Conditions: Primary Biliary Cholangitis
Keywords: Primary Biliary Cirrhosis, PBC Primary Biliary Cholangitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
A multi-part study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with primary biliary cholangitis

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Part 1: LJN452 intervention 2: Part 1: Placebo intervention 3: Part 2: LJN452 Dose level 1 intervention 4: Part 2: Placebo intervention 5: Part 2: LJN452 Dose level 2
Intervention descriptions: intervention 1: LJN452 capsules administered once daily for 28 days intervention 2: Matching placebo capsules administered once daily for 28 days intervention 3: LJN452 capsules administered once a day for 12 weeks intervention 4: Matching placebo to LJN452 administered once a day for 12 weeks intervention 5: LJN452

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research 
Tropifexor (LJN452) 
Clinical Trial Protocol CLJN452X2201 / NCT02516605
A multi-part, randomized, double-blind, placebo-controlled 
study to assess the safety, tolerability and efficacy of 
tropifexor (LJN452) in patients with Primary Biliary 
Cholangitis 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2015-001590-41 
Version number: 
v06 (Clean) 
Development phase: 
II 
Release date: 
27-Nov-2017
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Site Operations Manual (SOM) 
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. 
 
Notification of serious adverse events 
Refer to Section 9.2 of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Chief 
Medical Office and Patient Safety Department and notify the Clinical Trial Leader). 
Contact information is listed in the Site Operations Manual. 


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Table of contents 
Site Operations Manual (SOM) ........................................................................................... 2 
Notification of serious adverse events ................................................................................. 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 6 
List of figures....................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Pharmacokinetic definitions and symbols ......................................................................... 10 
Amendment 6 (November 2017) ....................................................................................... 11 
Amendment 5 (June 2017) ................................................................................................ 12 
Amendment 4 (July 2016) ................................................................................................. 16 
Amendment 3 (March 2016) ............................................................................................. 18 
Amendment 2 (November 2015) ....................................................................................... 19 
Amendment 1 (September 2015) ....................................................................................... 20 
Protocol synopsis ............................................................................................................... 21 
1 
Introduction ....................................................................................................................... 25 
1.1 
Background ............................................................................................................ 25 
1.1.1 
Relevant data summary ......................................................................... 25 
1.2 
Study purpose ........................................................................................................ 30 
2 
Study objectives ................................................................................................................. 31 
2.1 
Primary objectives ................................................................................................. 31 
2.2 
Secondary objectives ............................................................................................. 31 
 
 32 
3 
Investigational plan ........................................................................................................... 32 
3.1 
Study design ........................................................................................................... 32 
3.2 
Rationale of study design ....................................................................................... 36 
 
 37 
3.4 
Rationale for choice of comparator ....................................................................... 38 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 39 
3.6 
Risks and benefits .................................................................................................. 40 
4 
Population .......................................................................................................................... 40 
4.1 
Inclusion criteria for Parts 1 and 2 ......................................................................... 40 
4.1.1 
Additional Inclusion Criteria for Part 1 ................................................ 41 
4.1.2 
Additional Inclusion Criteria for Part 2 ................................................ 41 
4.2 
Exclusion criteria for Parts 1 and 2 ........................................................................ 41 
5 
Restrictions for Study Subjects .......................................................................................... 43 


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5.1 
Contraception requirements ................................................................................... 43 
5.2 
Prohibited treatment ............................................................................................... 44 
5.3 
Dietary restrictions and smoking ........................................................................... 44 
5.4 
General restrictions ................................................................................................ 44 
6 
Treatment ........................................................................................................................... 45 
6.1 
Study treatment ...................................................................................................... 45 
6.1.1 
Investigational treatment ....................................................................... 45 
6.2 
Treatment arms ...................................................................................................... 45 
6.2.1 
Permitted dose adjustments and interruptions of study treatment ......... 46 
6.3 
Treatment assignment ............................................................................................ 47 
6.4 
Treatment blinding ................................................................................................. 48 
6.5 
Emergency breaking of assigned treatment code .................................................. 49 
6.6 
Treatment exposure and compliance ..................................................................... 50 
6.7 
Recommended treatment of adverse events........................................................... 50 
6.8 
Rescue medication ................................................................................................. 50 
6.9 
Concomitant treatment ........................................................................................... 50 
7 
Discontinuation and study completion .............................................................................. 50 
7.1 
Discontinuation of study treatment ........................................................................ 50 
7.2 
Study completion and post-study treatment ........................................................... 51 
7.2.1 
Lost to follow-up ................................................................................... 52 
7.3 
Withdrawal of informed consent ........................................................................... 52 
7.4 
Study Stopping rules .............................................................................................. 52 
7.5 
Early study termination .......................................................................................... 54 
8 
Procedures and assessments .............................................................................................. 54 
8.1 
Informed consent procedures ................................................................................. 57 
8.2 
Subject demographics/other baseline characteristics ............................................. 58 
8.3 
Efficacy / Pharmacodynamics ............................................................................... 58 
8.3.1 
Liver Function Tests ............................................................................. 59 
8.3.2 
Patient-Reported Outcome .................................................................... 59 
8.4 
Safety ..................................................................................................................... 59 
8.4.1 
Physical examination ............................................................................ 59 
8.4.2 
Vital signs .............................................................................................. 59 
8.4.3 
Height and weight ................................................................................. 60 
8.4.4 
Laboratory evaluations .......................................................................... 60 
8.4.5 
Electrocardiogram (ECG) ..................................................................... 60 
8.4.6 
Pregnancy .............................................................................................. 61 


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8.5 
Pharmacokinetics ................................................................................................... 61 
8.5.1 
PK Blood collection and processing ..................................................... 61 
8.5.2 
Pharmacokinetic analytical method(s) .................................................. 61 
 
 61 
 
 61 
9 
Safety monitoring .............................................................................................................. 64 
9.1 
Adverse events ....................................................................................................... 64 
9.2 
Serious adverse event reporting ............................................................................. 66 
9.2.1 
Definition of SAE .................................................................................. 66 
9.2.2 
SAE reporting........................................................................................ 67 
9.3 
Liver safety monitoring ......................................................................................... 68 
9.4 
Renal safety monitoring ......................................................................................... 68 
9.5 
Pregnancy reporting ............................................................................................... 68 
9.6 
Early phase safety monitoring ............................................................................... 69 
10 Data review and database management ............................................................................. 69 
10.1 
Site monitoring ...................................................................................................... 69 
10.2 
Data collection ....................................................................................................... 70 
10.3 
Data Monitoring Committee .................................................................................. 71 
10.4 
Adjudication Committee ........................................................................................ 71 
11 Data analysis ...................................................................................................................... 72 
11.1 
Analysis sets .......................................................................................................... 72 
11.2 
Subject demographics and other baseline characteristics ...................................... 72 
11.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ............................................................................................................ 72 
11.4 
Analysis of the primary variable(s) ....................................................................... 72 
11.4.1 
Variable(s) ............................................................................................. 72 
11.4.2 
Statistical model, hypothesis, and method of analysis .......................... 73 
11.4.3 
Handling of missing values/censoring/discontinuations ....................... 73 
11.4.4 
Supportive analyses ............................................................................... 73 
11.5 
Analysis of secondary 
 variables .................................................. 73 
11.5.1 
Efficacy / Pharmacodynamics ............................................................... 73 
11.5.2 
Safety ..................................................................................................... 74 
11.5.3 
Pharmacokinetics .................................................................................. 75 
11.5.4 
Pharmacokinetic / pharmacodynamic interactions ................................ 76 
 
 76 
11.6 
Sample size calculation .......................................................................................... 77 
11.7 
Power for analysis of key secondary variables ...................................................... 77 


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11.8 
Interim analyses ..................................................................................................... 77 
11.9 
Interim analyses on locked data ............................................................................. 78 
12 Ethical considerations ........................................................................................................ 79 
12.1 
Regulatory and ethical compliance ........................................................................ 79 
12.2 
Responsibilities of the investigator and IRB/IEC .................................................. 79 
12.3 
Publication of study protocol and results ............................................................... 79 
13 Protocol adherence ............................................................................................................ 80 
13.1 
Protocol Amendments ........................................................................................... 80 
14 References ......................................................................................................................... 81 
15 Appendix 1: Liver and Renal events definitions and required actions .............................. 83 
16 Appendix 2: Pruritus event definitions and required actions ............................................ 90 
 
 
List of tables 
 
 29 
Table 6-1 
Part 2 Permitted dose reductions ........................................................... 47 
Table 8-1 
Part 1 Assessment schedule ................................................................... 55 
Table 8-2 
Part 2 Assessment schedule ................................................................... 57 
Table 15-1 
Liver Triggers and Events: definition and Follow-up Requirements .... 84 
Table 15-2 
Renal events: definition and follow up requirements............................ 89 
Table 16-1 
Pruritus event definitions and required actions ..................................... 90 
 
 
List of figures 
 
 26 
Figure 3-1 
Study design .......................................................................................... 33 
Figure 3-2 
Study design Part 1 ................................................................................ 34 
Figure 3-3 
Study design Part 2 ................................................................................ 35 


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List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
ANIT 
alpha-naphthyl -isothiocyanate 
(A)PPT 
(activated) partial thromboplastin time 
AST 
aspartate aminotransferase (SGOT) 
BMI 
Body Mass Index 
BSEP 
bile salt export pump 
BUN 
blood urea nitrogen 
CD-ROM 
compact disc – read only memory 
CFR 
Code of Federal Regulation 
CK 
creatinine kinase 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Clinical Trial Leader 
CTT 
Clinical Trial Team 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
 
 
FGF15 
Fibroblast growth factor 15 
FPFV 
First patient first visit 
FXR 
Farnesyl X receptor 
GCP 
Good Clinical Practice 


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GLP 
Good laboratory practice 
GGT 
Gamma-glutamyl transferase 
h 
hour 
HDL 
high-density lipoprotein 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LFT 
Liver function test 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
MELD 
Model for End Stage Liver Disease 
mg 
milligram(s) 
ml 
milliliter(s) 
 
