disease. 
As long as Criteria A, B or C are met WITHOUT identification and documentation of 
an alternative cause, these abnormal liver tests will be considered suspected DILI and 
be reported to the Sponsor as AESI and go for adjudication. Once an alternative cause 
has been identified and documented, for the laboratory abnormalities qualifying 
Criteria A, B, or C of Appendix II, the alternative clinical event is to be reported as an 
AE/SAE. 
In addition, undertake the following for patients who meet the stopping criteria for both 
ALT and total bilirubin OR experiences clinical symptoms of hepatitis: 
1. Antinuclear antibody, antismooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). Analyses are performed at the central laboratory. 
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 high 
performance liquid chromatography assay (quantifies potential acetaminophen 
contribution to liver injury in patients with definite or likely acetaminophen use in 
the preceding week). 
4. Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease at the discretion of the Investigator. 
 
 


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17.3 
APPENDIX III – MELD Score 
The MELD score will be calculated based on the results from the liver biochemistry 
(total bilirubin), biochemistry (creatinine, and sodium if MELD score >11), and 
hematology (INR) blood samples, according to the following formulas: 
a. MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum 
creatinine (mg/dL)] + 6.43 
b. When MELD>11: MELD–Na = MELD + 1.32×(137 – Na (mmol/L) – 
(0.033×MELD×(137 – Na (mmol/L)))) 
 
 
 


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17.4 
APPENDIX IV – West Haven Criteria and Clinical Description 
 
WHC 
including 
MHE 
Description 
Suggested Operative 
Criteria 
Comment 
Unimpaired 
No encephalopathy at all, 
no history of HE 
Tested and proved to be 
normal 
 
Minimal  
Psychometric or 
neuropsychological 
alterations of tests 
exploring psychomotor 
speed/executive 
functions or 
neurophysiological 
alterations without 
clinical evidence of 
mental change 
Abnormal results of 
established psychometric 
or neuropsychological tests 
without clinical 
manifestations 
No universal criteria for 
diagnosis 
Local standards and 
expertise required 
Grade I 
• Trivial lack of 
awareness 
• Euphoria or anxiety 
• Shortened attention 
span 
• Impairment of addition 
or subtraction 
• Altered sleep rhythm 
Despite oriented in time 
and space (see below), the 
patient appears to have 
some cognitive/behavioral 
decay with respect to his 
or her standard on clinical 
examination or to the 
caregivers 
Clinical findings usually 
not reproducible 
Grade II 
• Lethargy or apathy 
• Disorientation for time 
• Obvious personality 
change 
• Inappropriate behavior 
• Dyspraxia 
• Asterixis 
Disoriented for time (at 
least 3 of the followings 
are wrong: day of the 
month, day of the week, 
month, season, or year) ± 
the other mentioned 
symptoms 
Clinical findings variable, 
but reproducible to some 
extent 
Grade III 
• Somnolence to 
semistupor 
• Responsive to stimuli 
• Confused 
• Gross disorientation 
• Bizarre behavior 
Disoriented also for space 
(at least 3 of the following 
wrongly reported: country, 
state [or region], city, or 
place) ± the other 
mentioned symptoms 
Clinical findings 
reproducible to some 
extent 
Grade IV 
Coma 
Does not respond even to 
painful stimuli 
Comatose state usually 
reproducible 
HE=hepatic encephalopathy; MHE=minimal hepatic encephalopathy; WHC=West Haven Criteria 
All conditions are required to be related to liver insufficiency and/or portosystemic shunting. 
Source: Vilstrup et al 2014 
 
 
 


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17.5 
APPENDIX V – Child-Pugh Classification of Severity of Cirrhosis 
Modified Child-Pugh classification of the severity of liver disease according to the 
degree of ascites, the serum concentrations of bilirubin and albumin, the prothrombin 
time, and the degree of encephalopathy is assessed as described in the table below. 
A total Child-Turcotte-Pugh score of 5 to 6 is considered Child-Pugh class A (well-
compensated disease), 7 to 9 is class B (significant functional compromise), and 10 to 
15 is class C (decompensated disease). These classes correlate with one- and two-year 
patient survival: class A: 100% and 85%; class B: 80% and 60%; and class C: 45% and 
35%. 
 
Parameter 
Points assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin 
<2 mg/dL (<34.2 
µmol/L) 
2 to 3 mg/dL (34.2 to 
51.3 µmol/L) 
>3 mg/dL (>51.3 
µmol/L) 
Albumin 
>3.5 g/dL (35 
g/L) 
2.8 to 3.5 g/dL (28 to 
35 g/L) 
<2.8 g/dL (<28 
g/L) 
Prothrombin time (seconds 
over control) or 
<4 
4 to 6 
>6 
INR 
<1.7 
1.7 to 2.3 
>2.3 
Encephalopathy 
None 
Grade 1 to 2 
Grade 3 to 4 
INR=international normalized ratio. 
Source: https://www.uptodate.com/contents/image?imageKey=GAST%2F78401 
 

SAP_001.pdf: 
 
Confidential 
 
 STATISTICAL ANALYSIS PLAN (SAP) 
 
Title: 
TRANSFORM: A 24-week, Randomized, Placebo-
controlled, Double-blind, Phase 2b Trial of Setanaxib in 
Patients with Primary Biliary Cholangitis (PBC) and 
Elevated Liver Stiffness 
NCT number:  
NCT05014672 
Unique Protocol 
ID:  
GSN000350 
Document Date:  
27 June 2024 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 1 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved. 
 
Statistical Analysis Plan (SAP) 
 
Protocol Title: 
TRANSFORM: A 24-week, Randomized, Placebo-controlled, Double-
blind, Phase 2b Trial of Setanaxib in Patients with Primary Biliary 
Cholangitis (PBC) and Elevated Liver Stiffness 
Protocol Version No./Date: 
1.0/ 06-May-2021 
2.0/ 16-Dec-2021 
3.0/ 07-Apr-2022 
4.0/ 09-Feb-2023 
5.0/ 27-Sep-2023 
CRF Version No./Date: 
6.0/ 03-Aug-2023 
SAP Version No./Date: 
4.0/ 27 Jun 2024 
 
 Approvals 
Sponsor 
Sponsor Name: 
Calliditas Therapeutics Suisse SA 
Representative/ Title: 
 
Signature /Date: 
 
 
 
 
 
ICON 
Biostatistician / Title: 
 
Signature /Date: 
 
 
 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
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  Change History 
Version/Date 
Change Log 
0.1/17 August 2021 
Created as new 
0.2/20 December 2021 
Updated for Protocol Version 2.0 and Sponsor Comments on V0.1 
0.3/10 June 2022 
Updated to align with TFL shells 
0.4/3 October 2022 
Updated per Sponsor comments on V0.3 and FDA feedback on V0.2 
0.5/15 February 2023 
Updated per Sponsor comments on V0.4 and Protocol Amendment version 4.0 
1.0/17 February 2023 
Updated per Sponsor comments on V0.5 and moving to stable version. 
1.1/27 October 2023 
Updated per Protocol Amendment version 5.0 
1.2/01 November 2023 
Updated per Sponsor comments on V1.1 
2.0/02 November 2023 
Moving to stable version V2.0 from V1.2 
3.0/06 June 2024 
Updated per Sponsor comments on dry-run #1 
3.0/27 June 2024 
Updated per Sponsor comments on dry-run #2 
 
 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
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 Table of Contents 
 Approvals ................................................................................................................................................ 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents .................................................................................................................................... 3 
 Purpose ................................................................................................................................................... 5 
 Scope ...................................................................................................................................................... 5 
 Introduction ............................................................................................................................................. 5 
6.1 Changes from Protocol .................................................................................................................... 6 
 Study Objectives ..................................................................................................................................... 6 
7.1 Primary Objective ............................................................................................................................. 6 
7.2 Secondary Objectives ...................................................................................................................... 6 
7.3 Exploratory Objectives ..................................................................................................................... 6 
 Study Design ........................................................................................................................................... 6 
8.1 Sample Size Considerations ............................................................................................................ 8 
8.2 Randomization ................................................................................................................................. 8 
8.3 Types of Planned Analysis............................................................................................................... 9 
8.3.1 IDMC Analysis ....................................................................................................................... 9 
8.3.2 Interim Analysis (Not Applicable) ........................................................................................... 9 
8.3.3 Primary Analysis .................................................................................................................... 9 
 Study Endpoints ...................................................................................................................................... 9 
9.1 Primary Efficacy Endpoint ................................................................................................................ 9 
9.2 Secondary Efficacy Endpoints ......................................................................................................... 9 
9.3 Secondary Safety Endpoints ......................................................................................................... 10 
9.4 Exploratory Endpoints .................................................................................................................... 11 
9.5 Estimand Attributes ........................................................................................................................ 12 
9.6 Analysis Sets ................................................................................................................................. 12 
9.6.1 All Enrolled Analysis Set ...................................................................................................... 12 
9.6.2 Safety Analysis Set .............................................................................................................. 12 
9.6.3 Full Analysis Sets ................................................................................................................ 12 
9.6.4 Per Protocol Analysis Set  ................................................................................................... 12 
9.6.5 PK Analysis Set (PKS)......................................................................................................... 12 
 Conventions and Derivations .............................................................................................................. 13 
10.1 Baseline and Change from Baseline ........................................................................................... 13 
10.1.1 Baseline Values for Liver Biochemistry ............................................................................. 13 
10.1.2 Baseline Values for Patient Reported Outcome Assessments ......................................... 13 
10.1.3 Baseline Values for Other Endpoints ................................................................................. 13 
10.1.4 Baseline Values for Extension Phase ................................................................................ 13 
10.1.5 Change from Baseline ....................................................................................................... 13 
10.2 Study Day .................................................................................................................................... 14 
10.3 Visit Windowing ............................................................................................................................ 14 
10.4 Dates of First and Last Dose of Study Drug ................................................................................ 16 
10.5 Actual Treatment .......................................................................................................................... 16 
10.6 Prior and Concomitant Medications ............................................................................................. 16 
10.7 Adverse Events ............................................................................................................................ 17 
10.7.1 Treatment Period ............................................................................................................... 17 
10.7.2 Treatment-Emergent Adverse Events (TEAE) .................................................................. 17 
10.7.3 TEAE Leading to Discontinuation of Study ....................................................................... 18 
10.7.4 TEAE leading to IMP Withdrawal ...................................................................................... 18 
10.7.5 TEAEs Related to IMP ....................................................................................................... 18 
10.7.6 Duration of AEs .................................................................................................................. 18 
10.7.7 AESIs ................................................................................................................................. 18 
10.8 Imputation of Missing Dates ........................................................................................................ 18 
10.9 Adverse Clinical Outcomes .......................................................................................................... 18 
10.10 PBC Medication ......................................................................................................................... 19 


Statistical Analysis Plan (SAP)  
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10.11 PROMIS-Short Form-Fatigue 7b Daily ...................................................................................... 19 
10.12 PBC-40 Item Questionnaire ....................................................................................................... 20 
10.13 PROMIS-29 ................................................................................................................................ 21 
10.14 Worst Itch Numerical Rating Scale  ........................................................................................... 21 
10.15 PGIS and PGIC Fatigue and Pruritus ........................................................................................ 22 
10.16 EuroQoL 5-D Utility Index .......................................................................................................... 22 
10.17 Definition of LLOQ ..................................................................................................................... 22 
10.18 Imputation of Missing Data ........................................................................................................ 22 
 Interim Analyses (N/A) ........................................................................................................................ 23 
 Statistical Methods .............................................................................................................................. 23 
12.1 Subject Disposition ...................................................................................................................... 24 
12.2 Demographic and Baseline Characteristics ................................................................................. 25 
12.3 Treatments ................................................................................................................................... 25 
12.3.1 Medical and PBC Treatment History ................................................................................. 25 
12.3.2 Prior and Concomitant Medications ................................................................................... 26 
12.3.3 Extent of Study Drug Exposure ......................................................................................... 27 
12.4 Important Protocol Deviations ...................................................................................................... 28 
12.5 Efficacy Analyses ......................................................................................................................... 28 
12.5.1 Hypothesis Testing Strategy and Multiplicity ..................................................................... 28 
12.5.2 Primary Estimand .............................................................................................................. 29 
12.5.3 Secondary Estimands ........................................................................................................ 36 
12.5.4 Other Secondary Endpoints Analyses ............................................................................... 39 
12.5.5 Exploratory Endpoint Analysis ........................................................................................... 40 
12.5.6 Additional exploratory analyses ......................................................................................... 40 
12.6 Safety Analyses ........................................................................................................................... 40 
12.6.1 Adverse Events .................................................................................................................. 40 
12.6.2 Adjudicated Events ............................................................................................................ 42 
12.6.3 Laboratory Data ................................................................................................................. 42 
12.6.4 eDISH Analysis .................................................................................................................. 44 
12.6.5 Vital Signs .......................................................................................................................... 44 
12.6.6 Physical Examinations, ECGs, and Other Observations Related to Safety ...................... 44 
12.6.7 Liver Biopsy and Liver Histology ....................................................................................... 45 
12.7 Pharmacokinetics Analyses ......................................................................................................... 45 
12.8 Data Collected Under Protocol Version 1.0 ................................................................................. 45 
 References .......................................................................................................................................... 45 
 Glossary of Abbreviations ................................................................................................................... 47 
Appendix ..................................................................................................................................................... 50 
Appendix 1: Handling of Partial Adverse Event Dates ........................................................................ 50 
Appendix 2: Handling of Partial Medications Dates ............................................................................. 51 
Appendix 3: PROMIS-Short Form-Fatigue 7b Daily Scoring Tables ................................................... 52 
Appendix 4: PROMIS-29 V2.1 Scoring Tables .................................................................................... 53 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
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 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Calliditas Therapeutics Suisse SA Protocol GSN000350 Amendment 
version 5.0. 
 Scope 
This Statistical Analysis Plan outlines the following: 
• 
Study Objectives 
• 
Study Design 
• 
Study Estimands 
• 
Analysis Sets 
• 
Conventions and Definitions 
• 
Applicable Study Definitions 
• 
Statistical Methods 
 Introduction 
This SAP should be read in conjunction with the study protocol and case report forms (CRF). This version 
of the plan has been developed by ICON using the protocol version 5.0 dated 27-Sep-2023 and CRF 
version 6.0 dated 03-Aug-2023. Any further changes to the protocol or CRF that have an impact on the 
design, or the planned statistical analysis will require updates to the SAP. 
The TRANSFORM study was initiated as a randomized, placebo controlled, double-blind, adaptive Phase 
2b/3 study with a 52-week treatment period and a 52-week open-label extension period. Enrolment into the 
study has been significantly slower than predicted and the feasibility of conducting the study within an 
acceptable timeframe has proven challenging. This is considered related to new and more frequently used 
treatment options, such as obeticholic acid (OCA) and off-label use of fibrates. One consequence of this is 
that fewer subjects are meeting the inclusion criteria for alkaline phosphatase (ALP) ≥ 1.67*ULN. 
Considering the challenges, under protocol version 5.0, the study has been revised to a randomized, 
placebo-controlled, double-blind, Phase 2b study of setanaxib in 60-70 subjects with PBC and elevated 
liver stiffness, to assess the safety and efficacy of the 1200 mg and 1600 mg doses of setanaxib versus 
placebo over a 24-week treatment period. The primary endpoint has been amended to evaluate change 
in ALP (%) on a continuous scale at 24 weeks, rather than the originally planned (binary) composite 
endpoint of change in ALP and total bilirubin at 52 weeks which requires a significantly larger sample size. 
The secondary endpoints of change in fatigue and liver stiffness are retained, as is the composite endpoint 
of changes in markers of cholestasis. The rationale for a 52-week Extension Phase Treatment Period and 
for an interim analysis is no longer applicable; therefore, the Extension Period, the 12-week Follow-up 
Period and interim analysis have been removed. A detailed rationale for changes to the study design is 
described in Protocol Amendment version 5.0 Section 1.2. The results from this Phase 2b study will inform 
the future development of setanaxib in PBC.   
This SAP describes the statistical methods that will be used for the analysis of this Phase 2b study and for 
summarizing data captured under previous versions of the protocol (v1.0 to 4.0). The first version of the 
SAP was developed and submitted to the FDA in December 2021, prior to enrollment of the first subject. 
Since this time, the Investigators, Subjects in the study, Sponsor and ICON have remained blind to 
randomized treatment assignment.  Furthermore, team members operating in a blinded capacity have not 
been granted access to data concerning ALP and bilirubin values over the course of the study. 
Consequently, any modifications to the ongoing study have not been influenced in any manner by emerging 
data or results derived from the study. 
The final version of the SAP will be finalized before the database is locked; subsequent to this stage, team 
members working in a blinded capacity will undergo an unblinding process to reveal the actual randomized 
assignments. 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
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6.1 Changes from Protocol 
• 
Protocol Amendment version 5.0 Section 8.2: the definition of PPS is more clearly defined as all 
subjects in the FAS who do not have any important protocol deviations during the 24-week 
treatment period that would potentially affect the efficacy of the study drug. 
• 
Protocol Amendment version 5.0 Section 8.4.2 states that “Abnormal laboratory values will be listed 
by subject and summaries of the incidence and frequency by treatment group, scheduled visit, 
severity, and relationship to IMP will be presented.” Clinically significant abnormalities will be 
recorded as an adverse event (AE) and the severity/relationship to investigational medicinal 
product (IMP) will be recorded on the AE CRF page. However specific summaries of other abnormal 
laboratory values will not contain the assessment of relationship to the IMP or severity as this will 
not be collected in the laboratory database. 
 Study Objectives  
7.1 Primary Objective  
• 
To evaluate the effect of setanaxib on ALP at Week 24 in patients with PBC and with elevated liver 
stiffness and intolerance or inadequate response to ursodeoxycholic acid (UDCA) 
7.2 Secondary Objectives  
• 
To evaluate the effect of setanaxib on fatigue at Week 24 
• 
To evaluate the effect of setanaxib on liver stiffness at Week 24 
• 
To evaluate the effect of setanaxib on ALP, fatigue and liver stiffness at Week 24, where setanaxib 
doses are combined 
• 
To evaluate the effect of setanaxib on pruritus at Week 24 
• 
To evaluate the effect of setanaxib on markers of cholestasis at Week 24 
• 
To evaluate the safety and tolerability of setanaxib over a 24-week treatment period 
7.3 Exploratory Objectives 
• 
To evaluate the effect of setanaxib over a 24-week treatment period on markers of liver fibrosis, 
cholestasis, bile acid metabolism, and liver function 
• 
To evaluate the effect of setanaxib on adverse clinical outcomes 
• 
To further evaluate the effect of setanaxib on patient-reported outcomes 
• 
To determine the pre-dose plasma levels of setanaxib and its metabolite GKT138184 
 Study Design 
This revised study is a randomized, placebo-controlled, double-blind, parallel-group, multicenter, Phase 2b 
study assessing oral setanaxib administered as an add-on therapy in subjects with PBC, elevated liver 
stiffness, and intolerance or inadequate response to UDCA. Intolerance to UDCA is defined as subjects 
unable to tolerate the full-labelled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported 
gastrointestinal symptoms such as diarrhoea and abdominal pain. The safety and efficacy of 1200 mg/day 
and 1600 mg/day setanaxib will be assessed against matching placebo over up to 24 weeks of treatment. 
It is planned to enroll 60-70 subjects at approximately 80 to 130 investigational centers in North America, 
Europe, Israel, Australia, and New Zealand.  
Subjects enrolled under previous versions (1.0 to 4.0) of the protocol were eligible to receive 52 weeks of 
treatment in the randomized “Main Part” of the study and then consented to a further 52 weeks of treatment 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
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with setanaxib in the open-label “Extension Phase”. The SAP will describe how additional data already 
collected beyond the 24-week treatment period will be summarized.  
The study design is outlined in Figure 1. For the schedule of assessments, refer to Table 1 in the Protocol 
Amendment version 5.0.  
Figure 1: Study Design 
 