 
NASH 
Non alcoholic steatohepatitis 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
Nonsteroidal Antiinflammatory drugs 
PBC 
Primary Biliary Cholangitis (formerly Primary Biliary Cirrhosis) 
PBC-40 
a disease specific quality of life measure for PBC 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PoC 
Proof of Concept 
PRO 
Patient reported outcomes 
PT 
prothrombin time 
RBC 
red blood cell(s) 
SAE 
serious adverse event 


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sCR 
serum creatinine 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase (same as AST) 
SGPT 
serum glutamic pyruvic transaminase (same as ALT) 
SHP 
small heterodimer partner 
SOM 
site operations manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
TIA 
transient ischemic attack 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
ULOQ 
upper limit of quantification 
VAS 
Visual Analog Score 
WBC 
white blood cell(s) 


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Pharmacokinetic definitions and symbols 
AUC0-t 
The area under the plasma concentration-time curve from time zero to time 
‘t’ where t is a defined time point after administration [mass x time / volume] 
AUCtau 
The area under the plasma concentration-time curve from time zero to the 
end of the dosing interval tau [mass x time / volume] 
 
 
 
Cav,ss 
The average steady state plasma concentration during multiple dosing 
Cmax 
The observed maximum plasma concentration following drug administration 
[mass / volume] 
Cmax,ss 
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume] 
Cmin,ss 
The lowest plasma concentration observed during a dosing interval at steady 
state [mass / volume] 
CL/F 
The apparent systemic (or total body) clearance from plasma following 
extravascular administration [volume / time] 
Tmax 
The time to reach the maximum concentration after drug administration 
[time] 
Vz/F 
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume] 


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Amendment 6 (November 2017) 
Amendment rationale 
The purpose of this amendment is to address comments 
 
 in response to protocol amendment 5. In addition, the 
blood volume was updated to enable the collection of additional samples for Vitamin D, 
 and PK back-up samples. 
 
Changes to the protocol 
• 
The blood volume for Parts 1 and 2 were updated to 490 mL and 450 mL, respectively, in 
Section 3.6 Risks and Benefits. This enables sample collection for Vitamin D, 
 
and back up sample collection for PK samples. 
• 
The inclusion and exclusion criteria in Section 4 were updated to exclude patients with: 
o significant hepatic impairment (Child-Pugh B and C), 
o serum creatinine above the normal range, 
o history of cirrhosis with complications 
o limit the population to PBC patients with mild/moderate disease by adapting the 
inclusion/exclusion criteria for ALT/AST, INR, and total bilirubin. 
• 
Section 7.1 Discontinuation of study treatment was updated to state that if a patient has a 
hepatic decompensation event, study treatment must be stopped. 
• 
Table 8-1 Part 1 Assessment schedule was updated to remove ‘-30m’ from the pre-dose 
assessment time for Day 28, which was erroneously left in when protocol amendment 5 
was made. 
• 
Table 15-1 Liver Triggers and Events: definition and Follow-up Requirements has been 
updated to increase the frequency of repeat tests following re-starting study drug and to 
clarify that if there is an elevation of liver biochemistries after re-starting the study 
treatment should be discontinued and the patient followed-up. 
• 
Table 15-2 Renal events: definition and follow up requirements has been updated to 
require discontinuation of study drug if there is a confirmed doubling of serum creatinine 
or serum creatinine ≥1.5 mg/dL 
• 
Editorial updates and corrections to typographical errors have also been made. 


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Amendment 5 (June 2017) 
Amendment rationale 
The purpose of this amendment is primarily to enable higher dose(s) in Parts 1 and 2 of the 
study, 
 and to update the Part 2 study design to allow 
12 weeks of treatment in patients with Primary Biliary Cholangitis (PBC), to provide longer- 
term safety, tolerability and efficacy data. 
Specific changes to Part 2 include: 
• increase the treatment duration from 4 weeks to 12 weeks, 
• broaden the population to include patients both taking and not taking UDCA 
(ursodeoxycholic acid), to be more representative of the PBC patient population, 
• assess two dose levels (plus placebo), to gain an insight into the dose-effect relationship, 
• increase patient numbers and alter randomization ratio to randomize more patients to 
receive active treatment compared to placebo, for collection of more safety data in this 
population, 
• reduce the burden for the patient by only collecting sparse PK samples. 
Changes also have been made to enable the staggered database lock of the study, so the 
database can be cleaned and locked in stages such as at completion of Part 1, or completion of 
a set of cohorts in Part 1 as well as the final database lock at the end of the study. Once the 
database has been locked, the locked data may be communicated beyond Novartis to groups 
including, but not limited to individuals treating the study’s subjects, Health Authorities and 
shared on clinical registries, as a means of greater transparency. 
 
Changes to the protocol 
• Title updated with the International Nonproprietary Name (INN) of tropifexor. 
• Objectives (Protocol synopsis and Section 2 Study objectives) updated to reflect the 
objectives relating to the amended Part 2. 


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• Study Design (Protocol synopsis and Section 3 Investigational Plan) updated to reflect 
the changes relating to the amended Part 2, including updating the design, the rationale 
for the study design and dose/regimen and associated interim analysis (Section 3.5 and 
Section 11.8). Section 1.2 Study purpose was also updated accordingly. 
• The amendment includes changes to enable the staggered locking of the database 
following completion of Part 1, or completion of Cohorts in Part 1 and the sharing of 
the locked data. Various parts of the protocol have been updated as a result of this, 
including: Section 3.2 Rationale of study design, Section 3.5 Purpose and timing of 
interim analyses/design adaptations, Section 6.4 Treatment blinding, Section 10.2 Data 
collection, Section 11.8 Interim analysis and Section 11.9 Interim analyses on locked 
data. 
• The total blood volume collected during the study was updated in Section 3.6 to reflect 
the recalculated and reduced volume for Part 1 and the new Part 2 volume. 
• Section 4 Population: has been updated to increase the sample size in Part 2, 
mentioning that the final sample size will  be  dependent  on  the  interim  analysis. 
The same section in the Protocol synopsis has also been updated with this information 
and to reflect the changes made to the eligibility criteria (see details below), together 
with the use of stratification in Part 2. 
• Section 4.1.2 Additional Inclusion Criteria for Part 2: has been updated to reflect that 
the population for Part 2 will now include patients taking a stable dose of UDCA as 
well as those who are not taking UDCA. 
• Several updates have been made to Section 4.2 Exclusion criteria to enhance patient 
safety, including to increase the time women of child-bearing potential need to use 
highly effective methods of contraception before and after treatment; to clarify the 
eligibility of those with previous viral hepatitis; to simplify the exclusion criteria 
related to hepatic decompensation to focus on cirrhosis with complications; to exclude 
patients that have laboratory results at screening that, if they occurred post-dose, 
would require them to discontinue study drug, to exclude the use of 
immunosuppressive drugs and FXR agonist obeticholic acid, and to exclude patients 
with a history of immunodeficiency diseases, including those with a positive HIV test 
result. Patients who have previously participated in Part 1 of the study are excluded 
from re-enrolling in Part 2 if they have received study medication within three months 
of randomization. 
• Section 5.2 Prohibited treatment: was updated with the addition of obeticholic acid, 
immunosuppressive drugs and investigational drugs as a prohibited treatment. 
• Section 5.3 was updated to lessen the restrictions on patients. 
 
 
 Fasting requirements in Part 2 have 
been changed to be no fluid for 30 min post dose and no food until 60 min post dose. 
The restriction on alcohol intake has been reduced from 12 hours to 8 hours prior to 
dosing or study visits. 


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• Section 6.1.1 Investigational treatment: An additional dose strength of 0.1 mg has  
been added In Part 1, a manual randomization process is used to provide 
randomization numbers upon confirmation of eligibility at the Baseline visit. In Part 2, 
an Interactive Response Technology (IRT) system will be used for management of 
randomization. Section 6.1.1 Investigational treatment, Section 6.3 Treatment 
assignment, Section 6.5 Emergency breaking of  assigned  treatment  code  and 
Section 10.2 Data collection have been updated to reflect these differences. 
• Updates have been made to reflect the doses administered in Cohorts 1-3 in the 
Protocol synopsis and Section 6.2 Treatment arms. 
• Treatment interruptions are permitted in Part 1 in response to elevations in AST, ALT 
or pruritus. Dose adjustments and treatment interruptions are permitted in Part 2 in 
response to elevations in AST, ALT or pruritus (interruption only). Section 6.2.1 
Permitted dose adjustments and interruptions of study treatment and Section 7.1 
Discontinuation of study treatment have been updated to reflect this. Table 15-1 and 
Table 6-1 provide the details for the follow up actions and when dose interruption or 
dose reductions are appropriate. 
• Section 6.4 Treatment blinding has been updated to reflect the use of a double dummy 
design in Part 2 to maintain the blind across the two dose arms of LJN452. 
• The use of paper diaries has been noted as an aide to treatment exposure and 
compliance in Section 6.6. The diaries will also be used to collect details of any 
concomitant medication the patient takes in response to an adverse event of itch. It has 
been noted the Investigator should review the use of the diary with the patient. 
• Section 6.8 Rescue medication has been updated to flag that patients with a high 
pruritus score at baseline or a history of pruritus should have a suitable supply of anti- 
pruritic therapy available at home. 
• Section 7.1 Discontinuation of study treatment has been revised to simplify the 
wording. Liver and renal related stopping criteria have been clarified and moved from 
Section 7.1 to Table 15-1 and Table 15-2 in Appendix 1 (adapted from previous   
Table 9-2 and Table 9-3 in Liver and Renal safety monitoring sections). The rationale 
for this change is to have all actions required following elevation of liver or renal 
markers in one place, as opposed to in multiple locations (e.g., stopping criteria, dose 
adjustment criteria and liver/renal safety monitoring) and to move to the back of the 
protocol for ease of reference by site staff. 
• Stopping criteria have been revised so that a CTCAE Grade 3 that is suspected to be 
related or a CTCAE Grade 4 (regardless of the relationship to study drug) have been 
identified as requirements to withdraw study medication, with the exception of 
pruritus, liver or renal parameters, which have their own stopping criteria outlined in 
Appendix 1 and Appendix 2 . 


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• Section 7.2 and Section 9.2.2 have been updated so that SAEs are collected from 
signing the informed consent until 30 days after the end of study treatment. Hence, the 
trigger for the safety follow up call is now 30 days after last treatment, rather than last 
visit, in line with revised Novartis requirements. Most patients will have a visit in this 
timeframe, so will not require a follow up safety call. 
• Section 7.4 Study stopping rules has been updated to reflect updates made to 
individual stopping criteria. It now specifies that the cohort stopping rules only apply 
to Part 1 (as dose escalation section of the study),
 
Details have been 
added to specify that for Part 2 the DMC will review safety data on a regular basis. 
• Section 8 has been updated with a Part 2 specific assessment schedule. In Part 1, the 
30 min pre-dose window was removed to make scheduling more practical. Medical 
history was added to the table and clarity was added to define which results remained 
as source data, as these were previously missing in error. 
• In Protocol Amendment 4, the option for the Investigator to delegate certain visit 
assessments to be performed at an alternative location was introduced. This has not 
been used and will not be available for Part 2, so references to this have been removed 
from Section 8 and throughout the protocol. 
• Section 8.4.4 Laboratory evaluations have been updated to add magnesium, phosphate 
and vitamin D as well as to specify all assessments performed as part of the clinical 
chemistry assessment (including fasting lipid panel). 
• Details of the pregnancy tests have been outlined in Section 8.4.6 Pregnancy. 
• Section 9.1 has been updated to remove collection of ‘outcome’ in the CRF as this is 
not collected in the CRF and clarification has been made as to when follow up of AEs 
continues until (end of study). 
• Section 9.3 Liver safety monitoring and Section 9.4 Renal safety monitoring have  
been streamlined and the information in Table 9-1, Table 9-2 and Table 9-3 moved 
and refined to be presented in Table 15-1 and Table 15-2 in Appendix 1, so easier to 
find. Table 15-1 includes study drug discontinuation (stopping criteria), liver safety 
monitoring (from Section 9) and new down titration options. Table 15-2 includes  
study drug discontinuation (stopping criteria) and renal safety monitoring (from 
Section 9). Since urinary protein-creatinine ratio varies by gender and age, one criteria 
has changed from ‘Protein-creatinine ratio (PCR) ≥ 150 mg/g or ≥ 15 mg/mmol’ to 
Protein-creatinine ratio (PCR) ≥ ULN’. 
• Section 10.3 Data Monitoring Committee has been updated to define the role the DMC 
will play in oversight of Part 2 of the study. 
• Data analysis has been updated to reflect the study design changes to Part  2  in 
Section 11 and in the Protocol synopsis. 


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• Creation of a table to outline the definitions of CTCAE Grades for Pruritus and the 
required actions, which include an option for study drug interruption of up to a week 
with CTCAE Grade 3 pruritus. 
• Section 14 References were updated with changes to references made in the text. 
• Editorial updates were made. 
Amendment 4 (July 2016) 
Amendment rationale 
The purpose of this amendment is to address feedback 
 
 on Amendment 3. Changes have also been made to the protocol to reduce the 
burden on the patients participating in the study. 
Additional changes have been made including clarification and slight modification of 
eligibility criteria, updated text describing the statistical analysis for clarification, addition of a 
higher dosage form, and minor editorial updates. 
The study is currently ongoing, with three patients dosed. It is not anticipated that the changes 
in the amendment will influence the study population or results of the study. 
 
Changes to the protocol 
• Section 3.1 ‘Study design’ has been updated to reflect the changes made to the timing of 
assessments on Days 1 and 28, that study medication for the full 28 days will be dispensed 
on Day 1 and that there is an option for Investigators to delegate responsibility for certain 
visits to be performed at an alternative location. 
• Figure 3-1 updated to remove day details for screening and baseline visits, as are a 
duplicate of the assessment schedule. 
• Updates have been made to 
 
Section 3.4 ‘Rationale for choice of comparator’ to reflect the recent approval of FXR 
agonist obeticholic acid. 
• Inclusion criteria 4 (Protocol synopsis and Section 4.1) has been updated to increase the 
BMI range from 18 – 35 kg/m2 to 18 – 40 kg/m2. 
• Additional inclusion criteria for Part 1 (Section 4.1.1) has been expanded to include 
patients who have been taking UCDA for at least 6 months (with no change in dose for 
≥ 3 months), provided they have reached maximal response to UCDA with a plateau in 
alkaline phosphatase levels. Whilst the initial requirement for 1 year of treatment is based 
on the widely held criteria to define UDCA response, it is clear that those that are non- 
responsive can be identified sooner (Carbone et al 2013). The minor change to the 
inclusion criteria will ensure that UDCA non-responder population will have early access 
to LJN452. Phenotypically these patients will be virtually identical to those recruited 
under previous inclusion criteria. 
• Exclusion criteria 3 and 4 have been clarified in Section 4.2. 
• Section 5.2 ‘Prohibited treatment’ has been updated to align with other studies with 
LJN452. 


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• Section 5.3 ‘On Day 1, no breakfast will be provided’ has been removed as is an 
unnecessary restriction. 
• The additional dose form of 0.03 mg has been added in Section 6.1.1 ‘Investigational 
treatment’. The higher strength dose form will simplify dosing if higher dose levels are 
reached through planned dose escalation. 
• ‘Liver safety monitoring’ (Section 9.3) and ‘Renal safety monitoring’ (Section 9.4) 
sections have been referred to in Section 7.1 ‘Discontinuation of study treatment’. 
• Addition of stopping rule for total bilirubin when elevated at baseline has been added to 
Section 7.1. ‘Discontinuation of study treatment’. 
• Section 7.4 ‘Study stopping rules’ has two updates: 
• Clarified stopping rule for when bilirubin is elevated at baseline. 
• Section 8 ‘Procedures and assessments’ and Table 8-1 ‘Assessment schedule’ have been 
updated as follows: 
• Visit windows for Screening and Baseline visits have been adjusted to avoid patients 
having to attend an additional visit to be re-screened to take account of when 
recruitment of patients ‘pauses’ for data review and dose escalation evaluation in- 
between cohorts. All subjects will have their eligibility reconfirmed at the baseline 
visit which will occur within 14 days prior to dosing. 
• Moved Day 1 pulse and blood pressure assessment timepoints from 6 hour to 4 hour 
post dose 
• Make later PK 
 sample collection timepoints optional on Days 1 and 28 
• 
 
 Additional 
pregnancy tests have been added to adhere to Novartis guidance on monthly 
pregnancy testing for women of childbearing potential that are able to be included in 
the study if they are taking highly effective contraception. Pregnancy testing has been 
added at Day 1, Day 28 and Day 56. 
• Provide the option for the Investigator to delegate certain visit assessments to be 
performed at an alternative location, which will have the required ethical approvals in 
place and be documented on the delegation of duties log 
• Add ‘Drug dispensing’ activity, to be performed on Day 1 (rather than at each visit) 
• Section 9.3 ‘Liver safety monitoring’ has been aligned with individual stopping criteria in 
Section 7.1, with guidance added for action in the event of initially elevated baseline 
values of ALT, AST, ALP or Bilirubin, plus provided more guidance on timeframes 
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• Table 9-3 ‘Specific Renal Alert Criteria and Actions’ has been updated to provide greater 
guidance on repeat test timeframe and requirement to withhold study drug until further 
evaluation if cannot be performed in this time-frame. 
• Updates have been made to provide greater clarity on the planned data analysis. 
Changes have been made in the synopsis and in Section 11 ‘Data analysis’. 
• Reference added to Section 14 ‘References’. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
 
Amendment 3 (March 2016) 
Amendment rationale 
The purpose of this amendment is to include emerging data
 
 As a result of the new data, a 
separate renal function exclusion criteria were added. In addition other minor changes, 
including the inclusion of ALP isozyme analysis, a patient dosing diary to monitor  
compliance and typographical corrections have been made to the protocol. 
 
Changes to the protocol 
• Section 1.1.1 has been updated to include emerging data from
 
 
• The total blood volume collected during the study was updated in Section 3.6 
• The description of highly effective contraception in the Exclusion Criteria was updated 
• The Exclusion Criteria have been updated to include a separate criteria related to renal 
function 
• Individual treatment discontinuation rules (Section 7.1) and study stopping rules 
(Section 7.4) have been updated 
• Section 8.1 was modified to remove the use of a legal representative giving consent on 
behalf of a patient unable to give consent themselves 
• A patient diary for compliance monitoring has been added to Section 8.3.2 
 
 
• Clarifying text was added in Section 11.4.1, Section 11.4.2 and Section 11.5.1 
• Primary Biliary Cirrhosis has been changed to Primary Biliary Cholangitis throughout the 
protocol 


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Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 
Amendment 2 (November 2015) 
Amendment rationale 
During the creating of Version No. 01 of the protocol, pregnancy testing was inadvertently 
removed from the Assessment Schedule. The purpose of this amendment is to re-add 
pregnancy testing into the protocol. 
 
Changes to the protocol 
• Pregnancy testing was re-added to the Assessment Schedule 
• Text was added to Section 8.4.1 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
This amendment is required for patient safety (i.e., necessary to eliminate immediate hazards 
to the trial subjects ICH GCP 3.3.8). Therefore it will be implemented prior to IRB/IEC 
approval, but will be sent for approval as well. 


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Amendment 1 (September 2015) 
Amendment rationale 
The purpose of this amendment is to address comments from the MHRA. 
 
Changes to the protocol 
• Text has been removed from Section 3.1 to remove the option of placebo patients being 
re-enrolled in future Cohorts in Part 1. 
• 
 Section 6.2 have been updated, to include text clarifying the maximum 
dose to be administered in Part 2. 
• Information has been added to the Additional Inclusion Criteria for Part 2 in Section 4.1.2, 
to provide specific information on patients not currently taking UDCA. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation. 