EoT=End-of-Treatment; V=Visit 
a The Independent data monitoring committee (IDMC) may recommend change(s) to the setanaxib dose regimen(s), 
or interruption or discontinuation of an active treatment group(s) based on the regular IDMC safety data reviews (as 
defined in the IDMC Charter). 
b Eligible subjects will be randomized to oral setanaxib 1200 mg/day, 1600 mg/day, or placebo, according to a 1:1:1 
randomization ratio. 
c Subjects who permanently discontinue IMP prior to Week 24 Visit (Visit 8) will have an EoT Visit 30 days after the 
last IMP dose, after which every possible effort should be made to complete the Week 24 Visit (Visit 8). 
 
The study will consist of a 4-week Screening Period, a 24-week Double-blind Treatment Period, and a 4-
week Follow-up Period. Under protocol version 5.0 (or later), the total duration of the study for subjects 
remaining in the study until their final follow-up assessment (end of treatment [EoT] visit 30 days after last 
investigational medicinal dose [IMP]) will be approximately 32 weeks (approximately 8 months). No interim 
analyses will be conducted. Unblinded safety data will be summarized by the unblinded programming team 
for the IDMC, for the purposes of ongoing safety review. 
Eligible subjects will be randomized to oral setanaxib 1200 mg/day, 1600 mg/day, or placebo, according to 
a 1:1:1 randomization ratio, stratified by Screening serum ALP < or ≥3.0×ULN. Refer to Section 8.2 for 
further details on the randomization in this study. 
Baseline assessments will be performed on Day 1 (Visit 3). Post-baseline assessments will be performed 
at Weeks 2 (Visit 4), 4 (Visit 5), 8 (Visit 6), 12 (Visit 7), and 24 (Visit 8). In addition, study subjects will be 
contacted by phone by the study site staff at Weeks 16 and 20. 
Following permanent IMP discontinuation at any time during any part of the study, subjects will undergo an 
EoT Visit 30 days after their last dose. If IMP is permanently discontinued the study assessments should 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
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continue until completion of the Week 24 Visit (Visit 8). If it is not feasible to complete all the visits, every 
possible effort should be made to complete the Week 24 Visit.  
The Investigator, the site personnel, the Sponsor and their representatives involved in monitoring and 
conducting the study, and the subjects will be blinded to treatment assignments until the database is locked 
and the study is unblinded for analysis.   
The IDMC will oversee the safety of participating subjects (see Protocol Amendment version 5.0 Section 
9.4.2). The role and responsibilities of the IDMC have been outlined in an IDMC Charter. An Adjudication 
Committee, who will remain blinded to subject treatment assignment, will adjudicate events requiring IMP 
interruption as per protocol and the adverse clinical outcomes (see Protocol Amendment version 5.0 
Section 9.4.1). The roles and responsibilities of the Adjudication Committee are outlined in an Adjudication 
Charter. 
8.1 Sample Size Considerations 
The primary efficacy endpoint is the change in ALP (%) over 24 weeks. It is planned to enroll approximately 
60 to 70 subjects. Subjects will be randomized and allocated to placebo, setanaxib 1200 mg/day, or 
setanaxib 1600 mg/day according to a 1:1:1 randomization ratio. 
This study is designed to detect a >25% reduction in ALP in setanaxib-treated subjects versus a 2.5% 
reduction in the placebo arm with an overall 2-sided p<0.05. Standard deviations are assumed to be 19% 
and 24%, respectively, based on the Phase 2a study with setanaxib and the Phase 3 POISE study with 
Ocaliva. With approximately 16 evaluable subjects per arm (48 subjects overall) and using a Hochberg 
step-up procedure (Benjamin and Hochberg, 1995; Section 12.5.1 for details) to control alpha across 2 
dose comparisons versus placebo, this study has 88.2% global power to detect at least 1 treatment arm as 
significantly different from placebo and 68.3% power to detect both treatment arms as statistically 
significant. Also, for the secondary endpoint of change in fatigue, there will be >80% power to detect a 20% 
(SD 20%) reduction in fatigue versus a 2.5% (23%) increase in the placebo arm. 
An assumed dropout rate of approximately 25% leads to a target sample size of 66 enrolled subjects (22 
per arm). A range of approximately 60 to 70 enrolled subjects allows for variability in the assumed dropout 
rate. 
8.2 Randomization 
The randomization schema remains unaffected by Protocol Amendment version 5.0. Eligible subjects 
enrolled according to Protocol Amendment version 5.0 will be randomly assigned to oral setanaxib 1200 
mg/day, 1600 mg/day, or placebo, according to a 1:1:1 randomization ratio, stratified by Screening serum 
ALP < or ≥3.0×ULN.  
Randomization will be performed via a centralized Interactive Web Response System (IXRS) contracted 
through Almac. At registration, the IXRS will assign a unique subject identification number that will be used 
on all of the subject’s eCRFs and serious adverse event (SAE) report forms. If a subject is rescreened (see 
Protocol Amendment version 5.0 Section 4.3), the rescreened subject should be assigned a new unique 
screening number.  
Any subjects who entered the Extension Phase under protocol versions 1.0 to 4.0 will have received the 
same setanaxib treatment dose they received during the first 52 weeks of study treatment (the Main Part). 
Subjects initially randomized to placebo will have been switched to setanaxib 1200 mg/day or 1600 mg/day 
according to a 1:1 randomization ratio in the Extension Phase. Randomization in the Extension Phase was 
not stratified. All subjects will have had a new randomization number assigned on enrollment into the 
Extension Phase, even if they were not re-randomized to a new treatment arm; this is to protect the blind 
for subjects prior to the completion of the double- part of the study.  
During the course of the study, the statistician and the programmers supporting the IDMC analysis will be 
unblinded and will remain separate from the wider project team throughout the life of the study. The 
randomization will be performed by the external IXRS provider, Almac. The blinded statistician supporting 
the study will have no access to the unblinded randomization schedule. The Investigator, the site personnel, 


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the Sponsor and their representatives involved in monitoring and conducting the study, the Adjudication 
Committee, and the subjects will be blinded to treatment assignments until the study is unblinded for the 
primary analysis. For full details refer to the Data Blinding and Documentation plan. 
8.3 Types of Planned Analysis 
8.3.1 IDMC Analysis 
The IDMC will oversee the safety of participating subjects. The IDMC will regularly review an aggregated 
list of events adjudicated by the Adjudication Committee. The IDMC will meet regularly over the life of the 
study for data review meetings as specified in the IDMC Charter. The IDMC may recommend change(s) to 
the setanaxib dose regimen(s), or interruption or discontinuation of an active treatment arm(s) based on 
the regular IDMC safety data reviews.   
During the study there will be at least 2 planned data review meetings. The first IDMC data review meeting 
took place after approximately 20 subjects have been randomized and the second review meeting will take 
place after approximately 50 subjects have been randomized. The frequency or number of meetings can 
be modified, as necessary, by the Sponsor and/or the IDMC. Study enrollment will not be halted during 
planned IDMC review of safety data.  
8.3.2 Interim Analysis (Not Applicable) 
The interim analysis is no longer applicable for this revised Phase 2b study.  
8.3.3 Primary Analysis 
The data cut-off for the primary analysis will occur when 60-70 subjects randomized have had the 
opportunity to complete or discontinue from the 24-week double-blind treatment period.  
The datasets extracted and cleaned for analysis will include all safety and efficacy data collected. 
• 
The datasets prepared for primary analysis will encompass all safety and efficacy data gathered 
during this period.  
• 
Data collected from 24-weeks to 52 weeks in the Main Part under protocol versions 1.0 to 4.0 will 
be descriptively summarized.  
• 
Data collected during the extension phase under protocol versions 1.0 to 4.0 will be presented in 
listings only.  
Once all outstanding data queries have been resolved or agreed as unresolvable after data cut-off and the 
analysis sets agreed, a soft lock of the database will occur when all week 24 data are available, and the 
primary analysis will be performed. Once all subjects have completed their end of treatment visit, a final 
hard lock of the database will occur, and no further updates can be made within the electronic data capture 
system. 
 Study Endpoints 
9.1 Primary Efficacy Endpoint  
The primary efficacy endpoint is the change in ALP (%) at Week 24 compared to Baseline.  
9.2 Secondary Efficacy Endpoints  
The secondary endpoints are: 
• 
Change in fatigue at Week 24 compared to Baseline, as assessed by  
o 
The Patient-Reported Outcomes Measurement Information System (PROMIS)-short form-
Fatigue 7b Daily 


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o 
the Patient’s Global Impression of Severity (PGIS) fatigue 
o 
the Patient’s Global Impression of Change (PGIC) fatigue  
o 
the PBC-40 questionnaire (PBC-40) fatigue domain 
• 
Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography 
(FibroScan®) 
• 
Change in ALP at Week 24 compared to Baseline, where setanaxib doses are combined 
• 
Change in fatigue at Week 24 compared to Baseline, as assessed by the PROMIS short form-
Fatigue 7b Daily, the PGIS fatigue, the PGIC fatigue, and the PBC-40 fatigue domain, where 
setanaxib doses are combined 
• 
Change in liver stiffness at Week 24 compared to Screening, as assessed by transient 
elastography (FibroScan®), where setanaxib doses are combined 
• 
Change in pruritus at Week 24 compared to Baseline, as assessed by the Worst Itch Numerical 
Rating Scale (WI-NRS), the PBC-40 itch domain, and the PGIS and the PGIC pruritus 
• 
Changes in markers of cholestasis as assessed by proportion of subjects at Week 24 with: 
o 
ALP reduction to <1.67×ULN and total bilirubin ≤1xULN and a ≥15% or ≥30% or ≥40% or ≥70% 
ALP reduction from Baseline, respectively 
o 
ALP reduction to <1.5×ULN and total bilirubin ≤1xULN and with a ≥40% ALP reduction from 
Baseline 
o 
ALP<1xULN and total bilirubin ≤1xULN 
o 
Total bilirubin <0.6×ULN 
9.3 Secondary Safety Endpoints  
• 
AEs. Monitoring for AEs at all Visits 
• 
AEs of special interest (AESIs): 
o 
Drug-induced liver injury (DILI) 
o 
Anemia  
o 
Hypothyroidism 
• 
Laboratory tests: 
o 
Hematology 
o 
Biochemistry 
o 
Urinalysis 
o 
Thyroid function 
• 
Vital Signs 
• 
12-lead electrocardiograms (ECGs): clinically significant abnormalities 
 


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9.4 Exploratory Endpoints  
• 
Changes in markers of liver fibrosis, as assessed by Enhanced Liver Fibrosis (ELF) score, PRO-
C3 (released N-terminal propeptide of Type III collagen), C3M (a peptide of helical collagen Type 
III degradation), and PRO-C3/C3M ratio at Week 24 compared to Baseline 
• 
Changes in total and conjugated bilirubin over 24 weeks compared to Baseline 
• 
Changes in markers of bile acid metabolism, as assessed by total bile acids, C4 (C4=7α-OH-4-
cholesten-3-one), fibroblast growth factor (FGF)19, and FGF21 over 24 weeks compared to 
Baseline 
• 
Changes in markers of liver function over 24 weeks compared to Baseline, as assessed by: 
o 
Serum fibrinogen, albumin, and international normalized ratio (INR) 
o 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl 
transpeptidase (GGT), high sensitivity C-reactive protein (hsCRP), and immunoglobulin M 
(IgM) indicating liver inflammation and injury 
• 
Assessment over a 24-week period of: 
o 
All-cause mortality 
o 
Proportion of subjects requiring a liver transplant (transplant list inclusion) 
o 
Proportion of subjects with a Model for End Stage Liver Disease (MELD) score of ≥15 
o 
Proportion of subjects with new onset of variceal/portal hypertension bleed and/or hepatic 
encephalopathy (West Haven criteria), spontaneous bacterial peritonitis, and ascites 
requiring treatment 
• 
Change over a 24-week period compared to Baseline in: 
o 
Social isolation symptoms, as assessed by the PBC-40 social domain 
o 
Overall health-related quality of life, as assessed by the PROMIS-29 questionnaire 
o 
EuroQol 5-dimension (EQ-5D) Utility Index 
• 
Predose plasma concentrations of setanaxib and GKT138184 over a 24-week period 
Secondary and exploratory endpoints captured for subjects who entered the extension phase under 
protocol versions 1.0 to 4.0 are described in protocol V4.0. 
 
 


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9.5 Estimand Attributes 
The primary and secondary estimands are described in section 12.5.2. 
9.6  Analysis Sets 
9.6.1 All Enrolled Analysis Set 
The All Enrolled analysis set (ENRL) consists of all subjects who signed informed consent for this study. 
The ENRL set will be used for summaries of disposition data. 
9.6.2 Safety Analysis Set 
The safety analysis set (SS) will include all randomized subjects who receive at least 1 tablet of IMP or 
placebo. Subjects included will be analyzed based on actual treatment initially received.  
Safety data collected from subjects who entered the extension phase will be listed only. 
9.6.3 Full Analysis Sets 
The Full Analysis Set (FAS) will include all subjects who receive at least 1 tablet of IMP or placebo during 
the randomized part and have at least 1 post-baseline ALP value for the primary endpoint. Subjects 
included will be analyzed based on the treatment group they were randomized to regardless of the actual 
treatment received.  
The FAS will be used for summaries of baseline data, efficacy data, and markers of liver fibrosis. Efficacy 
data collected from subjects who entered the extension phase will be listed only. 
9.6.4 Per Protocol Analysis Set  
Per Protocol analysis set (PPS) comprises of all subjects in the FAS who do not have any important protocol 
deviations during the 24-week treatment period that would potentially affect the efficacy of the study drug. 
Subjects will be analyzed based on the treatment group they were randomized to regardless of the actual 
treatment received. 
Important protocol deviations are defined in the Protocol Deviation Guidance Document for the study. Prior 
to database lock and unblinding of the study, a blinded data review of the important protocol deviations 
(including programmatically determined deviations) will be performed to identify the important deviations 
impacting on the efficacy endpoints. This analysis set will be defined in a blinded manner prior to unblinding 
the study and agreed with Sponsor. 
Deviations impacting efficacy that may lead to exclusion from the PPS will include: 
• 
Deviations related to inclusion/exclusion criteria 
• 
Incorrect treatment received (i.e. the actual treatment received is different to the initially randomized 
treatment at any point during the first 24-weeks of treatment) 
• 
Non-compliance with study drug intake (≤80%) during the first 24-weeks of treatment 
• 
Efficacy assessments at Week 24 performed significantly out of the protocol specified window 
• 
Missing baseline data for the primary endpoint  
• 
Use of prohibited concomitant medication that could have impacted the efficacy of study treatment. 
9.6.5 PK Analysis Set (PKS) 
PKS includes all subjects who receive at least 1 dose of setanaxib and have at least 1 measured 
concentration at a scheduled PK time point post-dose. Subjects may be excluded if they have an important 
AE or protocol deviations that may affect PK. 