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Protocol synopsis 
Protocol number 
CLJN452X2201 
Title 
A multi-part, randomized, double-blind, placebo-controlled study to assess 
the safety, tolerability and efficacy of tropifexor (LJN452) in patients with 
Primary Biliary Cholangitis 
Brief title 
Study of safety, tolerability and efficacy of LJN452 in patients with Primary 
Biliary Cholangitis 
Sponsor and Clinical 
Phase 
Novartis 
Phase 2 
Intervention type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study to assess the safety, tolerability and efficacy of 
LJN452 in patients with Primary Biliary Cholangitis 
Primary Objective(s) 
• 
To determine the safety and tolerability of daily dosing of LJN452 in 
patients with Primary Biliary Cholangitis 
• 
To determine the effect of LJN452 on cholestatic markers in patients with 
Primary Biliary Cholangitis. More specifically, in Part 2 to determine the 
dose-response relationship of LJN452 on GGT following 12 weeks of 
treatment 
Secondary 
Objectives 
• 
To determine the change in the itch domain of PBC40 questionnaire 
• 
To evaluate the change in overall disease specific quality of life 
• 
To evaluate the change in itch based on 100 mm visual analog score 
(VAS) 
• 
To evaluate the pharmacokinetics (PK) of LJN452 in patients with PBC 
• 
Part 2: To determine the dose-response relationship of LJN452 on ALP  
in patients with PBC following 12 weeks of treatment 
Study design 
This is a randomized, double-blind, placebo controlled, multi-part study to 
assess safety, tolerability and efficacy of LJN452 in patients with Primary 
Biliary Cholangitis (PBC). 
Part 1 uses an escalating multiple dose design in PBC patients with 
incomplete biochemical response to, but still taking, ursodeoxycholic acid 
(UDCA). 
Part 2 is a parallel-group, 12-week study to assess the safety, tolerability and 
efficacy of two doses of LJN452 as compared to placebo in PBC patients with 
an incomplete biochemical response to, but still taking UDCA or in those not 
currently taking UDCA. 
The two LJN452 doses for Part 2 will be selected based on safety, tolerability 
and efficacy data from Part 1. 
Once approximately 40 patients from Part 2 have completed 8 weeks of 
treatment, an interim analysis will be conducted to re-assess the sample size. 
Recruitment will continue while the interim analysis is performed. 


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Population 
The study population will comprise male or female patients with PBC aged 18 
and above. 
In Part 1 of the study a minimum of 30 and maximum of approximately 75 
PBC patients with an incomplete biochemical response, but still currently 
taking UDCA will be randomized to LJN452 or placebo. 
In Part 2 approximately 88 PBC patients will be randomized to either Dose 
level 1 or Dose level 2 of LJN452, or matching placebo in a 3:3:2 ratio. 
The maximum dose to be used in the study is 0.18 mg. 
Patients with an incomplete biochemical response to, but still taking, UDCA 
and those not currently taking UDCA will be stratified across treatment arms. 
Severity of pruritus will also be used to stratify patient across treatment arms. 
Final sample size for Part 2 will be informed by the interim analysis. 
Inclusion criteria 
• 
Age ≥ 18 years 
• 
Diagnosis of PBC as demonstrated by the presence of ≥ 2 of the 
following 3 diagnostic criteria: 
• 
History of Alkaline Phosphatase elevated above upper limit of 
normal for at least 6 months 
• 
Positive antimitochondrial antibodies (AMA) titer or if AMA 
negative or in low titer (<1:80) PBC specific antibodies (anti- 
GP210 and/or anti-SP100 and/or antibodies against the major 
M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase 
complex)) 
• 
Previous liver biopsy consistent with PBC 
• 
At least 1 of the following markers of disease severity: 
• 
ALP ≥ 1.67× upper limit of normal (ULN) 
• 
Total bilirubin > ULN but < 1.5 × ULN 
In addition, patients must meet the following biochemical criteria at 
enrollment 
• 
ALT/AST ≤5 × ULN 
• 
Total bilirubin ≤1.5 × ULN 
• 
INR ≤ ULN 
• 
Subjects must weigh at least 40 kg to participate in the study, and must 
have a body mass index (BMI) within the range of 18 - 40 kg/m2. BMI = 
Body weight (kg) / [Height (m)]2. 
• 
Able to communicate well with the investigator, to understand and comply 
with the requirements of the study. 
Exclusion criteria 
• 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception for 30 days before randomization, during 
dosing and for 30 days following the end of treatment. 
• 
Presence of other concomitant liver diseases. 
• 
Cirrhosis with complications, including history or presence of: 
• 
Variceal bleed 
• 
Uncontrolled ascites 
• 
Encephalopathy 
• 
Spontaneous bacterial peritonitis 


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• 
Significant hepatic impairment as defined by Child-Pugh classification of 
B or C, history of liver transplantation, current placement on a liver 
transplant list or current Model for End Stage Liver Disease (MELD) 
score ≥15. 
• 
History of conditions that may cause increases in ALP (e.g., Paget's 
disease). 
• 
Use of investigational drugs, or immunosuppressive drugs at the time of 
enrollment, or within 5 half-lives, or 30 days of randomization, whichever 
is longer; or longer if required by local regulations. Use of high dose oral 
steroids to treat co-morbid conditions (e.g., airways disease) will be 
allowed but must be properly documented as such in concomitant 
medications. 
• 
Currently taking obeticholic acid or have taken obeticholic acid within 
30 days of randomization 
• 
Previous participation in CLJN452X2201 and received study medication 
within three months of randomization (or longer if required by local 
regulations). 
Investigational and 
reference therapy 
• 
Part 1: 
• 
Cohort 1 LJN452 0.03 mg or placebo once daily for 28 days, 
• 
Cohort 2 LJN452 0.06 mg or placebo once daily for 28 days, 
• 
Cohort 3 LJN452 0.09 mg or placebo once daily for 28 days 
• 
Cohorts 4-5 LJN452 TBD mg or placebo once daily for 28 days 
• 
Part 2: Two dose levels of LJN452 (doses TBD from Part 1 data), or 
placebo once daily for 12 weeks. Dose adjustments will be permitted. 
Efficacy/PD 
assessments 
• 
Liver function tests, specifically GGT, ALP and bilirubin 
• 
PBC40 for quality of life and itch 
• 
VAS for itch and sleep 
Safety assessments 
• 
Physical exam 
• 
Vital signs 
• 
Laboratory evaluations 
• 
ECG 


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Data analysis 
Part 1: The primary efficacy endpoint (Serum GGT measured at Day 28) will 
be analyzed by repeated measures analysis of covariance. The analysis will 
take place on the log-transformed scale and encompass all available GGT 
measurements over time. The model will use a saturated within-subject 
covariance structure and a separate fixed effect for treatment, visit, 
treatment*visit interaction and log baseline as well as log(baseline)* visit 
interaction. The treatment difference between each LJN452 dose and 
placebo will be estimated and summarized at each visit by a 90% two-sided 
confidence interval. Dose response may be assessed using appropriate 
contrasts. 
Part 2: The same repeated measures ANCOVA described above for Part 1 
with the UDCA and pruritus stratification factor included as an additional fixed 
effect will be employed in Part 2. 
Whole study: Summary statistics will be provided for Safety endpoints, PK 
parameters 
. 
Key words 
Primary Biliary Cirrhosis, Primary Biliary Cholangitis, PBC 


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1 
Introduction 
LJN452 is a highly potent agonist of the farnesyl X receptor (FXR) which modulates bile acid 
synthesis and detoxifying metabolism in the liver. Cholestasis is a pathological condition in 
which bile flow from the liver to the intestine is reduced or blocked. Causes of cholestasis 
include developmental abnormalities,  trauma,  chemical  or  immunological  damage.  
Chronic cholestasis leads to fibrosis, cirrhosis and potentially the need for liver 
transplantation. LJN452 is expected to provide significant therapeutic benefit in patients with 
cholestatic conditions such as Primary Biliary Cholangitis (PBC). 
 
1.1 
Background 
Cholestasis is a pathological condition in which bile flow from the liver to the gall bladder or 
intestine is reduced or blocked, leading to accumulation of potentially toxic biliary 
constituents. PBC is an autoimmune disease of unknown etiology characterized by slowly 
progressive cholestasis that may lead to cirrhosis, liver transplantation or death. The only 
approved therapy for PBC is the bile acid ursodeoxycholic acid (UDCA), however this is 
ineffective in approximately 40% patients, which highlights the need for new drugs. 
FXR is a nuclear receptor activated by bile acids (Chen et al 2004; Makishima et al 1999; 
Parks et al 1999; Wang et al 1999). When activated, FXR initiates a sensitive, negative 
feedback loop affecting various aspects of bile acid metabolism resulting in reduced bile acid 
levels (Zollner et al 2006). Pharmacological activation of FXR is proposed to be an effective 
treatment for intrahepatic cholestasis by increasing bile flow from the liver to the intestine, 
reducing hepatic bile acid uptake and bile acid synthesis, increasing renal bile acid excretion, 
decreasing circulating bile acid levels and reducing hepatic fibrosis. The therapeutic potential 
of FXR agonism has been studied in Phase 2 clinical trials and a reduction in biomarkers of 
cholestatic disease, such as alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT), 
has been demonstrated (Mason et al 2010a; Kowdley et al 2011; Hirschfield et al 2015). 
LJN452 is a highly potent, specific and orally available FXR agonist. This is a study to 
determine the safety, tolerability, pharmacokinetics efficacy of LJN452 in patients with PBC. 
 
1.1.1 
Relevant data summary 
Detailed background information on the chemistry, pharmacology, toxicology and 
pharmacokinetics of LJN452 are given in the Investigator’s Brochure. The most relevant data 
for the present study are summarized in the sections below. 
 