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 Conventions and Derivations 
10.1 Baseline and Change from Baseline 
10.1.1 Baseline Values for Liver Biochemistry 
Baseline values for liver biochemistry (ALP, ALT, AST, total and direct bilirubin, and GGT) are 
determined by the geometric mean of the last (up to) 3 measurements preceding the first administration of 
study drug. This includes unscheduled and screening visits. The formula for the geometric mean (GM) 
given three measurements a, b, and c is expressed as follows: 
𝐺𝐺𝐺𝐺= exp(log(𝑎𝑎) + log(𝑏𝑏) + log(𝑐𝑐) /3) 
For subjects who have records for both Screening/Visit 1 and Baseline Visit 3, the baseline will be 
calculated as the geometric mean of these two values. If there is an additional unscheduled pre-dose 
result, the geometric mean will be calculated using up to three values. 
For subjects who have records for Screening/Visit 1, Screening/Visit 2, and Baseline Visit 3, the 
Screening/Visit 1 result should be disregarded due to the subject's re-screening. The baseline should be 
calculated as the geometric mean of the Screening/Visit 2 and Baseline Visit 3 results. If there is an 
additional unscheduled pre-dose result, the geometric mean should include up to three values. 
10.1.2 Baseline Values for Patient Reported Outcome Assessments 
For the Patient Reported Outcome (PRO) assessments PROMIS-short form-Fatigue 7b Daily, PGIS 
Fatigue and Pruritus and WI-NRS introduced in protocol version 2.0, subjects enrolled under protocol 
version 1.0 will not have a baseline value collected. The baseline value for subjects enrolled under version 
1.0 for these questionnaires will be imputed prior to analysis (Section 12.5.3). For the PBC-40, only the 
recall period was changed and the baseline value captured under protocol version 1.0 is considered 
relevant. 
10.1.3 Baseline Values for Other Endpoints 
For all other efficacy and safety endpoints, baseline is defined as the last non-missing assessment obtained 
prior to the first administration of study drug. Where time of assessment is not collected and the assessment 
is collected on the same date as the first dose of IMP, the assessment will be assumed to be per protocol 
i.e. prior to first dose administration. If multiple continuous assessments for safety and efficacy endpoints 
occur on the same day as first dose and no time is recorded, the arithmetic mean will be used as baseline. 
If multiple categorical assessments occur on the same day as first dose and no time is recorded, the worst 
severity will be used as the baseline value.  
10.1.4 Baseline Values for Extension Phase 
For subjects enrolled into the Extension Phase under protocol versions 1.0 to 4.0, “Extension Baseline” 
value will be defined as the value obtained prior to receiving the first dose of the active treatment. Thus, for 
subjects who were initially randomized to receive placebo and then switched to setanaxib in the extension 
phase, the value obtained prior to receiving the first administration of active drug will be the extension 
baseline value. 
10.1.5 Change from Baseline 
If the value at baseline and at post-baseline timepoint are not missing, change from baseline at any post-
baseline time point will be defined as: 
𝐶𝐶ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏= 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 
Percentage change from baseline at any post-baseline time point will be defined as: 


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𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏= 100 ∗(𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏)
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
 
Fold change from baseline at any post-baseline time point will be defined as the below ratio: 
𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏= 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
 
For the primary endpoints, reductions in ALP from baseline will be defined as: 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑖𝑖𝑖𝑖 𝐴𝐴𝐴𝐴𝐴𝐴 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 = 100 ∗(𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝)
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
 
10.2 Study Day 
Study Day 1 is defined as the first date of study treatment.  
• 
For dates prior to Study Day 1, the Study Day is calculated as: 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷 = (𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼/𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 –  𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷 1) 
• 
For dates on or post Study Day 1,  
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷 = (𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼/𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 –  𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷 1)+1 
If the patient was never treated, the date of randomization will be used in lieu of the first date of study 
treatment in the above calculations.  
For subjects enrolled into the Extension Phase under protocol versions 1.0 to 4.0, study day in the Extension 
Phase may be defined from the date of first dose of setanaxib in the extension phase. 
10.3 Visit Windowing  
Subjects may not be able to attend visits on protocol specified days. For the purposes of the analysis, 
observations will be assigned to analysis windows (Tables 1a and 1b). Table 2 displays the analysis 
windows to be applied for any subjects enrolled under protocol versions 1.0 to 4.0 and entered in the 
extension phase. 
Tabulations will summarize scheduled time points only. All visits (including unscheduled and EoT visits) will 
be windowed to the appropriate analysis visit regardless of the visit label entered in the eCRF.   
For the efficacy data (including a selection of the liver functions tests, liver stiffness as assessed by 
fibroscan and QoL), 
• 
If more than one measurement falls within a visit window, the geometric mean (for ALP, ALT, AST, 
total and direct bilirubin, GGT and liver stiffness) and arithmetic mean (for QoL) of all measurements 
within the window will be used in the analysis. 
• 
For the same endpoints described above, if data for the week 24 assessment is missing, but an 
EOT result at week 28 is available, the week 24 result will be substituted by the week 28 result. 
The week 28 result will also be retained in summary tables. 
• 
For a small number of patients (<5) who had liver stiffness values captured at week 8 without a 
further assessment at week 12, the week 8 result will be carried forward to week 12 in the analysis. 
The week 8 result will also be retained in summary tables. 
• 
For QoL assessment collected using a daily diary over multiple days prior to the visits (including 
WI-NRS and PROMIS-Short Form-Fatigue 7b Daily), the last assessment within the window will be 
used to define the analysis visit for each assessment.  When deriving the baseline, the 7 days prior 
to the start of treatment will be included. If the questionnaire was incorrectly completed over 8 or 
more days, the additional records will not be included in the calculation of baseline. For post-


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baseline assessments, if there are 8 recorded collected, they will be included in the calculation of 
arithmetic means. 
 
For all other assessments (including all other liver function tests captured in Table 8 [serum fibrinogen, 
albumin, hsCRP and IgM]), the value closest to the target day will be selected for use in the analysis. If 
more than one assessment is equidistant from the target day, the assessment later in time will be selected. 
If there is more than 1 record on the selected day, the arithmetic mean of the continuous assessments will 
be applied, or the worst assessment (for categorical parameters) will be selected. If there is an EoT 
assessment and a scheduled assessment within a time point, the scheduled assessment should always be 
selected for use in the analysis. For analysis for determination of worst case values, for example shift tables 
to the worst post-baseline value, all post-baseline values collected during the time period defined by the 
analysis set, including unscheduled visits, will be considered. 
Table 1a: Analysis Windows for Main Part  
Analysis Visit 
Target Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
 
1 (pre-dose) 
Day 1 
1 (post-dose) 
 
 
Week 2 
15 
2 
22 
Week 4 
29 
23 
43 
Week 8 
57 
44 
71 
Week 12 
85 
72 
127 
Week 24 
169 
128 
183 
Week 28 - EOT  
196 
184 
225 
 
 
Table 2b: Analysis Windows for Main Part for ADQS domains (PROMIS-Short Form Fatigue 7b Daily, PBC-
40, PROMIS-29, EQ5L, PGIC, PGIS and WI-NRS) 
 
Analysis Visit 
Target Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
 
1 (pre-dose) 
Day 1 
1 (post-dose) 
 
 
Week 4 
29 
2 
71 
Week 12 
85 
72 
127 
Week 24 
169 
128 
183 
Week 28 - EOT  
196 
184 
225 
 
 
Table 3: Analysis Windows for data collected under protocol versions 1.0 to 4.0, including Extension Phase 
(EP) 
Analysis Visit 
Target EP Study Day 
Lower Limit 
Upper Limit 
Week 36 
253 
226 
309 
Week 52 
365 
310 
460 


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Extension Baseline 
1 
 
1 (pre-dose in Extension)* 
Week 68/Week 16 Extension 
113 
2 
155 
Week 80/Week 28 Extension 
197 
156 
239 
Week 92/Week 40 Extension 
281 
240 
323 
Week 104/Week 52 Extension 
365 
324 
407 
*for subjects on Placebo in the Main Part. Study day is relative to first dose in the Extension Phase. 
10.4 Dates of First and Last Dose of Study Drug  
The date of first dose of IMP will be the first dose date recorded on the Study Drug page of the CRF. The 
date of the first dose of IMP in the Extension Phase, will be the first dose date on the Study Drug 
Administration (Extension Phase) page of the CRF. 
If no date of first dose of IMP is available and the subject was not treated, date of first dose of IMP will be 
missing and the date of randomization will be used in any calculations requiring treatment start date. 
Date of last dose of IMP will be the date collected as the completion/discontinuation date on the End of 
Treatment page of the CRF. If date of last dose of IMP is not available and subject is lost to follow-up based 
on End of Treatment CRF page, date of last scheduled visit or date of last telephone contact where a dose 
is recorded, will be used as the date of last dose of IMP. 
Subjects who entered the Extension Phase under protocol versions 1.0 to 4.0 will have no End of Treatment 
page completed after completion of the randomized part. For these subjects, date of the last dose of IMP 
in the randomized part will be the day prior to the date of the first dose of IMP in the Extension Phase. 
10.5 Actual Treatment 
To determine the actual treatment in the study for the purpose of safety analysis, subjects will have actual 
treatment assigned as the dose the subject first received regardless of any dispensing issues at a later visit. 
For example, if a subject was randomized to placebo but the subjects first dispensed dose in the study was 
active treatment, they will be assigned actual treatment as the active arm they first received, even if they 
were later dispensed placebo at all remaining visits. 
For subjects entered in the Extension Phase under protocol versions 1.0.to 4.0, subjects on placebo will 
have actual arm in the Extension Phase set to the active dose they first receive in the extension phase 
regardless of the active dose they were randomized to. Subjects in the active arm, will remain assigned the 
actual treatment in the Extension Phase they first had dispensed. 
10.6 Prior and Concomitant Medications 
Prior medications will be defined as those medications which started prior to the first administration of study 
drug. 
Concomitant medications will be defined as medications starting prior to but ongoing after first 
administration of IMP or with a start date on or after first dose of IMP in the randomized part.  
Concomitant medications for the Extension Phase will be defined as medications starting prior to but 
ongoing after first administration of IMP in the Extension Phase or with a start date on or after first dose of 
IMP in the Extension Phase.  
Medications which start prior to the first dose of IMP and are ongoing at the time of first dose of IMP will be 
summarized as both prior and concomitant medications. 


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10.7 Adverse Events 
10.7.1 Treatment Period 
The analysis of safety assessments over the 24-week treatment period (Week 24 + 30 days) will be 
conducted: 
• 
For patients enrolled under protocol version 5.0 or later who complete the 24-week treatment 
period, a Week 28 (EoT) visit will occur 30 days after the date and time of last dose of IMP. All 
safety data will be analyzed. 
• 
For patients enrolled under protocol versions 1.0 to 4.0, treatment may have continued beyond 
Week 24.  Regardless, the safety data will be cut at Week 28 (Week 24 + 30 days) to ensure a 
consistent safety follow-up period for all patients. 
This approach enables the evaluation of the safety and tolerability of setanaxib over a 24-week treatment 
period, consistent with the study objectives. 
The analysis of safety assessments over the 52-week treatment period (Week 52 + 30 days) will also be 
conducted: 
• 
Patients enrolled under protocol version 5.0 will contribute safety data up to Week 28 only. All 
safety data will be analyzed. 
• 
For patients enrolled under protocol versions 1.0 to 4.0 who complete the 52-week treatment period 
and do not enter the extension phase, a Week 56 (EoT) visit will occur 30 days after the date and 
time of last dose of IMP. All safety data will be analyzed. 
• 
For patients enrolled under protocol versions 1.0 to 4.0 who entered the extension phase, the safety 
data will be cut at Week 56 (Week 52 + 30 days) to ensure a consistent safety follow-up period for 
all patients. 
This approach enables the evaluation of the safety and tolerability of setanaxib over the whole randomized 
treatment period and provides longer-term safety information. This approach will be applied to other safety 
endpoints. 
Note: For the analysis of study drug exposure and compliance (Section 12.3.3), the last dose of IMP in the 
24-week treatment period will be cut at week 24, and the last dose in the 52-week treatment period (for 
subjects who received more than 24 weeks of treatment) will be cut at week 52. "+ 30 days" will not be 
considered in the drug exposure and compliance. 
10.7.2 Treatment-Emergent Adverse Events (TEAE) 
The treatment emergent period will be defined in two ways: 
(1) TEAEs over a 24-week treatment period will be defined as AEs that occur, having been absent before 
the date and time of the first dose of the IMP, or have worsened in severity or seriousness after initiating 
the IMP until Week 28 (Week 24 + 30 days) in the 24-week treatment period.  
For patients enrolled under protocol versions 1.0 to 4.0, the AEs that occur, or have worsened in severity 
or seriousness after Week 28 (Week 24 + 30 days) will NOT be taken into consideration in TEAEs over a 
24-week treatment period. 
(2) TEAEs over a 52-week treatment period will be defined as AEs that occur, having been absent before 
the date and time of the first dose of the IMP, or have worsened in severity or seriousness after initiating 
the IMP until Week 56 (Week 52 + 30 days) in the 52-week treatment period. 
For patients enrolled under protocol versions 1.0 to 4.0 who entered the extension phase, the AEs that 
occur, or have worsened in severity or seriousness after Week 56 (Week 52 + 30 days) will NOT be taken 
into consideration in TEAEs over a 52-week treatment period. 
TEAEs will be assigned to the Extension Phase based on AE start date: 


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• 
If the start date of the TEAE is on or after the first dose in the Extension Phase, the TEAE will be 
assigned to the Extension Phase.  
10.7.3 TEAE Leading to Discontinuation of Study 
A TEAE will be classified as a TEAE leading to discontinuation of the study if the answer to the question 
“Did the adverse event cause the subject to be discontinued from the study?” is Yes on the AE CRF page. 
10.7.4 TEAE leading to IMP Withdrawal 
A TEAE will be classified as  
• 
a TEAE leading to study drug withdrawal if the answer to the question “Action Taken with Study 
Treatment” on the AE CRF page is “Drug Withdrawn” or “Unknown”. 
and/or 
• 
a TEAE leading to treatment discontinuation if the answer to question “Reason for Discontinuation” 
on the End of Treatment CRF page is “Adverse Event”.  
10.7.5 TEAEs Related to IMP 
A TEAE will be classified as related to IMP if the relationship to study treatment is indicated as Related on 
the AE CRF page. Additionally, if the relationship is missing, then the TEAE will be deemed related. 
10.7.6 Duration of AEs 
Duration of AEs will be calculated as AE end date – AE start date + 1. AE duration will only be calculated 
when complete dates for the start and stop date are provided. 
10.7.7 AESIs 
An AE will be classified as an AESI is the question “Is this event of special interest?” is marked as Yes on 
the CRF. 
10.8 Imputation of Missing Dates 
For the purposes of assigning events as on-treatment or medications as prior/concomitant imputation of 
partial dates will be performed. The rules for imputation for AEs and medications are outlined in Appendix 
1 and  2 respectively. 
The duration of events and time to onset if applicable will not be calculated if start or stop date is partial or 
missing. Listings will display the collected date and not the imputed date.  
10.9 Adverse Clinical Outcomes 
A subject has an adverse clinical outcome if any of the following criteria are met: 
• 
Death 
• 
Transplant list inclusion 
• 
MELD score ≥ 15 (confirmed at repeat testing at least 14 days apart) 
• 
Variceal blead 
• 
Portal hypertension bleed 
• 
Hepatic encephalopathy 
• 
Spontaneous bacterial peritonitis 
• 
Uncontrolled ascites requiring treatment 


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Subjects who discontinue treatment due to adverse clinical outcomes will be identified via medical review 
and provided to statistics prior to database lock. 
10.10 PBC Medication 
The initiation of PBC medication while on the study will be treated as rescue medication in the analysis. All 
PBC medication usage during the study will be collected on the Prior and Concomitant medication CRF 
page and the category will be “PBC Treatment”. PBC medication that was ongoing at the time of screening 
will not be considered as impacting the efficacy analysis. If a subject with ongoing PBC medication at time 
of screening has a temporary medication interruption during the study and the medication is subsequently 
resumed, this will not be considered a new PBC medication impacting efficacy.  The use of UDCA is 
required during the study, unless the subject is intolerant to UDCA. Obeticholic acid (OCA), fenofibrate and 
bezafibrate are also permitted during the study. If a stable dose is maintained throughout the study these 
may not be considered rescue therapies.  
All PBC treatment will be reviewed and assessed for the impact on efficacy. If a subject is identified as 
having a record that potentially impacts efficacy (i.e., the PBC medication started after randomization), all 
efficacy data collected following the start date of the medication will be treated as missing data for the 
analysis of the primary, secondary and exploratory endpoints.  
The date of PBC medication initiation is defined as the first date/time of PBC treatment identified as 
impacting efficacy record in the CRF. For imputation of partial dates refer to Appendix 2. An assessment or 
event will be defined as prior to PBC medication initiation if the date/time of the assessment or event 
occurred prior to the date/time of the first PBC medication usage. Otherwise, the event will be considered 
after PBC medication use. If the assessment of event only has date collected, then prior to PBC medication 
includes assessments or events that occurred on the day of the first PBC medication usage. Time to PBC 
medication use will be defined as: 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑡𝑡𝑡𝑡 𝑃𝑃𝑃𝑃𝑃𝑃 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑈𝑈𝑈𝑈𝑈𝑈= 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃𝑃𝑃 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼+ 1 
The identification of PBC medication impacting on efficacy will be conducted through a blinded medical 
review prior to the primary analysis. 
10.11 PROMIS-Short Form-Fatigue 7b Daily 
The PROMIS-short form-Fatigue 7b Daily comprises of 7 questions asking the subject to evaluate their 
fatigue since waking up. Each of the questions on a 5-point scale (range 1-5) with a range of possible 
values for the score for the daily form from 7 to 35. Higher scores indicate worse functioning for fatigue. 
This measure will be completed at home by the subject via daily diary over 7 consecutive days prior to the 
study visits.  
Total daily raw scores will be obtained by summing item scores, which are converted into T-scores 
standardized (mean=50, SD=10). The standardized T-score is reported as the final daily score for each 
participant. The daily raw scores will be converted into T-scores using the table in Appendix 3 
(HealthMeasures, 2019). All questions must be answered in order to produce a valid score using the scoring 
tables, if the subject does not answer all 7 questions completely, the total daily raw scores are set to 
missing.  
The T-scores for baseline and post-baseline visits will be calculated by averaging the daily T- scores before 
the visit date (inclusive). The calculation of this average value will proceed only if 4 or more daily T-scores 
are available; otherwise, the final score will be treated as missing for the corresponding visit. The baseline 
T score will be defined as the mean of the daily T scores over the last 7 days prior to first treatment 
administration. For post-baseline assessments only, if data over 8 days is collected, all 8 days will be 
included in the calculation of the average value. 
Approximately 15 subjects will have no baseline value for the PROMIS-short form-Fatigue 7b Daily as they 
were enrolled under Protocol Version 1.0 and this questionnaire was not added until Protocol Version 2.0. 
These missing data will not be imputed for the main analysis. 