1.1.1.1 
Preclinical data 
Pharmacology 
In vitro pharmacology studies demonstrate that LJN452 is a potent human FXR agonist with an 
EC50 of 0.2 nM and 0.3 nM in a cell-based FXR reporter gene assay and in a biochemical co-
activator interaction assay, respectively, with >30,000 fold selectivity over other nuclear receptors. 
Furthermore, LJN452 demonstrated no off-target binding/activity (up to 30 µM) in a broad 
specificity-screening panel of receptors, transporters, ion channels, nuclear receptors or 
enzymes. 


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FXR agonism has been shown to modify gene expression of a number of enzymes and 
transporters responsible for drug metabolism  and  secretion  (Calkin and Tontonoz 2012). 
The time course of effects of LJN452 on the bile salt export pump (BSEP) in preclinical 
species is detailed in the Investigator’s Brochure in addition to potential induction of drug 
metabolizing enzymes. Drug secretion into bile is typically considered a safe route of 
clearance. However, biliary delivery of some drugs or their reactive metabolites to the 
intestinal tract may evoke adverse consequences due to direct toxic actions or indirect 
disruption  of  intestinal  homeostasis.   For   example,   delivery   of   reactive   metabolites  
of diclofenac via MRP2 into bile has been linked  with  NSAID  enteropathy  (Treinen-
Moslen and Kanz 2006).
 
 
In vivo a single oral dose of LJN452 in naïve rats ranging from 0.03-10 mg/kg demonstrated a 
dose-dependent increase in expression of FXR target genes (liver BSEP and small 
heterodimer partner (SHP), ileum SHP and FGF15). Dosing of  naïve  rats  with  LJN452 
(p.o., q.d. for 2 weeks) resulted in modulation of gene expression and clinically relevant 
pharmacodynamic and biomarker (FGF15) changes at doses as low as 0.01 mg/kg/day. 
 
 
 
 
 
 
 
 


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Pharmacokinetics 
LJN452  has  moderate  oral  bioavailability  in  animals  (≥10%).  Plasma  terminal  T1/2  
was moderate  to  long.  Clearance  and  volume  distribution  were  low   to   moderate.   
After repeated doses, the exposure was dose proportional with no consistent sex difference. 
No accumulation was observed in dog, but mild accumulation noted in rat. LJN452 is highly 
plasma protein bound (>97%). 
 
     
 
 
 
 
 
 
 
 


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1.2 
Study purpose 
The purpose of Part 1 is to assess the safety, tolerability and efficacy of LJN452 
administration for 4 weeks on markers of cholestasis in patients with Primary Biliary 
Cholangitis (PBC), to enable decisions regarding the further development of LJN452 in the 
indication of PBC. In addition, data obtained in Part 1 will inform dose selection for Part 2. 
The purpose of Part 2 is to further assess the safety and efficacy of two dose levels of LJN452, 
when administered for longer (12 weeks) and in a wider patient population (both those taking 
and not taking UDCA). This will provide data to support further development of LJN452 in 
patients with PBC. 


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2 
Study objectives 
2.1 
Primary objectives 
 
Objective 
Endpoint 
 
• To determine the effect of LJN452 on 
cholestatic markers in patients with PBC. 
More specifically, in Part 2 to determine 
the dose-response relationship of LJN452 
on GGT following 12 weeks of treatment 
• To determine the safety and tolerability of 
daily dosing of LJN452 in patients with 
PBC 
• Liver function tests, specifically GGT 
 
 
 
• All safety endpoints (including physical 
exam, vital signs, ECG, safety laboratory 
tests) 
• Serious adverse events, adverse events 
 
 
 
2.2 
Secondary objectives 
 
Objective 
Endpoint 
 
• To evaluate the pharmacokinetics (PK) of 
LJN452 in patients with PBC 
• To evaluate the change in overall disease 
specific quality of life 
• To determine the change in the itch 
domain of PBC40 questionnaire 
• To evaluate the change in itch based on 
100 mm visual analog score (VAS) 
• Part 2: To determine the dose-response 
relationship of LJN452 on ALP in 
patients with PBC following 12 weeks of 
• PK Blood collection 
 
• PBC40 
 
• PBC40 
 
• Global Itch Visual Analogue Scale 
 
• ALP at baseline and week 13 
  
treatment 
 


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3 
Investigational plan 
3.1 
Study design 
This is a randomized, double-blind, placebo-controlled, multi-part study to assess safety, 
tolerability and efficacy of LJN452 in patients with Primary Biliary Cholangitis (PBC). 
Part 1 uses an escalating multiple dose design in PBC patients with incomplete biochemical 
response to, but still taking, ursodeoxycholic acid (UDCA). 
Part 2 is a parallel-group, 12-week study to assess the safety, tolerability and efficacy of two 
doses of LJN452 compared to placebo in PBC patients with an incomplete biochemical 
response to, but still taking, UDCA or those not currently taking UDCA. The two LJN452 
doses for Part 2 will be selected based on safety, tolerability and efficacy data from Part 1. 
Once approximately 40 patients from Part 2 have completed 8 weeks of treatment, an interim 
analysis will be conducted to re-assess the sample size for Part 2. Recruitment will continue 
while the interim analysis is performed. Figure 3-1 shows how Parts 1 and 2 are connected. 


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Part 1: Multiple (1 to 5) cohorts; 4 weeks treatment 
Cohort 1 
28 Day treatment 
Cohort 1 
Follow up 
Dose 
Escalation 
Meeting 
Cohort 2 
28 Day treatment 
Cohort 2 
Follow up 
Dose 
Escalation 
Meeting 
Cohort 3 etc 
28 Day treatment 
Cohort 3 etc 
Follow up 
Day 28 data available 
Two dose levels approved by DMC 
Part 2: Parallel design, 2 dose levels,12 weeks treatment 
Dose Level 1 12 week treatment 
Follow up 
Dose Level 2 12 week treatment 
Follow up 
Placebo 12 week treatment 
Follow up 
 
Figure 3-1 
Study design 
 
 
Part 1 
A minimum of 2 and maximum of 5 cohorts of approximately 15 patients with PBC with 
incomplete biochemical response, but still taking UDCA treatment will be enrolled into Part 1, 
with the aim of a minimum of 12 patients per cohort completing. Patients withdrawing for 
reasons other than AEs may be replaced throughout the study. Patients withdrawing from a 
cohort may not be enrolled in a subsequent cohort. 
Figure 3-2 shows the study design of Part 1. At the beginning of Part 1, a screening visit will 
take place, where a patient's eligibility to enter the study will be assessed. Eligible patients 
will be admitted to the study site and re-evaluated for inclusion / exclusion criteria during the 
baseline visit. All baseline safety evaluation results must be available and reviewed prior to 
first dosing. 


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Figure 3-2 
Study design Part 1 
Study Day 
1 
7 
14 
21 
28 
29 
56 
84 
Study visit 
 
 
 
 
 
 
 
 
 
 
Screening 
BL 
        4 week treatment period 
 
Follow up 
EOS 
 
BL = Baseline assessments 
EOS = End of Study visit 
 = Study visit  = Optional study visit 
Patients will be asked to arrive at the study site approximately 2 hours  prior to  dosing on  
Day 1. Patients in Cohort 1 will be randomized in a 2:1 ratio to receive the starting dose of 
0.03 mg LJN452 or placebo. Safety assessments will be performed for 4 hours post dose and 
pharmacokinetic 
 assessments will be performed for up to 8 hours post first 
dose (see Assessment schedule for details). Prior to discharge, the patients will be given a 
supply of LJN452 or placebo and instructed to take first thing in the morning with water, prior 
to eating every day. 
Patients will then return on Days 7, 14 and 21 for safety, pharmacokinetic 
 
assessments and dosing. Patients will be asked to return to the study site on Day 28, for the 
final dosing visit, when safety, pharmacokinetic 
 assessments will be performed. 
Patients will be asked to return to the study site for an optional ambulatory visit on Day 29, 
where 24 hour post dose pharmacokinetic 
 assessments will be performed. 
Patients are asked to return to the study site on approximately Day 56 for follow up 
assessments. An end of study visit will take place at approximately Day 84. 
A dose escalation review and an interim analysis are planned when at least 12 patients have 
completed dosing and Day 28 assessments in Cohort 1. The main purpose of the interim 
analysis will be to evaluate the observed variability in GGT levels and, if needed, consider a 
sample size re-estimation. 
The Lead PI from each active country and Investigators with patients recruited into the cohort 
will be invited to be involved in the review of blinded data from that cohort and the decision 
on the dose for the next cohort of subjects (if applicable). Full details of the process are 
outlined in the Dose Escalation Charter and the SOM. 
Additional cohorts will follow the same schedule as Cohort 1. Further cohorts may be added 
depending on emerging safety and PK/PD data. Additional interim analyses may be  
performed after a minimum of 12 patients in each cohort finish dosing and Day 28 assessment. 
The sponsor will be unblinded and the Clinical Trial Team may be unblinded when  all 
subjects in a cohort have completed 28 day of study hence at the time of the planned IAs. 


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Part 2 
Approximately 88 patients with PBC, with an incomplete biochemical response to, but still 
taking, UDCA or those not currently taking UDCA are planned to be recruited into Part 2, 
with the aim that 80 will complete the study. Patients who participated in Part 1 may be 
recruited to Part 2, provided they meet all required eligibility criteria and have not received 
study medication within 3 months of Randomization, (or longer if required by local 
regulations) – see exclusion criteria. 
 