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10.12 PBC-40 Item Questionnaire 
The PBC-40, is a disease-specific health-related quality of life measure validated for use in subjects with 
PBC (Jacoby et al 2005). The questionnaire comprises of 40 questions in 6 domains related to fatigue, 
emotional, social, and cognitive function, general symptoms, and itch. An additional 3 questions are asked 
relating to the subjects general health and well-being.  
Subjects will be asked to select his/her most appropriate response for all 43 questions applying a 1-week 
recall period under protocol version 2.0 or later. For subjects enrolled under protocol version 1.0, a 4-week 
recall period will apply. All PBC-40 records collected prior to the date of informed consent for the Protocol 
Amendment (collect on the eCRF page Protocol Amendment Re-Consent) will be assumed to have a recall 
period corresponding to version 1.0 (4-week). All records on or following the informed consent date for the 
Protocol Amendment will be assigned a 1-week recall period. 
PBC-40 scores are calculated using subject responses to 40 questions in the questionnaire. There are a 
total of 6 domains across the 40 questions: 
• 
Symptoms 
• 
Itch 
• 
Fatigue 
• 
Cognitive Function 
• 
Emotional function 
• 
Social Function 
Items scores often range from 1 to 5 or 0 to 5, with 0 or 1 representing the lowest impact and 5 representing 
the highest impact of PBC on quality of life. The individual item scores are summed to obtain a total domain 
score, high scores represent high 
impact and low scores indicate low impact of PBC on the quality of life.  
Analysis of the PBC-40 is conducted by domain, and scoring is elucidated in the Table 3 below. Instead of 
considering a cumulative PBC-40 score, data should be evaluated on a domain-by-domain basis.  
• 
In instances where data are missing from a domain, the entire domain should be excluded if less 
than 50% of items are completed (≥ 50% of items are missing). The total score of the domains will 
be imputed using the MCMC method in a Sensitivity Analysis see Table 4. 
• 
Conversely, if more than 50% of responses are present then the median value for the completed 
items in the domain should be ascribed to the missing item in the main analysis. The total score of 
domains can be calculated and will not be treated as missing. 
The score for the six domains will be derived as per Table 3. 
Table 4: PBC-40 domain scoring 
Domain (No of questions) 
Response Score 
Symptoms (7) 
Range: 6 to 35 
Q1 
Never=5; Rarely=4; Sometimes=3; Most of the time=2; Always=1 
Q2, Q4-Q7 
Never=1; Rarely=2; Sometimes=3; Most of the time=4; Always=5 
Q3 
Never=1; Rarely=2; Sometimes=3; Most of the time=4; Always=5; Did not 
apply/never drink alcohol=0 
Itch (3) 
Range: 0 to 15 


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Domain (No of questions) 
Response Score 
Q8-Q10 
Never=1; Rarely=2; Sometimes=3; Most of the time=4; Always=5; Did not 
apply/no itch=0 
Fatigue (11) 
Range: 11 to 55 
Q11-Q21 
Never=1; Rarely=2; Sometimes=3; Most of the time=4; Always=5 
Cognitive Function (6) 
Range: 6 to 30 
Q22-Q27 
Never=1; Rarely=2; Sometimes=3; Most of the time=4; Always=5 
Social Function (10) 
Range: 8 to 50 
Q29, Q31 
Not at all=1; A little=2; Somewhat=3; Quite a bit=4; Very Much=5; Does not 
apply=0 
Q32 
Not at all=1; A little=2; Somewhat=3; Quite a bit=4; Very Much=5; 
Q34-Q39 
Strongly agree=5; Agree=4; Neither agree not disagree=3; Disagree=2; Strongly 
disagree=1 
Q40 
Strongly agree=1; Agree=2; Neither agree not disagree=3; Disagree=4; Strongly 
disagree=5 
Emotional Function (6) 
Range: 3 to 15 
Q28, Q30, Q33 
Not at all=1; A little=2; Somewhat=3; Quite a bit=4; Very Much=5 
10.13 PROMIS-29 
The PROMIS-29 Profile (v2.1) comprises of 7 domains (anxiety, depression, fatigue, pain interference, 
physical function, sleep disturbance, and ability to participate in social roles and activities) and a single pain 
intensity item (Cella et al 2010). Each of the 7 domains consists of 4 questions on a 5-point scale (range 1-
5) with a range of possible values for the score for each domain from 4 to 20. Higher scores for the physical 
function and ability to participate in social roles and activities represent better functioning in those domains. 
Higher scores in the anxiety, depression, fatigue, pain interference and sleep disturbance indicate worse 
functioning in these domains. The single pain intensity item is measured on an 11-point rating scale with 0 
representing no pain and 10 representing worst pain imaginable.  
Total raw scores for each domain will be obtained by summing item scores for each domain, which are 
converted into T-scores standardized (mean=50, SD=10). The standardized T-score is reported as the final 
score for each participant. The raw scores will be converted into T-scores using the table in Appendix 4 
(HealthMeasures, 2019).  
All questions must be answered in order to produce a valid score using the scoring tables.  
10.14 Worst Itch Numerical Rating Scale  
The WI-NRS is a daily patient-reported measure of itch intensity using an 11-point scale (where 0=no itch 
and 10=worst itching imaginable). The WI-NRS will be completed and collected via daily diary over 7 days 
prior to the visits. 
The WI-NRS score for baseline and post-baseline visits will be calculated by averaging the daily WI-NRS 
scores before the visit date (inclusive). The calculation of this average value will proceed only if 4 or more 
daily scores are available; otherwise, the final score will be treated as missing for the corresponding visit. 
The baseline WI-NRS score will be defined as the mean of the daily WI-NRS scores over the last 7 days 
prior to first treatment administration. For post-baseline assessments only, if data over 8 days is collected, 
all 8 days will be included in the calculation of the average value. 


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10.15 PGIS and PGIC Fatigue and Pruritus 
PGIS and PGIC-Fatigue and PGIS and PGIC-Pruritus will be recorded prior to each study visit on the day 
prior to this visit. The PGIS is a global index where subjects will be asked to rate the severity of Fatigue and 
Pruritus on a 5-point scale within the past 7 days, with choices of 1=none, 2=Mild, 3=Moderate, 4=Severe 
and 5=Very Severe. Higher scores indicate a worst assessment for fatigue and pruritus. 
The PGIC is a 7-point scale reflecting a subject’s rating of overall change. Subjects will be asked to rate 
their overall change with fatigue and pruritus with 1=Very much improved, 2=Much improved, 3=Minimally 
improved, 4=No change, 5=Worse, 6=Much worse, 7=Very much worse. Higher scores indicate greater 
severity of fatigue and pruritus, respectively. There is no baseline assessment for PGIC. 
No missing data will be imputed 
10.16 EuroQoL 5-D Utility Index 
The 5-level version of the EQ-5D (EQ-5D-5L) comprises a descriptive system with 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) and the EQ VAS (Herdman et al 2011; 
EuroQoL Research foundation 2019).  
Each of the 5 dimensions in the descriptive system has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. This decision results in a 1-digit number that expresses 
the level selected for that dimension. The digits for the 5 dimensions will be combined into a 5-digit number 
that describes the subject’s health state with 1 representing the best clinical status and 5 the worse. 
The EQ VAS is a vertical VAS numbered from 0 to 100, where 0=The worst health you can imagine, and 
100=The best health you can imagine. The subject will be asked to mark an X on the scale to indicate how 
his/her health is today, and to write the number he/she marked on the scale in the box next to the scale. 
For EQ-5D, questions not answered will be considered missing and no missing data will be imputed. A 
single EQ-5D utility index value will be derived which reflects how good or bad a health state is according 
to the preferences of the general population country/region. This utility index can be computed from the 
EQ-5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 
(best imaginable health state). The EQ-5D summary index will be derived by applying a formula that 
attaches weight to each of the levels in each dimension. Country specific weights will be applied (if 
available) or US weights (if country specific validated weights are not available).  
10.17 Definition of LLOQ  
Values below lower limit of quantification (LLOQ) 
To include safety assessments that are flagged as being below the lower limit of quantification in 
calculations they will be imputed by 
𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿
2
. 
To not display a misleading precision of the measurements, all descriptive summary statistics with value 
below the LLOQ will be set to “< <LLOQ>” in tables where “<LLOQ>” is a placeholder for the numerical 
value of the LLOQ. The LLOQs for Setanaxib and GKT138184 are 5.00 ng/mL and 1.00 ng/mL, 
respectively. 
10.18 Imputation of Missing Data 
In general, missing safety data will not be imputed.  
For the primary and secondary endpoints (Sections 12.5.2 and 12.5.3) analyzed by Mixed Model Repeated 
Measures (MMRM) analysis, imputation of missing data will be performed in sensitivity analyses, the 
methods used are summarized in Table 4 below. Data following usage of PBC-related medication after 
randomization will be set to missing. 
Table 5: Summary of Imputation Methods 


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Analysis 
Endpoint 
Imputation Method (Sensitivity Analysis) 
Primary 
Analysis 
The change in ALP 
(%) over 24 weeks 
Markov chain Monte Carlo (MCMC) monotone imputation as described in 
Section 12.5.2.2.1 
 
The 
change 
in 
fatigue assessed by 
the PROMIS-short 
form-Fatigue 
7b 
Daily 
if the final score for the subject is missing for the corresponding visit, MCMC 
monotone imputation will be used as described in Section 12.5.2.2.1 
analogously.  
Secondary 
Analyses 
The 
change 
in 
fatigue assessed by 
the PBC40 fatigue 
domain 
If >50% of responses are present in the domain then the median value for the 
completed items in the domain should be ascribed to the missing item in the 
main analysis. 
If ≤50% of responses are present in the domain, the total score of the domain 
will be set to missing and imputed using MCMC monotone imputation as 
described in Section 12.5.2.2.1 analogously 
 
The change in liver 
stiffness over 24 
weeks 
MCMC monotone imputation as described in Section 12.5.2.2.1 analogously 
 Interim Analyses (N/A) 
No interim efficacy analyses of the Phase 2b study data will be conducted. 
 Statistical Methods 
All statistical analyses will use SAS® version 9.4 or higher. Unless otherwise noted, categorical variables 
will be summarized using counts and percentages. Percentages will be rounded to one decimal place, 
except 100% will be displayed without any decimal places and percentages will not be displayed for zero 
counts.  
Continuous variables will be summarized using the number of observations (n), mean, Standard Deviation 
(SD), median, Q1, Q3, minimum and maximum, unless otherwise stated. The minimum and maximum 
values will be displayed to the same level of precision as the raw data, the mean, median, Q1, and Q3 to a 
further decimal place and the SD to two additional decimal places. The maximum number of decimal places 
will be 4, unless otherwise noted. P-values will be presented to 3 decimal places, with values less than 
0.001 presented as <0.001. If not stated otherwise, p-values from statistical tests will be 1-sided (type I 
error 2.5%) and 2-sided 95% CIs will be calculated.  
For MMRM analysis, the mean will be presented to two decimal places, and the SD and confidence interval 
(CI) will be presented to three additional decimal places. P-values will be presented to four decimal places. 
In general, all data summaries will be presented by treatment group and total group. Efficacy outputs will 
not have a total column.  
All data collected during this study regarding subject characteristics, efficacy and safety will be listed, unless 
otherwise specified. Listings will not show imputed data but will present data as reported. 
Stratification will be performed based on Screening serum ALP < or ≥ 3.0xULN. If there are differences 
between the randomization strata and the actual strata, these will be listed.  
Subjects who are screen failures may be rescreened at the discretion of the Investigator or Medical Monitor. 
Rescreen subjects will be analyzed under their rescreen subject identifier and data collected under the 
screen failure identification will be listed under the rescreen identifier. Screen failures will be excluded from 
all listings and tables if not otherwise noted.  
Missing data will be handled as described in Section 10.17. The FAS will be used to analyze endpoints 
related to the efficacy objectives, the PP will be used for supplementary analysis related to efficacy 


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objectives, the SS will be used to analyze safety endpoints and assessments related to safety over two 
treatment periods, as defined in Section 10.7.1. PK analysis will be presented using the PKS.  
For information on the control of overall Type 1 error rate in the primary endpoint refer to Section 12.5.1. 
Formal statistical testing will be conducted for the primary endpoint of change in ALP, secondary endpoint 
of fatigue (based on PROMIS short form and PBC40 questionnaires) and change in liver stiffness. 
12.1 Subject Disposition 
A summary of subject disposition will be provided by treatment group and total for the ENRL set. The 
number and percentage of subjects in the below categories will be summarized: 
Analysis 
Comment 
• 
Subjects screened (total n only) 
 
• 
Subjects randomized 
 
• 
Subjects randomized but not treated 
 
• 
Subjects treated 
 
• 
Subjects who completed at least 24-weeks treatment  
The subject will be defined as completing treatment 
if they complete the Week 24 exposure CRF visit 
(or Week 28 in the absence of Week 24). 
• 
Subjects who discontinued treatment prior to 24-weeks 
with reasons for discontinuation 
 
• 
Subjects who discontinued study prior to 24 weeks with 
reasons for discontinuation  
A subject will be defined as completing the Study, 
if they complete Week 24 CRF visit. 
• 
Subjects who completed at least 52-weeks treatment 
(protocol version 1.0 to 4.0) 
The subject will be defined as completing treatment 
at least 52-weeks if they complete the Week 52 
exposure CRF visit. 
• 
Subjects who discontinued treatment prior to 52-weeks 
with reasons for discontinuation 
 
• 
Subjects who discontinued the study prior to 52 weeks 
with reasons for discontinuation  
The subject will be defined as discontinued study 
prior to 52-weeks if they do not complete the Week 
52 exposure CRF visit. 
• 
Subjects enrolled in the extension phase  
o 
Subjects assigned to 1200mg 
o 
Subjects assigned to 1600mg 
CRF Study Drug Administration (Extension Phase) 
• 
Subjects treated in the extension phase  
o 
Subjects treated with 1200mg 
o 
Subjects treated with 1600mg 
CRF Study Drug Administration (Extension Phase) 
 
The flow of subjects through each stage of a trial, from recruitment to analysis, will be summarized using 
CONSORT (Consolidated Standards of Reporting Trials) diagram. 
Screen failure and reasons for screen failure will be listed and summarized using the ENRL set.  
Subjects disposition and screening information will be listed. For subjects who entered the extension phase, 
listings will include the dose received in the randomized phase and dose received in the extension phase 
together with dates. 


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Enrollment will be summarized by region (North America, South and Central America, Europe, Asia, Africa), 
country and site by number enrolled, n(%) randomized and n(%) treated for the ENRL set. 
Summaries for the number and percentage of subjects included in each analysis set, a breakdown for the 
reason for exclusion from each analysis set will be provided in listing. The number of subjects on treatment 
will be provided by time points of 24-week Double-blind Treatment Period under Protocol v5.0 and 52-week 
Double-blind Treatment Period under Protocol v1.0 to v4.0. 
12.2 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the FAS. Descriptive statistics will be 
provided for: 
• 
Sex (Female, Male, Undifferentiated, Unknown) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian 
or Other Pacific Islander, Other, Not Reported, Unknown) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• 
Age (years) at informed consent (as collected on the Demographics CRF page),  
• 
Age group (≥18 and <65 years, ≥ 65 years) 
• 
Baseline body weight, height, and body mass index (BMI). BMI kg/m2 will be derived as Weight (in 
kg)/Height (in m)2  
• 
Randomized Screening serum ALP strata (<3 or ≥3.0xULN based on value used in randomization) 
Descriptive statistics will also be provided for the following baseline characteristics: 
• 
Screening serum ALP 
• 
Baseline serum ALP  
• 
Baseline total bilirubin  
• 
Baseline Anti-SP100 (Positive (incl. Weakly Positive), Negative) 
• 
Baseline Anti-GP210 (Positive (incl. Weakly Positive), Negative) 
• 
Baseline AMA titer (Positive, Negative)  
• 
Liver biopsy performed (Performed/Not performed) 
• 
Baseline liver stiffness score as assessed by transient elastography using FibroScan® 
• 
Baseline Child-Pugh Score and Class (Class A, Class B, Class C) 
• 
Baseline MELD score 
• 
Baseline MELD score (proportion of subjects with a score <15 and ≥ 15) 
A listing for demographics and baseline disease characteristics will be provided for all subjects in the FAS. 
Discrepancies between randomization stratification information and actual strata based on the collected 
Screening serum ALP value will be flagged.  
12.3 Treatments 
12.3.1 Medical and PBC Treatment History 
Medical history conditions will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0 or later. The number and percentage of subjects with each medical history term will be listed 


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and summarized by the MedDRA system organ class (SOC) and preferred term (PT) using the FAS. A 
listing for medical history will be presented for the FAS. 
PBC treatment history will also be presented for the FAS with the following baseline disease characteristics 
summarized: 
Analysis (Yes/No) 
Comment 
• 
Any Prior PBC Treatment prior to or at 
randomization 
The number and percentage of subjects have at least one 
ongoing PBC record at randomization, or a record on the PBC 
Treatment History page of the CRF  
o 
UDCA use prior to or at randomization 
Yes, if subjects have an ongoing UDCA record at randomization 
or a record for UDCA on the PBC Treatment History page of the 
CRF 
o 
OCA use prior to or at randomization 
Yes, if subjects have an ongoing OCA record at randomization 
or a record for OCA on the PBC Treatment History page of the 
CRF 
o 
Fibrate use (bezafibrate or fenofibrate) 
prior to or at randomization 
Yes, if subjects have an ongoing fibrate record at randomization 
or a record for OCA on the PBC Treatment History page of the 
CRF 
o 
Bezafibrate use prior to or at 
randomization 
Yes, 
if 
subjects 
have 
ongoing 
Bezafibrate 
record 
at 
randomization or a record for Bezafibrate on the PBC Treatment 
History page of the CRF 
o 
Fenofibrate use prior to or at 
randomization 
Yes, 
if 
subjects 
have 
ongoing 
Fenofibrate 
record 
at 
randomization or a record for Fenofibrate on the PBC Treatment 
History page of the CRF 
• 
Any Prior PBC Treatment at randomization 
The number and percentage of subjects have at least one 
ongoing PBC record at randomization. 
o 
UDCA use at randomization 
Yes, if subjects have an ongoing UDCA record at randomization 
o 
OCA use at randomization 
Yes, if subjects have ongoing OCA record at randomization 
o 
Fibrate use (bezafibrate or fenofibrate) 
at randomization 
Yes, if subjects have ongoing Fibrate record at randomization 
o 
Bezafibrate use at randomization 
Yes, 
if 
subjects 
have 
ongoing 
Bezafibrate 
record 
at 
randomization 
o 
Fenofibrate use at randomization 
Yes, 
if 
subjects 
have 
ongoing 
Fenofibrate 
record 
at 
randomization 
• 
Intolerance to UDCA 
Yes, if a subject has a record on the PBC Treatment History page 
of the CRF with drug UDCA and reason for Reason Treatment 
was Discontinued is intolerance, otherwise if subject has an 
ongoing record for UDCA set to No 
 
All PBC treatment history will be listed for the FAS, Subjects who started PBC medication after 
randomization and subjects who stopped PBC medication prior to stopping randomized treatment will be 
flagged and a further flag if they were assessed to impact efficacy. Time to medication use will be derived 
and included in the listing. 
12.3.2 Prior and Concomitant Medications 
Prior Non-PBC medications, concomitant Non-PBC medications (by treatment periods) and concomitant 
PBC medications (by treatment periods) received with IMP, categorized by medication group according to 
the World Health Organization Drug Dictionary (WHODRUG) Global version March 2021 B3 or later will be 
summarized using the SS.  


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Prior and concomitant medications will be summarized using Anatomic Therapeutic Chemical (ATC) 
classification and PT for the SS. Where multiple ATC codes are assigned to the same treatment, the blinded 
Calliditas medical monitor will identify the primary code for inclusion in the summary tables. The number 
and percentage of subjects using each medication will be displayed together with the number and 
percentage of subjects using at least one medication within each medication group and subgroup. The 
summaries will be repeated for each treatment period, as defined in Section 10.7.1. 
All Non-PBC medications will be provided in listing and flags will be provided, to indicate prior or 
concomitant medications, and to indicate treatment periods. 
During the blinded data review meeting that was conducted prior to database lock, it was identified that a 
small number of concomitant Non-PBC medications were included on the concomitant PBC medication 
eCRF form. A list of associated ATC codes were provided by the Calliditas medical monitor to the ICON 
programming group to facilitate a move of these medications to the correct summary table.  
12.3.3 Extent of Study Drug Exposure 
The extent of exposure will be characterized for the SS according to the number of subjects who received 
at least one dose, the total number of doses received, the duration of therapy (weeks), duration of 
interruptions, the reasons for interruptions and study drug compliance. The summaries will be repeated for 
each treatment period, as defined in Section 10.7.1. 
At each dispensing visit, subjects will be dispensed kit(s) comprising of 4 bottles containing 70 tablets each. 
Subjects are expected to take 4 tablets per day, 1 tablet from each bottle, 2 in the morning, 2 tablets in the 
evening. 
The duration of exposure, regardless of temporary interruptions, will be defined as the  
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤) = (𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼) + 1
7
 
The date of last dose of IMP in the 24-week treatment period and date of last dose in the 52-week treatment 
period (for subjects who received more than 24 weeks of treatment), respectively will be used in the above 
derivation. For the Extension Phase, the date of last dose of IMP in the Extension Phase will be used in the 
extension phase will be used in the above derivation and this data will be listed only.  
During the course of the study, the dose may be interrupted due to safety concerns. The start date and end 
date of the interruption will be recorded on the Dose Interruptions page of the CRF. The number of subjects 
with an interruption at any point of the study will be summarized and the duration of interruption will be 
calculated as: 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 (𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤) = (𝐸𝐸𝐸𝐸𝐸𝐸 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼−𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼) + 1
7
 
The reasons for the interruption will also be presented.  If a subject has multiple interruptions during the 
study period, all individual interruptions will be summed to determine the overall period of treatment 
interruption. 
The total number of doses administered will be calculated using values from the Drug Accountability CRF 
form and will be defined as: 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴= 𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 
With the doses dispensed at a visit calculated as the number of bottles dispensed at a visit multiplied by 
the amount of tablets per bottle dispensed (70 tablets per bottle). The number of doses returned at a visit 
will be the sum of all tablets returned per bottle. If at a visit the number of doses returned for a bottle is 
missing, it will be assumed that the subject used the full amount of tablets in a bottle i.e. 0 will be used as 
the returned amount in the calculation. The total number of doses administered will be summarized for the 
Main Part, Extension Phase and Overall.  
The compliance to study drug will also be calculated as: 


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𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 100 ∗𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 
The expected number of tablets to be taken will be estimated based on the duration of exposure and 
defined as:   
• 
(Date of last dose in the period of interest – date of first dose in the study +1) X 4 tablets/day 
The following compliance categories will also be displayed: <75%, ≥75 to <90%, ≥90%, 100%. Compliance 
and total number of doses administered will be calculated for the SS (by treatment period defined in Section 
10.7.1) and Extension Phase (where applicable), where expected number of tablets will be the expected 
number during each reporting phase and total number of doses administered the number administered 
during each phase.  
Study drug accountability, study drug compliance and interruptions will be listed.  
12.4 Important Protocol Deviations 
Per ICON processes, protocol deviations data will be entered into the ICON system of record (PSO), in 
accordance with the Protocol Deviation Guidance Document. Important protocol deviations are defined in 
the protocol deviation guidance document. The final approved version of protocol deviation guidance will 
be finalized before the database lock for the primary analysis. The study team and the Sponsor will conduct 
on-going reviews of the deviation data from PSO, adjusting the deviation criteria as seems appropriate.  
Protocol deviation data will be reviewed prior to database lock and important deviations with a potential  
impact on efficacy leading to the elimination of subjects from the PP will be identified. The PP must be 
finalized at the blinded data review meeting (or earlier), prior to database lock for the primary analysis and 
agreed with the Sponsor. 
During the blinded data review meeting that was conducted prior to database lock, it was identified that 
several important deviations with impact on efficacy per section 9.6.4 were not entered into PSO. As such, 
programmatic PDs for deviations related to inclusion/exclusion criteria and non-compliance with study drug 
intake (≤80%) were derived and agreed in the blinded data review meeting and subsequently used as an 
additional protocol deviation source for analysis. 
The number of subjects with important protocol deviations will be summarized in the FAS by category of 
violation and by treatment group including subset of Important protocol deviations leading to exclusion from 
the PP. For the primary analysis, all protocol deviations will also be listed. Deviations that occurred over a 
24-weeks treatment period, over a 52-weeks treatment period and occurred during the extension phase will 
be flagged in the listings. 
12.5 Efficacy Analyses 
12.5.1 Hypothesis Testing Strategy and Multiplicity 
The objective of the primary efficacy analysis will be to evaluate the efficacy of setanaxib versus placebo 
in the treatment of subjects with PBC and elevated liver stiffness. The aim of the efficacy analysis is to 
demonstrate superiority of setanaxib over placebo.  
The null hypothesis is no difference in change in ALP (%) between setanaxib and placebo over 24 weeks. 
The alternative hypothesis is that setanaxib demonstrates a difference in change in ALP (%) over placebo. 
To control the study-wise error rate, that is, the probability of rejecting the true null hypothesis for the primary 
endpoint at 1-sided 0.025, a Hochberg step-up procedure will be applied to adjust for 2 dose comparisons 
versus placebo. The hypothetical example below is used to illustrate the procedure. 
• 
The primary analysis will be performed and the p-values for each setanaxib dose versus placebo will 
be assigned a rank (#1 for the smallest p-value and #2 for the largest p-value).  


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• 
Next, the Benjamini-Hochberg (BH) critical value will be calculated for each p-value, using the formula: 
(i/m)*Q where i = rank of p-value (1 or 2), m is the number of tests (this will be set to 2) and Q is the 
false positive risk (this will be set to 0.025, for a 1-sided test). Thus, the p-value with Rank 1 will have 
a BH critical value of 0.0125 and the p-value with Rank 2 will have a BH critical value of 0.025. 
Example 
Comparison 
Hypothetical 
observed P-value 
Rank 
BH-critical value 
(i/m)*Q 
1. Setanaxib 1600mg vs placebo 
0.020 
1 
0.0125 
2. Setanaxib 1200mg vs placebo 
0.024 
2 
0.025 
• 
The test with the largest p-value that is less than its Benjamini-Hochberg critical value is comparison 
#2. This test and all tests with a smaller p-value will be considered significant. Therefore, in this 
hypothetical example, both dose comparisons will be deemed statistically significant. 
For the analysis of secondary and exploratory endpoints, multiplicity will not be adjusted. “Nominal” p-values 
will be presented and will not be considered as part of the study-wise control of type I error. This is 
considered appropriate for an exploratory Phase 2b study. 
12.5.2 Primary Estimand 
For the primary efficacy analysis, each setanaxib treatment group (1600 mg and 1200 mg) will be compared 
with placebo. The primary estimand is to assess the change in ALP (%) over 24 weeks in subjects with 
PBC, elevated liver stiffness, and intolerance or inadequate response to UDCA.  
The intercurrent events of Important protocol deviations impacting efficacy and treatment discontinuation 
prior to Week 24 for any reason not considered under the Composite Strategy (below) will be handled with 
a treatment policy strategy (the primary estimand) and the value recorded for the variable of interest is used 
regardless of whether or not the intercurrent event occurs (ICH E9 R1 addendum). The intercurrent events 
of starting additional PBC-related medications after randomization and prior to Week 24 or death prior to 
week 24 will be handled with a composite variable strategy, where efficacy data collected following the 
intercurrent event will be excluded from the primary analysis. PBC-related medication(s) will be identified 
through blinded medical review prior to database lock.  
Table 6: Definition of Intercurrent Events 
Intercurrent Event 
Strategy 
Comment 
Important protocol deviations that impact 
efficacy 
Treatment 
policy 
strategy 
The occurrence of the intercurrent event is 
considered irrelevant in defining the treatment 
effect of interest, the value for the variable of 
interest is used regardless of whether or not the 
intercurrent event occurs 
Starting additional PBC-related medications 
after randomization and before Week 24 
Composite 
variable 
strategies 
Efficacy data collected after these events will be 
excluded from the primary analysis. 
Death before Week 24 
12.5.2.1 Primary Analysis 
Change in ALP at each scheduled timepoint up to Week 24 will be explored via tabulation and graphs for 
the FAS.  Counts for the number of subjects that have a ≥15%, ≥30%, ≥40%, ≥50% and ≥70% reductions 
in ALP from baseline will be presented (these counts will be cumulative i.e a subject with ≥30% reduction 
at Week 24 will be counted in both ≥15% and ≥30% categories. Summary statistics for each schedule 
timepoints will be presented. These will include the geometric mean, geometric mean +/- geometric 


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standard deviation, median, minimum, maximum. Baseline will be summarized in two ways – including all 
baseline data and baseline recalculated for subjects with evaluable Week 24 results (i.e. the subset of 
patients who have both baseline and week 24 ALP results). 
In order to summarize % change at each scheduled timepoint, the ratio of ALP to baseline will be calculate 
for each scheduled timepoint and a logarithmic transformation applied. The mean and mean +/- standard 
deviation and mean +/- standard error of the log ratios will be calculated. The results will be back-
transformed to get the geometric mean ratio (+/- geometric standard deviation and +/- geometric SE). 
These results will be converted to the % scale and plotted as a line graph for each treatment group. ALP 
values after initiation of PBC-related medication will be treated as missing values at the analysis visit 
following initiation of the medication.  
For the primary analysis, the ratio of ALP at week 24 to baseline will be log-transformed, as will ALP data 
from other timepoints used in the model. This will be analyzed using a Mixed Model Repeated Measures 
(MMRM) analysis based on the FAS and incorporating ALP data from baseline, weeks 2,4,8,12 and 24.   
Baseline ALP will be included as a covariate and will be calculated as the geometric mean of pre-
randomization ALP results, as defined in section 10.1 and log-transformed prior to inclusion in the analysis 
model. The model will also include terms for treatment group, visit, log(baseline) by visit, and visit by 
treatment group interaction. Subject will be included as a random effect.  
the Mixed Model Repeated Measures (MMRM) model can be mathematically represented as follows: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1 ⋅ Treatment 𝑖𝑖+ 𝛽𝛽2 ⋅ Visit 𝑗𝑗+ 𝛽𝛽3 ⋅൫log ൫ Baseline ALP 𝑖𝑖𝑖𝑖൯) +
𝛽𝛽4 ⋅൫log ൫ Baseline ALP 𝑖𝑖𝑖𝑖×  Visit 𝑗𝑗൯+ 𝛽𝛽5൫ Treatment 𝑖𝑖×  Visit 𝑗𝑗൯+ 𝑏𝑏𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖
 
• 
𝑌𝑌𝑖𝑖𝑖𝑖 is the observed response (log-transformed ratio of ALP at visit 𝑗𝑗 (up to Week 24) to baseline). 
• 
𝛽𝛽0 is the overall intercept. 
• 
𝛽𝛽1 is the effect of treatment group 𝑖𝑖. 
• 
𝛽𝛽2 is the effect of visit 𝑗𝑗. 
• 
𝛽𝛽3 is the effect of baseline ALP. 
• 
𝛽𝛽4 is the interaction between log-transformed baseline and visit. 
• 
𝛽𝛽5 is the interaction between treatment and visit. 
• 
𝑏𝑏𝑖𝑖𝑖𝑖𝑖𝑖 represents the random effect for the subject 𝑘𝑘. 
• 
𝜖𝜖𝑖𝑖𝑖𝑖 is the residual error term. 
An unstructured covariance matrix will be used to model the within-subject correlation of data. The 
Kenward-Roger’s degrees-of-freedom adjustment will be used. Restricted maximum likelihood will be used 
to obtain parameter estimates.  
Assessment of model assumptions:  
Model assumptions of the MMRM will be assessed. Where the residual errors 𝜖𝜖𝑖𝑖𝑖𝑖 are assumed to be 
independent and identically distributed with constant variance; the random effects 𝑏𝑏𝑖𝑖𝑖𝑖𝑖𝑖 are assumed to be 
normally distributed with mean zero. 
1. The assumption of linearity (linear relationship between log-transformed ratio of ALP with 
independent variables) and homoscedasticity will be checked using residual plots. 
2. The assumption for normality of residuals will be checked using QQ plots. 
Assessment of model convergence:  


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• 
If the model using unstructured covariance matrix does not converge, heterogeneous Toeplitz 
covariance structure will be used instead of the unstructured covariance matrix. If the model still 
fails to converge , the Toeplitz structure will be used. 
• 
If the above method does not lead to convergence of the model, consideration will be given to 
increasing the maximum number of iterations, changing the optimization technique, or adjusting 
the convergence criteria to promote model convergence. 
• 
If the above optimization still fails to make the model converge, the following models (removing 
baseline * visit interaction term and removing the baseline term) will be used until the model 
converges. 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1 ⋅ Treatment 𝑖𝑖+ 𝛽𝛽2 ⋅ Visit 𝑗𝑗+ 𝛽𝛽3 ⋅൫log ൫ Baseline ALP 𝑖𝑖𝑖𝑖൯) +𝛽𝛽4൫ Treatment 𝑖𝑖×  Visit 𝑗𝑗൯+ 𝑏𝑏𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖 
 