Figure 3-3 
Study design Part 2 
Week 
-12 to -2 
1 
2 
3 
5 
9 
13 
17 
Study visit 
 
 
TC 
 
 
 
 
 
Screening 
BL 
12 week treatment period 
Follow up 
EOS 
BL = Baseline assessments (performed pre-dose Day 1) 
 = Study visit 
TC = Telephone Contact 
EOS = End of Study visit 
A screening visit will take place, where patient's eligibility to enter the study will be assessed. 
Eligible patients will be asked to arrive at the study site approximately 2 hours prior to dosing 
on Day 1 to perform Baseline assessments. 
Patients will be randomized in a 3:3:2 ratio to receive either LJN452 Dose level 1, LJN452 
Dose level 2 or placebo. Following drug administration, safety, pharmacokinetic 
 
 assessments will be performed at two hours post dose. 
Prior to discharge, the patients will be given a supply of LJN452 or placebo and instructed to 
take their dose first thing in the morning with water, prior to eating every day. New supplies 
will be dispensed on a monthly basis during regular study visits. 
Patients will then return at weeks 3, 5, 9 and 13 for safety, tolerability, pharmacokinetic 
 
. A telephone contact will be made one week after start of dosing to 
check their progress and check they have no questions. 
Patients will be asked to return to the study site in week 17 for follow up assessments and to 
complete their end of study assessments. 
If a patient has a medically important AE that is considered related to study drug and which 
has not resolved or stabilized at their scheduled end of study visit (week 17), they will be 
followed, until resolution or stabilization of the AE. 
The following will be considered as medically important: 
i) An AE with CTCAE Grade ≥3 
ii) SAE 
iii) hepatic and renal events should be followed up per the guidance in Table 15-1 and 
Table 16-1 


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These patients will be monitored by the investigator and have unscheduled visits to collect 
safety and/or laboratory data. It is advised that the first follow up of these patients with such 
events will be scheduled at approximately week 21, or sooner based on Investigator’s 
discretion. If events are not resolved or stabilized at this time point, further follow up will be 
scheduled at the Investigator’s discretion and unscheduled visits will be used to collect safety 
and/or laboratory data. As soon as the event is resolved and/or stabilized, and as long as there 
are no additional medically important AEs from the treatment period ongoing, no further 
follow up is required. 
 
3.2 
Rationale of study design 
This randomized, multi-center, double-blind, placebo-controlled, parallel-group, multi-part 
study is designed to evaluate safety, tolerability and efficacy of LJN452 (in doses of 0.01 mg 
and above) relative to placebo in patients with PBC. This will be assessed by a reduction in 
the cholestatic marker GGT after 4 weeks of double-blind treatment in Part 1 and 12 weeks of 
double-blind treatment in Part 2. 
In Part 1 up to 5 dose levels will be explored to allow characterization of dose exposure 
response relationship in PBC patients. Randomization in Part 1 has been chosen on a 2:1 ratio 
in order to rapidly obtain safety and PK data for LJN452. Since 2 cohorts are initially 
anticipated, the chosen ratio will provide a similar number of patients treated at each dose 
level to compare with placebo. 
In Part 2 two dose levels of LJN452 will be selected based on the safety, tolerability and 
efficacy data from Part 1. 
Randomization in Part 2 has been chosen on a 3:3:2 ratio to enable more safety data to be 
obtained from patients receiving LJN452. Thus assessment of the safety, tolerability and 
efficacy of 12 weeks treatment with two dose levels of LJN452 will be assessed, to provide 
data to support dose selection for future development. In addition, an interim analysis is 
planned in Part 2 to determine the effect of LJN452 on GGT and itch parameters and to assess 
the variability for sample size re-estimation, if needed. 
In order to maintain the scientific integrity of the study, the investigator and patient will 
remain blinded to their treatment assignment until database lock (either at the end of the study, 
or earlier in the event of a staggered lock of Part 1 or cohorts in Part 1). 
The use of multiple cohorts of ascending dose in Part 1 will allow evaluation of safety, PD 
and PK starting  at a  dose  below the  maximum dose tested so  far in  healthy volunteers.  
The multiple cohort dose escalation design will allow characterization of the dose-exposure-
response relationship in PBC patients. Escalation will depend on safety parameters and the 
increment in dose will not exceed 1.67 fold at doses greater than 0.09 mg. 
Part 1 will provide safety and efficacy data for LJN452 in a population who have not had 
satisfactory biochemical response to the first line standard of care UDCA and hence are at 
increased risk of disease progression to hepatic decompensation, transplantation or death. 
Data obtained in Part 1 will allow selection of doses to be used in Part 2. 


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Part 2 will provide safety and efficacy data from a longer treatment duration with LJN452 in 
the same population as well as widening the population to include patients who are not 
currently taking standard of care, UDCA (patients will be stratified across the treatment 
groups based on their UDCA status). This group has a high unmet clinical need and is likely 
to make up a significant minority population in later phase studies. 
Patients will also be stratified across the treatment groups based on the severity of any 
pruritus. Patients with a PBC-40 score at screening of <7 will be classed as low severity and 
those with a score ≥7 will be classed as high severity. 
 
  


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3.4 
Rationale for choice of comparator 
A placebo will be used as a comparator in this study to ensure the effects of LJN452 are 
related to the study drug. Recently, the FXR agonist obeticholic acid (Ocaliva™, Intercept 
Pharmaceuticals) was approved for those with PBC non-responsive to or intolerant of UDCA. 
However, obeticholic acid is not universally utilized for treatment of PBC. Furthermore, PBC 
patients with severe itch were  excluded  from  Phase  3  POISE  study  (Nevens et al 2016). 
In order to allow those with severe itch to be enrolled into the study placebo will be used as a 
comparator. 


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3.5 
Purpose and timing of interim analyses/design adaptations 
The first interim analysis will be performed when at least 12 patients in Cohort 1 have 
completed 4 weeks of dosing at 0.03 mg and Day 28 post dose assessments. The purpose of 
this interim analysis is to assess patient safety, to evaluate the assumption on intra-subject 
variability of GGT, which was used for sample size calculations, and to select a dose for the 
next cohort. An ANCOVA model will be fitted to estimate the change from baseline in GGT 
and its variability, and an unblinded sample size re-estimation conducted. The results may be 
used to adjust the size of the next cohort. 
Doses in subsequent cohorts of Part 1 will be decided based on accumulated information 
collected from all previous cohorts including safety, PK and PD data. 
Additional interim analyses will be performed when at least 12 patients in subsequent cohorts 
of Part 1 have completed 4 weeks of dosing and Day 28 assessments. Placebo data from all 
cohorts will be pooled in the ANCOVA model to evaluate the treatment difference between 
each dose level of LJN452 versus placebo. No multiplicity adjustment will be made due to the 
exploratory nature of the study. 
Results from Part 1 will be used to select the doses for Part 2, which may be initiated prior to 
the completion of Part 1. Part 2 will not be initiated if the estimated change from baseline in 
GGT at Day 28 is smaller than 20% at the highest dose level of LJN452 in Part 1. 
Unblinded interim analysis results from Part 1 will be reviewed by an internal Novartis 
Interim Analysis Team which may include some CTT members. The Interim Analysis Team 
may communicate interim results to relevant Novartis teams for information, consulting 
and/or decision purposes. 
In Part 2 of the study, an interim analysis is planned when approximately 40 patients have 
completed their Week 8 visit. The purpose of this interim analysis is to review the sample size 
(calculated based on GGT and ALP changes) to assess if it is also adequate to provide precise 
enough treatment difference estimates in itch parameters, a key tolerability endpoint. 
This study will utilize a staggered lock of the clinical database, so that the data can be locked 
after completion of Part 1, or a set of Cohorts in Part 1. 
Once a Cohort’s data has been locked, treatment codes for the relevant cohort(s) will be 
released and made available for data analysis. 
The results from the locked Part 1 interim analysis can be communicated beyond Novartis to 
groups including, but not limited to individuals treating the study’s subjects, Health 
Authorities and reported on clinical registries. 
Additional interim analyses 
 may be conducted to support decision 
making concerning the current clinical study, the sponsor’s clinical development projects in 
general or in case of any safety concerns. No dose escalation is planned in Part 2. 
Additional information is presented in Section 11.8. 


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3.6 
Risks and benefits 
There is no benefit expected for subjects participating in this short-term study. 
Preliminary data from study CLJN452X2101 have demonstrated isolated increases in 
transaminases ALT and AST 
. These changes normalized 
spontaneously have not been observed at the proposed starting dose. 
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and stopping rules. 
A maximum of 500 mL of blood is planned to be collected over a period of 16 weeks, from 
subjects as part of the study (Part 1 sample volume will be approximately 490 mL and Part 2 
will be approximately 450 mL). Additional samples for monitoring of any safety findings may 
be required, and would be in addition to this volume. This is not considered to be a risk for 
this population. 
There may be unknown risks of LJN452 which may be serious and unforeseen. 
 
4 
Population 
The study population will be comprised of patients with PBC. 
In Part 1, a total of approximately 15 patients will be enrolled in each cohort of the study and 
randomized. 
In Part 2, a total of approximately 88 patients will be enrolled and randomized. Final sample 
size for Part 2 will be informed by the interim analysis. 
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects. 
Subject selection is to be established by checking through all eligibility criteria at screening 
and baseline (for Part 1). A relevant record (e.g., checklist) of the eligibility criteria must be 
stored with the source documentation at the study site. 
Deviation from any entry criterion excludes a subject from enrollment into the study. 
In Part 1 replacement subjects may be enrolled to replace subjects who discontinue the study 
for reasons other than safety. 
 
4.1 Inclusion criteria for Parts 1 and 2 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Age ≥ 18 years 
3. Diagnosis of PBC as demonstrated by the presence of at least 2 of the following 
3 diagnostic criteria: 
• History of Alkaline Phosphatase elevated above upper limit of normal for at least 
6 months 


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• Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer 
(<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies 
against the major M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase 
complex)) 
• Previous liver biopsy findings consistent with PBC 
4. At least 1 of the following markers of disease severity: 
• ALP ≥ 1.67× upper limit of normal (ULN) 
• Total bilirubin > ULN but < 1.5 × ULN 
In addition, patients must meet the following biochemical criteria at enrollment 
• ALT or AST ≤ 5 × ULN 
• Total bilirubin ≤ 1.5 × ULN 
• INR ≤ ULN 
5. Subjects must weigh at least 40 kg to participate in the study, and must have a body mass 
index (BMI) within the range of 18 - 40 kg/m2. BMI = Body weight (kg) / [Height (m)]2. 
6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
 
4.1.1 
Additional Inclusion Criteria for Part 1 
All patients enrolled in Part 1 must meet the following criteria: 
1. Taking UDCA for at least 12 months, or for at least 6 months and has reached maximal 
response to UDCA with a plateau in alkaline phosphatase, (with no changes in dose for 
≥ 3 months) prior to Day 1. 
 