 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1 ⋅ Treatment 𝑖𝑖+ 𝛽𝛽2 ⋅ Visit 𝑗𝑗+ 𝛽𝛽3 ⋅൫ Treatment 𝑖𝑖×  Visit 𝑗𝑗൯+ 𝑏𝑏𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖 
Data presentation:  
The least squares means will be estimated by visit along with the associated 95% CI. Geometric least 
squares mean values will be obtained by exponentiating the least squares means.   
The treatment effect will be expressed as the % change in ALP for each setanaxib dose versus placebo, 
derived from the geometric least squares mean ratios estimated at Week 24 (and scheduled timepoints up 
to Week 24) interacted with each treatment arm. The 95% CI and 1-sided p-value will be presented. 
To aid interpretation, corresponding estimated absolute change from baseline for each arm and the 
estimate absolute change versus placebo and 95% CIs will be estimated from the ratios.  
12.5.2.2 Sensitivity Analyses 
For continuous endpoints to be analyzed using MMRM, no explicit imputation of missing data is needed as 
the MMRM analysis will be performed on observed cases and implicitly imputes missing data. = 
Sensitivity analyses using different ways of handling missing ALP data will be performed for the primary 
endpoint to assess the impact of missing data and the intercurrent strategy on the primary efficacy results: 
1. Sensitivity analysis #1 While it is intended that complete data will be recorded at 24 weeks, if there 
is a significant amount of missing data, the robustness of the primary analysis will be assessed 
using multiple imputation (Section 12.5.2.2.1) 
2. Sensitivity analysis #2: If examination of residual plots indicates significant outliers, then ALP data 
at 24 weeks will additionally be analyzed using a Robust Regression approach after first multiple 
imputing any missing data (Section 12.5.2.2.2) 
12.5.2.2.1 Sensitivity Analysis #1 - Multiple Imputation for Sensitivity Analysis of Primary 
Endpoint 
If missing data are observed following discontinuation, the MMRM will estimate what would have happened 
had patients not discontinued, and the treatment effect may be biased. To assess the robustness, a multiple 
imputation approach will be performed where the relationship between ALP data and time from 
discontinuation will be modelled within each treatment group separately, and using that relationship, data 
missing post-discontinuation will be imputed based on data observed post-discontinuation in other patients.  
The imputation model will include data from baseline and Weeks 2, 4, 8, 12, and 24 and will impute missing 
ALP values as follows:  
• 
For subjects who discontinue study treatment and who do not have subsequent ALP 
measurements, the missing data imputation method will use subjects in the same treatment arm 
who discontinue study treatment and do have subsequent ALP measurements (defined as 


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‘retrieved dropouts’) allowing for how long prior to each visit the subject discontinued. Therefore, if 
there is some loss of efficacy post discontinuation of therapy, subjects who discontinue study 
treatment and have missing data will have data imputed based on such a loss of efficacy. 
• 
For subjects who initiate a new PBC medication, all data collected post the commencement of PBC 
medication will be treated as missing data in the model. 
• 
In the unlikely event that subjects die before a visit, they will have the largest ALP value, observed 
across treatment arms, imputed at that visit. 
The variables to be used in the analysis are described below together with sample SAS® code [Note the 
actual variable names may vary in the analysis]:  
• 
TRT = treatment group  
• 
VAL1-VAL5 = log-ALP value at each post-baseline visit for Weeks 2,4,8,12 and 24, respectively 
• 
WDAW1-WDAW5 = Time from treatment discontinuation at Weeks 2,4,8,12 and 24, respectively. 
Covariates will be constructed for each scheduled visit up to Week 24 and depending on the time 
point being imputed, the corresponding covariate will be used in the imputation model. For example, 
if Week 24 is being imputed the Week 24 covariate below will be used to determine time from 
treatment discontinuation in the model. Each WDAW covariate takes a value of 0 if a subject is still 
receiving therapy at that visit and will be fitted as class variables. The value of the covariates will 
be derived as follows (the visit windows defined in section 10.3 will be applied): 
o 
WDAW1 (Week 2 Visit): If the subject discontinued treatment prior to Week 2 Visit set to 
1; otherwise set to 0 
o 
WDAW2 (Week 4 Visit): If the subject discontinued treatment prior to Week 2 Visit set to 
2; if the subject discontinued IMP on or after Week 2 Visit but prior to Week 4 Visit set to 
1; otherwise set to 0 
o 
WDAW3 (Week 8 Visit): If the subject discontinued treatment prior to Week 2 Visit set to 
3; if the subject discontinued IMP on or after Week 2 Visit but prior to Week 4 Visit set to 
2; if the subject discontinued treatment on or after Week 4 Visit but prior to Week 8 Visit 
set to 1; otherwise set to 0 
o 
WDAW4 (Week 12 Visit): If the subject discontinued treatment prior to Week 2 Visit set to 
4; if the subject discontinued treatment on or after Week 2 Visit but prior to Week 4 Visit 
set to 3; if the subject discontinued treatment on or after Week 4 Visit but prior to Week 8 
Visit set to 2; if the subject discontinued treatment on or after Week 8 Visit but prior to Week 
12 Visit set to 1; otherwise set to 0 
o 
WDAW5 (Week 24 Visit): If the subject discontinued treatment prior to Week 2 Visit set to 
5; if the subject discontinued treatment on or after Week 2 Visit but prior to Week 4 Visit 
set to 4; if the subject discontinued treatment on or after Week 4 Visit but prior to Week 8 
Visit set to 3; if the subject discontinued treatment on or after Week 8 Visit but prior to Week 
12 Visit set to 2; if the subject discontinued treatment on or after Week 12 Visit but prior to 
Week 24 Visit set to 1; otherwise set to 0 
• 
WD = binary covariate indicating whether the subject had discontinued from therapy prior to Week 
24 Visit  
• 
USUBJID = Subject ID  
• 
VISIT = Visit name  
• 
CHG = Change of log-ALP baseline ratio at each visit  
• 
BASE = log-baseline ALP 


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Using the monotone datasets generated for ALP, the missing ALP data will be imputed separately for each 
treatment group using a REGRESSION method in conjunction with the MONOTONE statement of the SAS 
MI procedure. The steps are as follows: 
Step 1: is to create data with a monotone data structure. For example, at this stage, data would only be 
imputed at Week 12 if the subject had data recorded at week 24. This allows subjects with a non-monotone 
pattern of missing data to be included in the analysis. The imputation model used to create monotone data 
pattern will include the following factors and covariates: randomized treatment group (TRT), log baseline 
ALP (BASE), covariate indicating if the subject discontinued treatment prior to Week 24 (WD) and the value 
of log-ALP at all visits up to Week 24 (VAL 1-VAL5). The WD covariate may be removed from the final 
model. 
proc mi data=data nimpute=20 seed=7872228 out=partial;  
var BASE WD VAL1-VAL5;  
mcmc chain=single nbiter=200 niter=200 impute=monotone;  
by TRT;  
run; 
 
NBITER will be set to 200, so 200 burn-in iterations are created before sampling the first imputed dataset, 
and NITER also set to 200 so that each subsequent imputation is separated by 200 from the same chain. 
An autocorrelation plot will be produced to confirm that NITER is long enough to ensure imputations are 
independent and a trace plot also produced to confirm there are no systematic trends.  
Step 2: Missing ALP data will be imputed separately for each treatment arm using a  
regression model and incorporating time from treatment discontinuation covariates as follows: 
proc mi data=partial nimpute=1 SEED=439384 OUT=imputed;  
class WDAW1-WDAW5;  
monotone reg(VAL1=BASE WDAW1/details);  
monotone reg(VAL2=BASE WDAW2 VAL1/details);  
monotone reg(VAL3=BASE WDAW3 VAL1 VAL2 /details);  
monotone reg(VAL4=BASE WDAW4 VAL1 VAL2 VAL3 /details);  
monotone reg(VAL5=BASE WDAW5 VAL1 VAL2 VAL3 VAL4 VAL5/details); 
var BASE WDAW1-WDAW5 VAL1-VAL5;  
by TRT _imputation;  
run; 
 
The number of imputations will depend on the percentage of missing data to be imputed and will range from 
a minimum of 5 to a maximum of 50 imputed datasets. The below formula will be used to calculate the 
number of imputations: 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼= 5 + 1.5 ∗(𝑚𝑚) 
where m is the proportion of missing data, expressed as a percentage. The smallest integer greater than 
or equal to the number will be used for the number of imputations. 
Note, individual covariate terms for time from treatment discontinuation may be dropped from the model 
and/or factor levels removed if a particular pattern of missing data is not present when data are unblinded. 
In particular, if there are subjects present with missing data for a specific level of one of the covariates for 
time from treatment discontinuation, but there are no matching subjects with data observed for the same 
level of the same factor in the same treatment arm, the factor level will be grouped with the next highest 
level to enable the imputation model to be run (for example Week 2 will be grouped with Week 4). This will 
require running separate MI procedures if the pattern differs by treatment arm. 
In the event that the above model fails, the time from treatment discontinuation covariates may be removed 
as follows 
 


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Proc mi data=partial nimpute=1 seed=439384 out=impute minmaxiter=100000; 
monotone regression ; 
var BASE VAL1-5; 
by  TRT imputation_; 
run;  
 
Step 3: the MMRM model is applied to the transposed, imputed data. Any subject who dies prior to a visit 
will have worst case data imputed only at this stage prior to analyzing the data. Baseline ALP will be 
included as a covariate and will be calculated as the geometric mean of pre-randomization ALP results, as 
defined in section 10.1 and log-transformed prior to inclusion in the analysis model. The model will also 
include terms for treatment group, visit, log(baseline) by visit, and visit by treatment group interaction. 
Subject will be included as a random effect.  
An unstructured covariance matrix will be used to model the within-subject correlation of data. The 
Kenward-Roger’s degrees-of-freedom adjustment will be used. Restricted maximum likelihood will be used 
to obtain parameter estimates. Model assumptions of the MMRM will be assessed using residual plots 
(such as q-q plots, histograms, box plots, and scatter plots). If the model above does not converge, 
heterogeneous Toeplitz covariance structure will be used instead of the unstructured covariance matrix. If 
convergence still does not meet, the Toeplitz structure will be used. 
 
proc mixed data=imputed method=reml;  
class TRT USUBJID VISIT;  
model CHG = TRT VISIT BASE BASE*VISIT VISIT*TRT /ddfm=kr;  
repeated VISIT/ sub = USUBJID type = un;  
lsmeans TRT*VISIT /cl pdiff;  
by _imputation_;  
ods output LSMeans=mixlsmean Diffs=mixdiff;  
run; 
Step 4: In the pooling phase, estimated treatment effects and associated standard errors from each 
imputation will be combined using Rubin’s rules (Rubin, 1987) to provide an overall treatment effect, 
associated 95% confidence interval (CI), and 1-sided p-value. 
proc mianalyze data=mixlsmean;  
by VISIT;  
modeleffects estimate;  
stderr stderr;  
ods output ParameterEstimates=lsmeans; 
run; 
 
This analysis will only be performed if there is sufficient data from ‘retrieved dropouts’ to ensure a reliable 
model with imputation.  
If there are insufficient data after grouping, the imputation model may be updated to reduce the number 
of covariates or apply a simplified imputation method.  
 
12.5.2.2.2 Sensitivity Analysis #2 - Robust regression for Sensitivity Analysis of Primary 
Endpoint 
If examination of residual plots indicates clear non-normality, then ALP data at Week 24 will additionally be 
analyzed using a Robust Regression approach after first multiply imputing any missing data in the same 
manner as described in 12.5.2.2.1 Step 1. ALP values will be log-transformed prior to analysis. Results will 
be presented in terms of the ratio of geometric least squares mean values and their associated 95% CI. 


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This will be achieved by exponentiating the treatment effect and 95% CI for the mean difference in log-
transformed values obtained from the robust regression model for the corresponding timepoint.  
Step 1: create data with a monotone data structure having imputed 20 datasets separately within each 
treatment arm. The number of burn-in iterations will be set to 200, and observations will be sampled every 
200 iterations within the same chain for each imputed dataset. An autocorrelation plot will be produced to 
confirm that NITER is long enough to ensure imputations are independent and a trace plot also produced 
to confirm there are no systematic trends. 
proc mi data=data nimpute=20 seed=2019301 out=mono;  
var BASE VAL1-VAL6;  
mcmc chain=single nbiter=200 niter=200 impute=monotone;  
by TRT;  
run; 
 
Step 2: data will be multiply imputed using a regression method sequentially imputing data across 
successive visits separately by treatment arm from each dataset imputed in the first step. This analysis 
assumes data are missing at random conditional on previous ALP recordings, which is the same 
assumption used in a MMRM model and therefore would be expected to give equivalent results (O’Kelly & 
Ratitch). 
proc mi data=mono nimpute=1 SEED=2019301 OUT=imputed;  
class TRT;  
var BASE VAL1-VAL5;  
monotone regression;  
by TRT _imputation_;  
run; 
 
log-transformed data will be analyzed using Robust Regression with independent variables of treatment 
and log transformed baseline ALP. M-estimation will be used with Huber weights and a cut-off value of 2 
with the median method used to estimate the scale parameter. This approach means that standardized 
residuals with an absolute value of ≤2, corresponding to the central 95% of the data if normally distributed, 
have equal weight and outlying data are weighted according to a pre-specified function, 𝑊𝑊𝑊𝑊 (𝑥𝑥), which gives 
lower weights to the most outlying data where 𝑊𝑊𝑐𝑐 (𝑥𝑥) = 𝑚𝑚𝑚𝑚𝑚𝑚 {1, 𝑐𝑐 / |𝑥𝑥| } where x is the standardized residual, 
corresponding to least square standardized residuals in the first iteration. Given that dependent variables 
are categorical and inclusion criteria for the only continuous covariate, log-transformed baseline ALP, 
prevents this variable from having outlying values, M-estimation will be appropriate.  
proc robustreg data=data method=m (wf=huber(c=2) scale=med) outest=est1 covout;  
by _imputation_;  
class TRT;  
model CHG = BASE TRT;  
run 
 
In the pooling phase, estimated treatment effects and associated standard errors from each imputation will 
be combined using Rubin’s rules to provide an overall treatment effect, associated 95% CI, and 1-sided p-
value.  
 
proc mianalyze data=est1;  
modeleffects estimate;  
stderr stderr;  
ods output ParameterEstimates=est2;  
run; 


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12.5.2.3 Supplementary Analyses 
If there are important protocol deviations that impact efficacy, the primary analysis (see Section 12.5.2.1) 
will be repeated using the PPS. Subjects with important protocol deviations could falsely draw the estimated 
treatment difference closer. Exclusion of these subjects in this sensitivity analysis will help assess the 
magnitude, if any, of this effect. 
12.5.2.4 Summary of Analyses for the Primary Endpoint 
The overview of analyses for the primary endpoint are summarized in the Table below. 
Table 7: Summary of Analyses for the Primary Endpoint 
Analysis 
Popula
tion 
Method 
Summary of reductions in ALP from 
baseline at each scheduled time point 
up to Week 24 
FAS 
• 
Cumulative counts for the number of subjects with specific 
percentage reductions (≥15%, ≥30%, ≥40%, ≥50%, and 
≥70%) from baseline 
• 
Bar chart visualization at each time point by treatment 
Summary of ALP at each scheduled 
time point up to Week 24 
 
FAS 
 
• 
Summary Statistics (including geometric mean, geometric 
standard deviation, median, minimum, and maximum, and 
geometric mean ratio of ALP to baseline) 
 
FAS 
• 
Individual line plots of ALP versus time for each subject by 
treatment 
• 
Line plot for geometric mean ALP vs time by treatment 
• 
Line plot for geometric mean ratio ALP (in % reduction) vs 
time by treatment 
Primary Analysis - % change in ALP 
for each setanaxib dose versus 
placebo, derived from geometric least 
squares mean ratios estimated 
FAS/PP
S 
Mixed Model Repeated Measures (MMRM)  
 
 
Forest plot of geometric mean to compare FAS, PPS, 
Sensitivity Analyses #1 and #2 
Sensitivity Analysis #1 – Deal with 
missing data 
FAS 
Multiple Imputation (MAR) + Mixed Model Repeated Measures 
(MMRM) to provide an overall treatment effect, associated 95% 
confidence interval (CI), and 1-sided p-value 
Sensitivity Analysis #2 – Assess 
impact of outliers 
FAS 
Multiple Imputation (MAR) + Robust Regression 
12.5.3 Secondary Estimands  
12.5.3.1 Secondary Analyses 
The secondary estimands are: 
• 
To assess the change in fatigue (as assessed by the PROMIS-short form-Fatigue 7b Daily and 
by the PBC40 fatigue domain) over 24 weeks in subjects with PBC, elevated liver stiffness, and 
intolerance or inadequate response to UDCA. The intercurrent events are as defined for the primary 
estimand (see Table 5). 
• 
To assess the change in liver stiffness over 24 weeks in subjects with PBC, elevated liver stiffness, 
and intolerance or inadequate response to UDCA. The intercurrent events are as defined for the 
primary estimand (see Table 5). 
• 
To assess the change in ALP, fatigue and liver stiffness in subjects with PBC, elevated liver 
stiffness, and intolerance or inadequate response to UDCA, where both setanaxib doses are 


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combined into one setanaxib treatment group. The intercurrent events are as defined for the 
primary estimand (see Table 5). 
The primary analysis methodology described in Section 12.5.2.1 will be repeated for the secondary 
estimands, with the exception that the outcome variable for analyses of fatigue will be absolute change 
from baseline (calculated as postbaseline minus baseline values) with no log transformation and the 
baseline covariate in the model will not be log transformed. As described below, 𝑌𝑌𝑖𝑖𝑖𝑖 is the observed 
response (absolute change in fatigue at visit 𝑗𝑗 (up to Week 24) to baseline). 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1 ⋅ Treatment 𝑖𝑖+ 𝛽𝛽2 ⋅ Visit 𝑗𝑗+ 𝛽𝛽3 ⋅ቀ Baseline fatigue  𝑖𝑖𝑖𝑖) +
𝛽𝛽4 ⋅ቀ Baseline fatigue   𝑖𝑖𝑖𝑖×  Visit 𝑗𝑗ቁ+ 𝛽𝛽5൫ Treatment 𝑖𝑖×  Visit 𝑗𝑗൯+ 𝑏𝑏𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖
 
For the analysis of fatigue, fatigue data captured at Baseline, Weeks 4, 12, and 24 will be included in the 
model. Subjects enrolled under protocol version 1.0 and reconsented to version 2.0 will have no baseline 
value for the PROMIS-short form-Fatigue 7b as this questionnaire was introduced in version 2.0 at the 
request of the FDA. A sensitivity analysis will be performed with  imputation of missing data. 
For the analysis of change in liver stiffness at Week 24 compared to baseline, as assessed using 
FibroScan®, liver stiffness data captured at Baseline, Weeks 12 and 24 will be included in the model. The 
log transformation of liver stiffness will be performed as the same as primary analysis, the MMRM model is 
mathematically represented as follows, where 𝑌𝑌𝑖𝑖𝑖𝑖 is the observed response (log-transformed ratio of liver 
stiffness at visit 𝑗𝑗 (up to Week 24) to baseline). 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1 ⋅ Treatment 𝑖𝑖+ 𝛽𝛽2 ⋅ Visit 𝑗𝑗+ 𝛽𝛽3 ⋅൫log ൫ Baseline liver stiffness𝑖𝑖𝑖𝑖൯) +
𝛽𝛽4 ⋅൫log ൫ Baseline liver stiffness𝑖𝑖𝑖𝑖×  Visit 𝑗𝑗൯+ 𝛽𝛽5൫ Treatment 𝑖𝑖×  Visit 𝑗𝑗൯+ 𝑏𝑏𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖
 
For the analysis of ALP, fatigue and liver stiffness for the combined setanaxib doses, the MMRM analyses 
will be repeated with 2 treatment groups rather than three.  
12.5.3.2 Sensitivity Analysis 
The sensitivity analysis with multiple imputation defined in 12.5.2.2.1 will be performed for the secondary 
estimands. 
12.5.3.3 Supplementary Analyses 
For the combined setanaxib treatment group versus placebo, where there is sufficient data (at least 10 
patients at each level of the subgroup within each treatment group), additional exploratory analyses 
examining the consistency of the treatment difference among subgroups using the FAS will be performed. 
The primary analysis will be repeated at each level of the subgroup. A tabulation at Week 24 will be 
presented for each of the following subgroups: 
• 
Age group: ≥18 and <65 years, ≥ 65 years 
• 
Sex: Female vs Male 
• 
Actual Randomization Strata: Screening serum ALP < or ≥3.0×ULN 
• 
UDCA use ongoing at Randomization: Yes vs No 
• 
UDCA use prior to or at Randomization: Yes vs No  
• 
OCA use ongoing at Randomization: Yes vs No 
• 
OCA use prior to or at Randomization: Yes vs No 
• 
Fibrate use (bezafibrate or fenofibrate) ongoing at Randomization: Yes vs No 
12.5.3.4 Summary of Secondary Analyses 
The overview of primary analyses are summarized in Table below. 
Table 8: Summary of Secondary Analyses 


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Endpoints 
Populatio
n 
Analysis 
Change in fatigue assessed by the 
PROMIS-short form-Fatigue 7b 
Daily (3 treatment groups) 
FAS 
• 
Summary Statistics of change (and % change) in the 
PROMIS short form fatigue 7b compared to baseline by 
time points 
• 
Line plot for mean of PROMIS short form fatigue 7b vs 
time point for by treatment 
 
FAS 
• 
MMRM Model of absolute change in the PROMIS short 
form fatigue 7b compared to baseline 
 
FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in fatigue assessed by the 
PBC40 
fatigue 
domain 
(3 
treatment groups) 
FAS 
• 
Summary Statistics of change (and % change) in the 
PBC40 fatigue domain compared to baseline  
• 
Line plot for mean of PBC40 fatigue domain vs time point 
by treatment 
 
FAS 
• 
MMRM Model of absolute change in the PBC40 fatigue 
domain compared to baseline 
 
FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in liver stiffness over 24 
weeks (3 treatment groups) 
FAS 
• 
Summary Statistics of change (geometric ratio) in the liver 
stiffness compared to baseline  
• 
Line plot for geometric mean vs time point by treatment 
 
FAS 
• 
MMRM Model of change in the liver stiffness compared to 
baseline 
 
FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in fatigue assessed by the 
PROMIS-short form-Fatigue 7b 
Daily (combined setanaxib group) 
FAS 
• 
Summary Statistics of change (and % change) in the 
PROMIS short form fatigue 7b compared to baseline 
 
FAS 
• 
MMRM Model of absolute change in the PROMIS short 
form fatigue 7b compared to baseline 
 
FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in fatigue assessed by the 
PBC40 fatigue domain (combined 
setanaxib group) 
FAS 
• 
Summary Statistics of change (and % change) in the 
PBC40 fatigue domain compared to baseline  
 
FAS 
• 
MMRM Model of absolute change in the PBC40 fatigue 
domain compared to baseline 
 
FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in liver stiffness over 24 
weeks 
(combined 
setanaxib 
group) 
FAS 
• 
Summary statistics for liver stiffness at each visit (including 
geometric mean, geometric standard deviation, median, 
minimum, and maximum) 
• 
Summary of geometric ratio of liver stiffness compared to 
baseline by time point  
 
FAS 
• 
MMRM Model of change in the liver stiffness compared to 
baseline 
 
FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in ALP up to Week 24 
(combined setanaxib group) 
FAS 
• 
Summary Statistics (including geometric mean, geometric 
standard deviation, median, minimum, and maximum) 
• 
Summary of geometric ratio of ALP compared to baseline 
by time point 
 
FAS 
• 
MMRM Model of change in the ALP compared to baseline 


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FAS 
• 
Sensitivity Analysis using MCMC monotone imputation 
Change in ALP up to Week 24 
(combined setanaxib group) by 
Subgroup  
• 
Age 
• 
Sex 
• 
Actual Randomization Strata 
• 
UDCA 
use 
ongoing 
at 
Randomization 
• 
UDCA use prior to or at 
Randomization 
• 
OCA 
use 
ongoing 
at 
Randomization 
• 
OCA use prior to or at 
Randomization 
• 
Fibrate use (bezafibrate or 
fenofibrate) 
ongoing 
at 
Randomization 
FAS 
• 
MMRM Model of change in the ALP compared to baseline 
(performed at least 10 patients at each level of the 
subgroup within each treatment group) 
12.5.4 Other Secondary Endpoints Analyses 
For the secondary endpoints listed below, summary statistics for each scheduled timepoint will be 
presented. These will include the arithmetic mean, standard deviation, geometric mean, geometric mean 
+/- geometric standard deviation, median, minimum, maximum. For the % change, if the data are 
lognormally distributed, the ratio of post-baseline result to baseline will be calculate for each scheduled 
timepoint and a logarithmic transformation applied.  
The mean and mean +/- standard deviation and mean +/- standard error of the log ratios will be calculated. 
The results will be back-transformed to get the geometric mean ratio (+/- geometric standard deviation and 
+/- geometric SE for graphical purposes). These results will be converted to the % scale and plotted as a 
line graph for each treatment group. Values after initiation of PBC-related medication will be treated as 
missing values at the analysis visit following initiation of the medication. Summary tables will include 
scheduled visit out to Week 52 + EoT (noting that the number of subjects will be small beyond week 24), 
but graphs will display data for the 24-week treatment period only. 
• 
Change in PGIS fatigue at Week 24 compared to baseline  
• 
PGIC fatigue by time point 
• 
Change in WI-NRS compared to baseline  
• 
Change in PBC-40 itch compared to baseline  
• 
Change in PGIS pruritus compared to baseline  
• 
PGIC pruritus by time point 
12.5.4.1 Markers of Cholestasis at Week 24 
To summarize the changes in markers of cholestasis, the number and percentage of subjects at each 
scheduled timepoint meeting the following criteria for FAS will be presented: 
• 
ALP reduction to <1.67×ULN and total bilirubin ≤1xULN and a ≥15% or ≥30% or ≥40% or ≥70% 
ALP reduction from Baseline, respectively 
• 
ALP reduction to <1.5×ULN and total bilirubin ≤1xULN and with a ≥40% ALP reduction from 
Baseline 
• 
ALP reduction to <1xULN and total bilirubin reduction to ≤1xULN 
• 
Total bilirubin reduction to <0.6×ULN 


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Descriptive proportions will be presented for all scheduled time points up to Week 24. Subjects who start a 
PBC-related medication will be considered a non-responder at the time point after initiation of the PBC 
medication. Subjects who experience and adverse clinical outcome prior to Week 24 will also be considered 
non-responders. 
12.5.5 Exploratory Endpoint Analysis 
Exploratory efficacy endpoint analysis will be non-inferential in nature. The following endpoints will have 
summary statistics produced All analysis will be performed based on the observed case i.e. only subjects 
with data at the visit will be summarized in the analysis, which will be based on the FAS. 
12.5.5.1 Change in Liver and Spleen Stiffness 
Any data collected for liver and spleen stiffness measured using MRE (Protocol versions 1.0 to 4.0 only) 
will be listed, including change from baseline values. Any results collected during the extension phase will 
be flagged.  
12.5.5.2 Change in Patient-Reported Outcomes 
The change from baseline over the 24 week treatment period for the following patient-reported outcomes 
will be summarized: 
• 
PBC 40 domains: Social Function, Cognitive Function, Emotional function, Symptoms (refer to 
Section 10.12) 
• 
Overall health-related quality of life as assessed by the PROMIS-29 questionnaire (refer to Section 
10.11). 
• 
The MMRM analysis will be conducted for PROMIS-29 fatigue domain in the same manner as the 
change in fatigue (refer to Section 12.5.3.1). No sensitivity analysis will be performed. 
• 
EQ-5D utility index (refer to Section 10.16) 
Only summary statistics for the absolute and change from baseline scores will be presented. 
12.5.6 Additional exploratory analyses 
Additional exploratory analyses may be performed by the Sponsor to aid data interpretation: 
• 
Scatter plots to show the correlation between QoL scores for fatigue at baseline versus change 
from baseline at week 24.  
• 
Scatter plots to show the correlation between QoL scores for fatigue domains and AEs of fatigue.   
• 
Scatter plots and summaries of change over time in fatigue and other QoL domains by severity of 
fatigue at baseline for PBC-40 (where mild <=28 and moderate/severe >=29)  
• 
Imputation of (baseline) missing PROMIS short form fatigue 7b using the modelled relationship with 
the baseline PBC40 data 
• 
Graphical presentation of changes in ALP, fatigue and liver stiffness where results from the PH2b 
study and the prior Ph2 study are combined in one plot.  
12.6 Safety Analyses 
12.6.1 Adverse Events 
All AEs will be coded using MedDRA Version 24.0 or later. All AEs (including non-treatment-emergent and 
post-treatment events) recorded on the CRF will be listed. AEs that are not treatment emergent will be 
flagged for both treatment emergent definitions described in Section 10.7.1 and AEs that are assigned to 
the extension phase will also be flagged. Only TEAEs (see Section 10.7.2) will be included in AE summary 
tabulations unless otherwise specified. Summary tables of TEAEs will be presented by treatment group and 


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total for  the SS and repeated for both treatment emergent definitions. The National Cancer Institute 
common terminology criteria for Adverse Events (CTCAE) toxicity grading criteria version 4.03 will be used 
for toxicity grading of AEs.  
All AE summaries will include the number and percentage of subjects in each category and the number of 
events. For the calculation of the incidence of events, subjects will only be counted once within the events. 
For summaries by SOC and PT, subjects will be counted once per unique PT and SOC. For summaries by 
SOC and PT tables should be sorted in descending order of SOC and then PT by subject counts in the total 
group.  
An overall summary of TEAEs will be presented with the following categories:  
• 
Any TEAEs  
o 
TEAEs related to IMP 
• 
Any severe TEAEs (CTCAE Grade 3 or greater) 
o 
Any severe TEAEs (CTCAE Grade 3 or greater) related to IMP 
• 
Any TESAEs 
o 
Any TESAES related to IMP 
• 
TEAEs with outcome of death (events with outcome of Fatal on the AE CRF page) 
o 
TEAEs related to IMP with outcome of death 
• 
TEAEs leading to discontinuation of study treatment 
o 
TEAEs related to IMP leading to discontinuation of study treatment 
• 
TEAEs leading to modification of study treatment 
o 
TEAEs related to IMP leading to modification of study treatment 
• 
TEAEs leading to study discontinuation 
o 
TEAEs related to IMP and leading to study discontinuation 
• 
TEAEs of special interest 
o 
TEAEs of special interest related to IMP 
• 
TEAEs requiring Adjudication 
• 
TEAE related to Hepatic Encephalopathy (as indicated by the Investigator on the AE CRF page) 
The following summaries will be presented by SOC and PT : 
• 
TEAEs 
• 
TEAEs by Maximum CTCAE Grade 
• 
TEAEs related to IMP 
• 
TEAEs related to IMP by Maximum CTCAE Grade 
• 
TEAEs of special interest 
• 
TEAEs of special interest related to IMP 
• 
TEAEs leading to discontinuation of study treatment 
• 
TEAEs leading to study discontinuation 
• 
TESAEs 


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• 
TESAEs related to IMP 
• 
Severe TEAEs of CTCAE Grade 3 or higher 
• 
Non-Serious TEAEs  
• 
TEAEs occurring in 2 or more of subjects (based on PT) in any treatment arm and summarized by 
PT only in descending order 
Subjects with multiple events within a particular SOC or PT will be counted under the category of their most 
drug-related event within that SOC or PT (first order by drug-related).  
Subjects with multiple events within a particular SOC or PT will be counted under the category of their most 
severe event within that SOC or PT (subsequent order by severity). 
A listing of all AEs will be produced with treatment emergent flags for each treatment emergent definition 
(Sections 10.7.1 and 10.7.2). Separate listings of TEAEs leading to death, leading to IMP discontinuation, 
CTCAE grade 3 or higher TEAEs, AESIs and SAEs will be provided.  
12.6.2 Adjudicated Events 
The following adverse clinical outcomes will be adjudicated during the study: 
• 
All-cause mortality/Death 
• 
Variceal bleed 
• 
Portal hypertension bleed 
• 
Hepatic encephalopathy (West Haven criteria) 
• 
Spontaneous bacterial peritonitis 
• 
Uncontrolled ascites requiring treatment 
Additionally, events that require IMP interruption (DILI, anemia and hypothyroidism) will also be adjudicated. 
The proportion of subjects with adjudicated events in the above categories will be summarized in the SS. 
All subjects with adjudicated events will be listed. 
An additional summary will be produced summarizing the proportion of subjects experience the following 
(not necessarily adjudicated) Safety events. 
• 
progression to cirrhosis  
• 
death (all-cause) 
• 
liver transplant 
• 
MELD ≥15 if the baseline MELD score was <12 
• 
new onset ascites requiring treatment (diuretics or paracentesis),  
• 
development of large varices if no varices at baseline,  
• 
hospitalization due to a decompensatory event (for example, variceal bleeding, hepatic 
encephalopathy, spontaneous bacterial peritonitis) 
If no such events are reported, this table will not be included. 
12.6.3 Laboratory Data 
Laboratory data will be reported in Système International (SI) units.  