4.1.2 
Additional Inclusion Criteria for Part 2 
All patients enrolled in Part 2 must meet the following criteria: 
1. Patients not currently taking UDCA and who have not taken UDCA for ≥ 3 months prior 
to Day 1 (for example UDCA naïve patients, patients who were unable to tolerate UDCA 
or had stopped taking due to lack of efficacy) OR Patients taking UDCA for at least 
12 months, or for at least 6 months and has reached maximal response to UDCA with a 
plateau in alkaline phosphatase, (with no changes in dose for ≥ 3 months) prior to Day 1 
 
4.2 
Exclusion criteria for Parts 1 and 2 
Patients fulfilling any of the following criteria are not eligible for  inclusion  in  this study.  
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Presence of other concomitant liver diseases including: 
• Active Hepatitis B or C virus (HCV, HBV) infection 
• Primary sclerosing cholangitis (PSC) 
• Alcoholic liver disease 
• Definite autoimmune hepatitis 
• Nonalcoholic steatohepatitis (NASH) 


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• Gilbert's Syndrome 
2. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception for 
30 days before randomization, and will continue to use it during dosing and for 30 days 
following the end of treatment. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 m prior to screening). For female subjects on the study, the 
vasectomized male partner should be the sole partner for that subject 
• Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment and should complete at least 
one full cycle after completing dosing. 
3. Cirrhosis with complications, including history or presence of: 
• Variceal bleed 
• Uncontrolled ascites 
• Encephalopathy 
• Spontaneous bacterial peritonitis 
4. Significant hepatic impairment as defined by Child-Pugh classification of B or C, history 
of liver transplantation, current placement on a liver transplant list or current Model for 
End Stage Liver Disease (MELD) score ≥15. 
5. History of medical conditions other than PBC that may cause increases in ALP 
(e.g., Paget's disease). 
6. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or treated cervical intraepithelial neoplasia), treated or untreated, within the past 
5 years, regardless of whether there is evidence of local recurrence or metastases. 
 
 
 
8. History of non-adherence to medical regimens, or patients who are considered to be 
unable to reliably comply with the requirements of the study. 


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9. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, 
or longer if required by local regulation. 
10. Use of other investigational drugs or immunosuppressive drugs at the time of enrollment, 
or within 5 half-lives/30 days of randomization, whichever is longer; (or longer if required 
by local regulations). Use of high dose oral steroids to treat co-morbid conditions 
(e.g. airways disease) will be allowed but must be properly documented as such in 
concomitant medications. 
11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
12. History of drug or alcohol abuse within the 12 months prior to dosing. 
13. Significant illness which has not resolved within two (2) weeks prior to initial dosing. 
14. Acute or chronic renal disease with a screening serum creatinine > ULN. 
15. Elevated liver function tests at screening defined as follows: 
• potential Hy’s Law case (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN 
without notable increase in ALP to > 2 × ULN) or 
• ALT or AST > 3 × ULN combined with INR > 1.5. 
• Total bilirubin > ULN combined with albumin outside of the normal range. 
16. Currently taking obeticholic acid or have taken obeticholic acid within 30 days of 
Randomization. 
17. Participation in CLJN452X2201 and received study medication within three months of 
Randomization (or longer if required by local regulations). 
18. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) 
test result. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
 
5 
Restrictions for Study Subjects 
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the following restrictions: 
 
5.1 
Contraception requirements 
Please refer to exclusion criteria (Section 4) for details of contraception requirements for the study. 


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5.2 
Prohibited treatment 
Obeticholic acid: 30 days prior to randomization, during treatment and until completion of the 
End of Study visit. 
Investigational drugs: within 5 half-lives/30 days  of randomization, whichever is longer;     
(or longer if required by local regulations). 
Immunosuppressive drugs: within 30 days of randomization. Exception; the use of high dose 
oral steroids to treat co-morbid conditions (e.g. airways disease) will be allowed but must be 
properly documented as such in concomitant medications. 
No medication or herbal remedies likely to have an impact on LJN452 metabolism will be 
allowed from the first dosing until day 28 (Part 1) or End of Study (Part 2) evaluations have 
been conducted. 
 
 
 
 
A full list of prohibited medications will be provided in the SOM. 
 
5.3 
Dietary restrictions and smoking 
• No alcohol consumption is allowed for 8 hours before dosing and each study visit until 
Study Completion evaluation. 
• In Part 1: all subjects will fast (i.e., no food and liquid except water) for at least 8 hours 
prior to administration of study drug and will continue to fast for at least 2 hours thereafter. 
No fluid intake apart from the fluid given at the time of drug intake is allowed from 2 h 
before until 2 h after dosing. 
• In Part 2: all patients will fast (i.e. no food and liquid except water) for at least 8 hours 
prior to each dose and should refrain from drinking for at least 30 min post dose, and 
refrain from eating  for  at least 60 min post dose. A light breakfast may be taken after    
60 minutes. 
 
5.4 
General restrictions 
• 
No strenuous physical exercise (e.g., weight training, aerobics, football) until after Study 
Completion evaluation. 
Note: Patients should be reminded by site staff that on the day of a study visit during the 
treatment period to not take their study medication at home that morning, and to come fasted 
and bring their study medication with them to take once their pre-dose assessments have been 
completed. 


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6 
Treatment 
6.1 
Study treatment 
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatment are outlined in Section 3 of the Site Operations 
Manual. 
 
6.1.1 
Investigational treatment 
The investigational drug, LJN452 0.01 mg, 0.03 mg or 0.1 mg and matching placebo will be 
prepared and supplied by Novartis as a single blind patient specific packs to be dispensed by 
the unblinded pharmacist at the investigator site. 
In Part 1, once a patient is confirmed as eligible after completion of their Baseline 
assessments, a Randomization Number can  be  requested,  following  the  process  in  the  
Site Operations Manual. The Pharmacist/unblinded designee then dispenses the study 
medication according to the treatment assignment for that Randomization number, according 
to the supplied randomization schedule (provided via Treatment Allocation Cards or 
Electronic Randomization list). 
In Part 2, once a patient is confirmed as eligible after completion of their Screening 
assessments, the site will contact the Interactive Response Technology (IRT) system, which 
will randomize the patient to the appropriate treatment. For further details, please see the Site 
Operations Manual and NIRT Site user manual. 
 
6.2 
Treatment arms 
Part 1 
Patients in each cohort will be assigned to one of the following treatment arms in a ratio of 2:1. 
The number of patients enrolled in Cohorts 2-5 may change based on data from IAs. 
Cohort 1: 
• LJN452 0.03 mg daily for 28 days (n=10) (given as 3 x LJN452 0.01 mg) 
• LJN452 Placebo daily for 28 days (n=5) 
Cohort 2: 
• LJN452 0.06 mg daily for 28 days (n=10) 
• LJN452 Placebo daily for 28 days (n=5) 
Cohort 3: 
• LJN452 0.09 mg daily for 28 days (n=10) 
• LJN452 Placebo daily for 28 days (n=5) 
Cohorts 4-5 (if required) may receive different doses: 
• LJN452 TBD mg daily for 28 days (n=10) 
• LJN452 Placebo daily for 28 days (n=5) 


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Part 2 
Patients in Part 2 will be assigned to one of the following treatment arms in a ratio of 3:3:2. 
• LJN452 Dose level 1: TBD 
 
daily for 12 weeks (n=33) 
• LJN452 Dose level 2: TBD 
 
daily for 12 weeks (n=33) 
• LJN452 Placebo daily for 12 weeks (n=22) 
Part 2 dose levels will be selected based on  a  balance of safety, tolerability and efficacy.   
The dose levels selected in Part 2 will be approved by the DMC and
 
 
 
6.2.1 
Permitted dose adjustments and interruptions of study treatment 
Part 1 
Within a cohort, once a dose is decided on, study drug dose adjustments are not permitted. 
Interruption to study drug may occur based on the criteria outlined in Table 15-1 (Liver events) 
and Table 6-1 (Pruritus event definitions and required actions). 
In case of notable adverse events or safety concerns during dose escalation of the study, the 
following changes to the next planned dose level may be considered: 
• Administration of a dose below the starting dose 
• Administration of an intermediate dose between the current and preceding dose 
• Administration of an intermediate dose between the current and next planned dose 
• Repeated administration of the current dose 
• Termination of any further dose escalation 
These changes must be recorded on the Dosage Administration Record CRF. 
 
Part 2: Option for dose reduction when ALT or AST > 2 × Baseline value AND 
≤8 x ULN 
For patients who experience ALT or AST elevations meeting the  definitions  outlined  in 
Table 15-1, a dose interruption or dose reduction to the next lower dose level, (or to placebo if 
receiving the lowest dose level) is permitted. One dose reduction step is allowed per patient. If, 
despite being on a reduced dose, a patient has persistent (i.e. remains > 90% of the original 
elevated level) or new ALT or AST elevation, they must be discontinued from study treatment. 
Increasing the dose to the original level is not permitted. 
If the patient has symptoms or other LFTs are also elevated please refer to Appendix 1 for 
appropriate actions. 
Patients with AST or ALT values meeting the requirement will be instructed to return to the 
clinic for an additional visit, where repeat tests will be performed, including a physical 
examination and laboratory assessment including ALT, AST, GGT, alkaline phosphatase, 
total bilirubin, albumin and PT/INR. 


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The central laboratory should be used, if this is not possible, the repeats can be performed at a 
local laboratory to monitor the safety of the patient. If tests are performed at local laboratory, 
results will be captured in source documents only. In all cases, a physical examination should 
be performed and recorded in source documents. 
Table 15-1 in Appendix 1 outlines the required testing frequency and resultant actions 
dependent on the outcome of the repeat assessments. 
If the additional laboratory evaluation confirms the increase of ALT and/or AST values, the 
study treatment will be reduced to the next dose level in a blinded manner (Table 6-1).       
The procedure for dose reduction is outlined in the Site Operations Manual. 
If the additional laboratory evaluation does not confirm the significant increase of ALT values, 
the patient will continue with the assigned/original dose level. 
If the additional laboratory evaluation shows a higher elevation of ALT and/or AST (e.g. > 8× 
ULN) as compared to the original elevation (e.g. > 5xULN but ≤ 8xULN), the guidance for 
this higher elevation (e.g. > 8× ULN) should be followed. 
 