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For clinical biochemistry, hematology and liver function tests (Table 8), shift tables from baseline to worst 
CTCAE grade on treatment will be produced for the SS, with separate summaries for each treatment period. 
Only parameters which have toxicity grading will be summarized. WBC and reticulocyte  
counts will be expressed in absolute values. Differential count will be expressed as both absolute count and 
percentage of WBCs. Only central lab data will be included in the table summaries. All lab data collected 
locally and centrally will be listed. 
Table 8: Laboratory Tests 
Laboratory Tests 
Parameters 
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, INR 
Biochemistry 
Glucose; total protein; creatinine; urea; total cholesterol; triglycerides; sodium; 
potassium; chloride 
Liver Function 
Serum fibrinogen, albumin, ALP, ALT, AST, total and conjugated bilirubin, GGT, 
hsCRP, IgM 
 
To further examine the liver function tests collected during the study, suspected drug-induced liver injury 
(sDILI) summaries will be produced. Proportion of subjects meeting any of the following criteria for any 
post-baseline assessments will be presented for the SS, for each treatment period: 
• 
AST or ALT ≥3xULN 
• 
AST or ALT >2xBaseline 
• 
Total bilirubin >2xULN 
• 
INR>1.5 
Any subjects with any of the above criteria for sDILI or cholestasis will be flagged in the listings. Subjects 
at risk of a drug induced liver injury according to Hy’s law will also be flagged. Hepatic function abnormality 
defined by an increase in AST and/or ALT to ≥ 3xULN concurrent with an increase in total bilirubin to ≥ 
2xULN but without increase in ALP (i.e., ALP < 2xULN) meets the criteria for Hy’s law and raises the 
concern for DILI. 
The MELD score will be calculated by the central laboratory based on the results from the liver biochemistry 
(total bilirubin), biochemistry (creatinine), and hematology (INR) blood samples. Subjects with a MELD 
score of ≥ 15 will be flagged in the listings. 
Data from the Extension Phase will be restricted to the period while a subject was on active and change 
from baseline comparisons using the extension baseline.  
Table 9: Other Laboratory Tests 
Laboratory Tests 
Parameters 
Markers of Liver Fibrosis 
ELF score components for calculation of ELF score (TIMP-1, PIIINP, and hyaluronic 
acid) and the other PBC-related biomarkers (PRO-C3 and C3M; PRO-C3/CRM ratio) 
Markers 
of 
bile 
acid 
metabolism 
Total bile acids, C4, FGF19, FGF21 
Autoantibodies 
AMA titer, PBC-specific antibodies (anti-GP210, anti-SP100, antibodies against major 
M2 components [PDC-e2, 2-oxo-glutaric acid dehydrogenase complex]) 


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Laboratory Tests 
Parameters 
Viral Serology 
HIV antibodies (1 and 2) and, if positive for HIV antibodies, HIV RNA; Hepatitis B 
surface antigen and hepatitis C virus antibodies and, if positive for HCV antibody, 
HCV RNA 
Pregnancy test  
Serum pregnancy test; urine Pregnancy test 
Thyroid function 
TSH and free T4 
Drug Screen (Urine) 
Urine drug screen 
Urinalysis 
pH; protein; glucose; ketones; bilirubin; blood; microscopic examination of the 
sediment 
 
Refer to Table 98, for a list of other laboratory parameters to be collected on this study and the laboratory 
test category each parameter will be summarized under. Autoantibodies, viral serology, pregnancy test, 
and drug screen parameters will be listed only. Markers of liver fibrosis, markers of bile acid metabolism, 
urinalysis, thyroid function will be summarized descriptively by scheduled visit using the SS. 
Standard ranges from the central laboratory will be used for the laboratory analysis. The assessment as to 
if a lab test is low, high, normal as applicable will be derived using the standard ranges for central lab data. 
Laboratory data outside study-specific reference ranges will be listed. 
Abnormal laboratory values, defined as values outside the normal range, will be listed by subject. 
Summaries of the incidence and frequency by treatment group and scheduled visit will be presented.  
12.6.4 eDISH Analysis 
Evaluation of drug-induced serious hepatotoxicity (eDISH) analysis will be conducted in order to explore 
potential liver toxicity signals by treatment group. A eDISH plot will be produced, which will display for each 
subject during the treatment period the maximal total ALT/AST value (expressed as a multiple of the ULN) 
against the maximal Total Bilirubin value (expressed multiple of the ULN) to identify possible values above 
Hy’s law range. The plot will be produced using the SS and treatment period of 52 weeks (Section 10.7.1) 
and will display the maximal on-treatment value of ALT/AST and total bilirubin. 
12.6.5 Vital Signs 
Observed values and change from baseline in vital signs will be summarized descriptively by scheduled 
visit and treatment group using the SS and treatment period of 52 weeks. Shift plots of baseline as 
compared to highest and lowest on treatment value by treatment group will be presented. Vital sign 
parameters to be summarized descriptively are pulse rate, systolic blood pressure (SBP), and diastolic 
blood pressure (DBP). By-subject listings of all the vital signs will also be provided. Body temperature will 
be listed only. 
12.6.6 Physical Examinations, ECGs, and Other Observations Related to Safety 
ECGs will be read centrally and ECG mean Heart Rate (HR), RR interval, PR Interval, QRS Duration, QT 
interval, QTcB interval and QTcF interval will be collected and summarized. In the Extension Phase, ECG 
may be read locally and HR, PR interval, RR interval, QRS interval, QT interval and QTcF interval will be 
listed. ECGs will be presented by the category normal, abnormal, unevaluable, and unknown for each 
assessment time point in the safety analysis, over the treatment period of 52 weeks. Shift plots of baseline 
as compared to highest and lowest on treatment value by treatment group will be presented for both 
treatment periods defined in Section 10.7.1. A listing of subjects ECG data will be provided.  
QTc outliers are defined as QTc values following dosing that are greater than 450 msec or are increases 
from baseline greater than 30 msec. QTc outliers will be highlighted in the data listings, with subjects 
meeting the criteria at any time point listed separately. Outliers will be summarized using separate shift 
tables for each treatment period defined in Section 10.7for the following categories:  
 


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• 
Values ≤450 msec, >450-480 msec, >480-500 msec, >500 msec at baseline versus values ≤450 
msec >450-480 msec, >480-500 msec, >500 msec post-dose  
• 
Values ≤450 msec, >450-480 msec, >480-500 msec, >500 msec at baseline versus increase from 
baseline of ≤30 msec, >30-60 msec, >60-90 msec or >90msec post-dose 
A summary of physical examination findings will be presented for each scheduled visits, showing the 
proportion of subjects with “Normal” and “Abnormal” physical examinations. The number of abnormal, 
clinically significant and not clinically significant assessments will be tabulated by scheduled visit using the 
SS and treatment period of 52 weeks. All physical examination findings will be provided in listings. 
The Child-Pugh score and Child-Pugh classification of Severity of Cirrhosis as collected on the CRF page 
will be listed for all scheduled visits with  flags to indicate in the value is treatment for each treatment periods 
defined in Section 10.7.1. The  individual components required to calculate the Child-Pugh score and class 
will also be listed).  
12.6.7 Liver Biopsy and Liver Histology 
For qualifying subjects in the SS, the absolute and change from baseline in the Nakamuna total score and 
fibrosis subscore at Week 52 will be summarized. A listing for the historical liver biopsy and liver biopsy 
data will be provided.  
12.7 Pharmacokinetics Analyses 
Blood samples will be collected for measurements of plasma concentrations of setanaxib and its metabolite 
GKT138184 during the Main Part of the study. Samples will be collected pre-dose at Week 6, Week 24 and 
(under protocol versions 1.0 to 4.0) also Week 52. The PK analysis set will be used for PK analysis. 
Plasma concentrations of setanaxib and GKT138184, along with blood sampling dates and actual blood 
sampling time relative to previous dosing time, will be listed by subject, dose group, actual treatment (can 
change within subject), by formulation; can change within subject] and nominal sampling time. Samples 
with time deviation from nominal time will be identified and listed. Plasma setanaxib and GK138184 
concentrations below the quantifiable limit (BQL) will be set to ½ the lower limit of quantification (LLOQ) in 
the computation of mean concentration values.  
Descriptive statistics (number of subjects, arithmetic mean, geometric mean, standard deviation, coefficient 
of variation for geometric mean, median, Q1, Q3, minimum, and maximum) will summarize the plasma 
concentrations of both setanaxib and GKT138184  at pre-dose Week 4, pre-dose Week 24 and, where 
relevant, pre-dose Week 52, by actual treatment (may change within subject). If 50% of the subjects at a 
given time point have values BQL then the descriptive statistics will not be presented and will instead display 
as BQL for the mean and minimum, with the exception of maximum all other statistics will be missing.   
Plasma setanaxib and GKT138184 concentrations (dose normalized as appropriate) vs study visit will be 
plotted as a box plot, by actual treatment (may change within subject) with corresponding sample sizes.  
12.8 Data Collected Under Protocol Version 1.0 
The following assessments will be collected under protocol version 1.0 and will not be included in the 
primary or final analysis. Listings will be produced for all subjects with data collected for these assessments:  
• 
5-D Itch Scale 
• 
Pruritus-Visual Analogue Scale.  
 References 
Benjamini, Y. and Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful 
approach to mulitple testing. Journal of the Royal Statistical Society, Series B, 57:289-300. 


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Cella D, Riley W, Stone A, et al. Initial Adult Health Item Banks and First Wave Testing of Patient-Reported 
Outcomes Measurement System (PROMISTM) Network: 2005-2008. J Clin Epidemiol. 2010 
Nov;63(11):1179-94.  
EuroQol Research Foundation. EQ-5D-5L User Guide. 2019. Version 3.0 dated Sept 2019. Available at: 
https://euroqol.org/publications/user-guides/. Last Accessed on 21 Mar 2021. 
HealthMeasures. PROMIS ADULT PROFILE INSTRUMENTS. A brief guide to the PROMIS® Profile 
instruments 
for 
adult 
respondents. 
https://staging.healthmeasures.net/images/PROMIS/manuals/PROMIS_Adult_Profile_Scoring_Manual.pd
f. Published January 17, 2019. Accessed August 6, 2021. 
HealthMeasures. 
FATIGUE. 
A 
brief 
guide 
to 
the 
PROMIS® 
Fatigue 
instruments. 
https://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_Manual.pdf. 
Published February 28, 2019. Accessed December 15, 2021. 
Herdman M, Gudex C, and Lloyd A, et al. Development and Preliminary Testing of the New Five-level 
Version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. 
Jacoby A, Rannard A, Buck D, et al. Development, Validation and Evaluation of the PBC-40, a Disease 
Specific Health Related Quality of Life Measure for Primary Biliary Cirrhosis. Gut. 2005 Nov;54(11):1622-
9. 
ICH. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in 
Clinical Trials – Guidance for Industry. https://www.fda.gov/media/148473/download. Published May 2021. 
Accessed June 4, 2021.  
Nakanuma Y, Zen Y, Harada K, et al. Application of a New Histological Staging and Grading System for 
Primary Biliary Cirrhosis to Liver Biopsy Specimens: Interobserver Agreement. Pathology International 
2010;60:167–74. 
Ratitch B, Lipkovich I, O’Kelly, M. Combining Analysis Results from Multiply Imputed Categorical Data. 
PharmaSUG.  2013 
Reich A, Heisig M, Phan NQ, et al. Visual Analogue Scale: Evaluation of the Instrument for the Assessment 
of Pruritus. Acta Derm Venereol. 2012 Sep;92(5):497-501. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: J Wiley & Sons, 1987.


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 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMA 
Antimitochondrial Antibodies 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Classification 
BMI 
Body Mass Index 
BQL 
Below Quantifiable Limit 
C3M 
A Peptide of Helical Collagen Type III Degradation 
CI 
Confidence Interval 
CMH 
Cochran Mantel Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DILI 
Drug-Induced Liver Injury 
ECG 
Electrocardiogram 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
EAS 
Extension Safety Analysis Set 
ELF 
Enhanced Liver Fibrosis 
ENRL 
All Enrolled Analysis Set  
EoT 
End of Treatment 
EQ-5D 
EuroQol 5-Dimension Utility Index 
ES 
Extension Analysis Set 
FAS 
Full Analysis Set 
FGF 
Fibroblast Growth Factor 
GGT 
Gamma Glutamyl Transpeptidase 
GM 
Geometric Mean 
HR 
Heart Rate  
hsCRP 
High Sensitivity C-reactive Protein 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
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Glossary of Abbreviations: 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IXRS 
Interactive Web Response System 
LLOQ 
Lower Limit of Quantification 
LOCF 
Last Observation Carried Forward 
LS 
Least Squares 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
MMRM 
Mixed Model Repeated Measures 
MRE 
Magnetic Resonance Elastography 
N/A 
Not Applicable 
OCA 
Obeticholic Acid 
PBC 
Primary Biliary Cholangitis 
PIIINP 
Amino Terminal Propeptide of Type III Procollagen 
PGIC 
Patient’s Global Impression of Change 
PGIS 
Patient’s Global Impression of Severity  
PK 
Pharmacokinetic(s) 
PKS 
PK Analysis Set 
PPS 
Per Protocol Analysis Set 
PRO 
Patient Reported Outcome 
PRO-C3 
Released N-terminal Propeptide of Type III Collagen 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PSO 
ICON System of Record 
PT 
Preferred Term 
RBC 
Red Blood Cell 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
sDILI 
Suspected drug induced liver injury 
SE 
Standard Error 
SI 
Système International  
SOC 
System Organ Class 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 49 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved. 
 
Glossary of Abbreviations: 
SS 
Safety Analysis Set 
TEAE 
Treatment-Emergent Adverse Event 
TIMP-1 
Tissue Inhibitor of Metalloproteinase 1 
UDCA 
Ursodeoxycholic Acid 
ULN 
Upper limit of Normal 
WBC 
White Blood Cell 
WI-NRS 
Worst Itch Numerical Rating Scale 
WHODRUG 
World Health Organization Drug Dictionary 
 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 50 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved. 
 
Appendix 
Appendix 1: Handling of Partial Adverse Event Dates 
In order to assign an AE with partial dates as treatment emergent in the Main Part and Extension Phase 
the following imputation rules will be used. 
Table 9: Handling of Partial AE dates (D = Day, M = Month, Y=Year) 
Date of Interest 
Missing 
Condition 
Imputation 
AE start date 
D 
M and Y is the same as M and Y of first dose 
of IMP 
Date of first dose of IMP 
Y is prior to Y of first dose of IMP 
Last day of the month 
Y is the same as Y of first dose of IMP, M is 
prior to M of first dose of IMP 
Last day of the month 
M and/or Y is after first dose of IMP 
First day of the month 
D, M 
Y is the same as the Y of first dose of IMP 
Date of first dose of IMP 
Y is prior to Y of first dose of IMP 
Use 31st of December 
Y is after Y of first dose of IMP 
Use 1st of January 
M 
Treat day as missing and use imputation rules 
for D and M as missing 
See D, M imputation rules 
D, M, Y 
None-date is completely missing 
Date of first dose of IMP 
AE End Date 
D 
M and Y same as date of last dose of IMP 
Date of last dose of IMP 
M and Y not the same as date of last dose of 
IMP/date of last dose of IMP is missing 
Set to the last day of the 
month, or the end of 
study/death 
date 
whichever is earliest 
D, M 
Y is the same as last dose of IMP 
Date of last dose of IMP 
Y is not the same as date of last dose of 
IMP/date of last dose of IMP is missing 
Set to 31st of Dec, or the 
end of study/death date 
whichever is earliest 
M 
Treat day as missing and use imputation rules 
for D and M as missing 
See D, M imputation rules 
D, M, Y 
None 
No imputation, assume 
Ongoing 
 
If the above imputation rules result in illogical dates adjust accordingly. If any estimated AE start date is 
after a complete/imputed AE end date, set the AE start date to be the first day in the AE end date month. If 
any estimated AE end date is prior to a complete/imputed AE start date set to be the last day of the AE 
start date month. Imputed values will not be displayed in listings. 
 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 51 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved. 
 
Appendix 2: Handling of Partial Medications Dates 
In order to assign medications as either prior and/or concomitant the following rules will be used. 
Table 10: Handling of Partial Medication dates (D = Day, M = Month, Y=Year) 
Date of Interest 
Missing 
Condition 
Imputation 
Medication 
start 
date 
D 
M and Y is the same as M and Y of first 
dose of IMP 
Date of first dose of IMP 
M and/or Y is not the same as the first dose 
of IMP 
First day of the month 
D, M 
Y is the same as the Y of first dose of IMP 
Date of first dose of IMP 
Y is not the same as first dose of IMP 
Use 1st of January 
M 
Treat day as missing and use imputation 
rules for D and M as missing 
See D, M imputation rules 
D, M, Y 
None-date is completely missing 
Assume 
prior 
and 
concomitant. Impute as 
the last day prior to the first 
dose of IMP. 
Medication 
End 
Date 
D 
M and Y same as date of last dose of IMP 
Date of last dose of IMP 
M and Y not the same as date of last dose 
of IMP/date of last dose of IMP is missing 
Set to the last day of the 
month, or the end of 
study/death 
date 
whichever is earliest 
D, M 
Y is the same as last dose of IMP 
Date of last dose of IMP 
Y is not the same as date of last dose of 
IMP/date of last dose of IMP is missing 
Set to the 31st of Dec, or 
the end of study/death 
date whichever is earliest 
M 
Treat day as missing and use imputation 
rules for D and M as missing 
See D, M imputation rules 
D, M, Y 
None 
No imputation, assume 
Ongoing 
 
If the above imputation rules result in illogical dates adjust accordingly. If any estimated medication start 
date is after a complete/imputed medication end date, set the medication start date to be the first day in the 
medication end date month. If any estimated medication end date is prior to a complete/imputed medication 
start date set to be the last day of the medication start date month. Imputed values will not be displayed in 
listings. For PBC medications collected on the concomitant medication page of the CRF with missing dates 
that are identified as impacting efficacy through medical review, the above rules will be used to impute 
partial dates and all assessments collected past the imputed partial dates will be seen as assessments 
collected while on rescue medication.  
 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 52 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved. 
 
Appendix 3: PROMIS-Short Form-Fatigue 7b Daily Scoring Tables 
Refer to HealthMeasures (2019) for further detail. 
 
 
 
 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 53 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved. 
 
Appendix 4: PROMIS-29 V2.1 Scoring Tables 
Refer to HealthMeasures (2019) for further detail. 
 


Statistical Analysis Plan (SAP)  
Version Date: 27-June-2024  
 
Sponsor: Calliditas Therapeutics Suisse SA  
 
Protocol No: GSN000350 
PRA-QMS-02745 9.0 
       Page 54 of 54 
Strictly Confidential.  © 2024, ICON.  All rights reserved.