Table 6-1 
Part 2 Permitted dose reductions 
Original treatment 
(daily dose) 
 
 
Reduced treatment 
(daily dose) 
Dose Level 1 
Placebo 
Dose Level 2 
Dose Level 1 
Placebo 
Placebo 
 
 
Repeat/second dose reductions are not permitted. Returning to the original treatment is not 
permitted. 
Patients with a persistent or a second cycle of elevated ALT or AST while on the reduced 
dose will be instructed to return to the clinic for repeat tests as outlined in Table 15-1. If the 
repeat tests confirm the elevated ALT or AST values, the patient will discontinue study 
treatment. If the repeat tests do not confirm elevation, the patient will continue with the 
reduced dose. 
 
6.3 
Treatment assignment 
Randomization numbers will be assigned in ascending, sequential order to eligible subjects 
(see Site Operations Manual for details). 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
In Part 1 a randomization list will be produced by or under the responsibility of Novartis Drug 
Supply Management using a validated system that automates the random assignment of 
treatment arms to randomization numbers in the specified ratio. The investigator will enter the 
randomization number on the CRF. 


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In Part 2 a subject randomization list will be produced by the IRT provider or by a delegate 
under their supervision, using a validated system that automates the random assignment of 
treatments to randomization numbers. These randomization numbers are linked to the 
different treatment arms. 
In Part 2 randomization will be stratified by whether the patient is taking UDCA or not and 
the severity of pruritus. 
Patients who participated in Part 1 may be enrolled in Part 2, provided they meet all the 
eligibility criteria. They will be  assigned  a  new  screening  and  randomization  number.  
The screening number a subject had in Part 1 will be recorded as part of the CRF data 
collected for Part 2, if a subject participates in both parts. 
The randomization scheme for all subjects will be reviewed and approved by a member of the 
Randomization Office. 
 
6.4 
Treatment blinding 
This is a double-blind study: subjects, investigator staff (with the exception of unblinded 
pharmacy staff or authorized designee responsible for dispensing study medication), persons 
performing the assessments, and data analysts will remain blinded to the identity of study 
treatments. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance and odor. In Part 2, the blind 
for the different dose levels will be maintained through the use of a double-dummy design, 
with additional placebo capsules given in active treatment groups when needed to maintain 
the blind. 
Randomization data are kept strictly confidential, and are accessible only to authorized 
personnel (unblinded pharmacist or authorized designee), until un-blinding of the trial as 
described in the table in the Blinding levels table in the Site Operations Manual. 
The bioanalyst will request a copy of the randomization to facilitate analysis of the samples. 
The  bioanalyst  will  provide  the  sample  data  to  the  team  under  blinded  conditions.   
The bioanalyst will keep this information confidential until interim analysis (Part 1 only) or 
final clinical database lock. 
Unblinding will only occur in the case of patient emergencies (see Section 6.5), at the time of 
the interim analysis and upon database lock, either at the conclusion of the study or 
completion of a Cohort or Part of the study. 
 
Part 1 
The sponsor will be unblinded and the randomization released to the CTT including the 
Modeler when the interim analysis is performed after subjects in a cohort have completed  
Day 28 of the study. 
The Interim Analysis Team may communicate interim analysis results (e.g., dose escalation 
decision, evaluation of PoC criteria or information needed for planning/modifying another 
study) to relevant Novartis teams for information, consulting and/or decision purposes. 


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Cohorts in Part 1 may have their data cleaned and locked before the conclusion of the whole 
study. In event of database lock for a Cohort or Part of the study, treatment codes for the 
subjects included in the locked cohort or part will be released and the data may be 
disseminated. 
 
Part 2 
The sponsor will remain  blinded  to  the  identity  of  study  treatments  during  the  study.  
An unblinded interim analysis will be performed by a study independent statistician and 
programmer when approximately 40 patients  have completed their Week  8  visit  in Part  2. 
A selected Novartis team not involved in the clinical conduct of the study (DMC) will be 
unblinded to the Week 8 results and will advise on whether sample size adjustment is required 
(see Section 11.8). 
 
6.5 
Emergency breaking of assigned treatment code 
Emergency un-blinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. 
In Part, 1 a complete set of emergency code break cards will be provided to the investigator 
sites and a complete set will be available at Novartis. All code break cards must be retained 
until the end of the study and returned to Novartis. They must be stored in a secure place but 
be accessible in case of emergency. The investigator will receive a blinded  code break card 
for each subject, with the details of drug treatment covered by a removable, scratch-off cover. 
In  an  emergency,  the  scratch-off  cover  can  be  removed  to  determine  the  treatment.  
The scratch-off covers are not to be removed for any reason  other  than  an  emergency. 
When the investigator removes the scratch-off cover he/she must note the date, time, and 
reason for removing it and retain this information with the case report form documentation. 
The unblinded treatment code should not be recorded on the CRF. The investigator must 
also immediately inform the Novartis local monitor that the code has been broken. 
In Part 2 emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide 
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The investigator will then receive details of the investigational drug 
treatment for the specified subject and a fax or email confirming this information. The system 
will automatically inform the study monitor for the site and the Study Team that the code has 
been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the code break cards or IRT in case of emergency. If appropriate, the investigator will 
inform the subject how to contact his/her backup in cases of emergency when he/she is 
unavailable. 


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6.6 
Treatment exposure and compliance 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with LJN452, as detailed in Section 8.5. 
To aid compliance, patients will be issued with a paper diary to record the time of dosing 
throughout the study. Information collected will include a confirmation that the patient took 
their UDCA and the time they took their study drug. In addition, patients will be asked to 
record details of any medication used in response to any adverse events of itch. 
The Investigator (or deputy) should review the diary with the patient to make sure they are 
familiar with the diary and understand what information needs to be completed. 
The data collected will be kept as source documentation. 
 
6.7 
Recommended treatment of adverse events 
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF. 
 
6.8 
Rescue medication 
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies CRF after start of study drug. Patients with high pruritus scores at baseline, or a 
history of pruritus, should have a suitable supply of anti-pruritic therapy at home. 
 
6.9 
Concomitant treatment 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the 
CRF. 
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy. 
 
7 
Discontinuation and study completion 
7.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator. 
Study treatment must be discontinued under the following circumstances: 
• Subject decision - subjects may choose to discontinue study treatment for any reason at 
any time. 
• The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation. 


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• Pregnancy. 
• Hypersensitivity reaction to LJN452. 
• Hepatic decompensation event such as variceal bleed, uncontrolled ascites, 
encephalopathy, spontaneous bacterial peritonitis. 
• A Liver or Renal event indicating discontinuation as defined in Table 15-1 - Follow up 
requirements for Liver events or Table 15-2- Follow up requirements for renal events 
• An AE with a CTCAE rating of Grade 3 that are suspected to be related to study drug 
(apart from pruritus, liver or renal parameters, see Table 15-1, Table 15-2 and Table 16-1 
for required actions). 
• An AE with a CTCAE rating of Grade 4 or higher, regardless of attribution to study drug 
• Emergence of the following adverse events: Diarrhea, nausea, vomiting, recurrent positive 
fecal occult blood or other GI symptoms that are deemed to be intolerable. 
The appropriate personnel from the study site and Novartis will assess whether study 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason. 
If discontinuation of study treatment occurs, the investigator must determine the primary 
reason for the subject’s premature discontinuation of study treatment and record this 
information on the Dosage Administration CRF. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3). Where possible, they should return for follow up assessments. 
If they fail to return for assessments for unknown reasons, every effort (e.g., telephone, e-mail, 
letter) should be made to contact them as specified in Section 7.2.1 
 
7.2 
Study completion and post-study treatment 
Each subject will be required to complete the study in its entirety and thereafter no further 
treatment with study drug will be made available to them. 
Study completion is defined as when the last subject completes their End of Study visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision. 


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All randomized subjects should have a safety follow-up call conducted 30 days after last 
administration of study treatment. For most subjects completing the study per protocol this 
will fall before or at the same time as their end of study visit, so no call will be necessary.      
If however a subject will not have their end of study visit 30 days after last administration of 
study treatment (e.g. in the event of withdrawal of consent) a safety follow-up call must be 
conducted. In this instance  the  information  collected  is  kept  as  source  documentation.  
All SAEs reported during this time period must be reported as described in Section 9.2 and  
the Site Operations Manual. Documentation of attempts to contact the subject should be 
recorded in the source documentation. 
Continuing care should be provided by investigator or referring physician. 
 
7.2.1 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of 
telephone calls, registered letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred. 
 
7.3 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contact and does not allow analysis of already obtained biologic material. 
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up. 
 
7.4 
Study Stopping rules 
Study “Stopping Rules” 
In Part 1, the study will be placed on hold to further enrollment, no new patients may be dosed, 
and the study may be stopped based on a full review of all available clinical safety data and 
discussion with the Investigators if any of the following occur: 
• Two or more subjects on study drug experience a similar adverse event that is a CTCAE 
Grade 3 or higher (excluding pruritus, liver or renal parameters, see Table 15-1, 
Table 15-2 and Table 16-1), unless it is caused by an accident that could not reasonably be 
attributable to the drug. 
• One subject on study drug experiences any adverse event that is CTCAE Grade 4 or 
higher that is classified as related to study drug. 


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• The Principal Investigator and the Sponsor consider that the number and/or severity of 
adverse events justify discontinuation of the study. 
• The Sponsor unilaterally requests it. 
In Part 2, in addition to frequent review of the emerging study data by the study team, the 
DMC will review safety,  including  AEs  and  laboratory  parameters,  on  a  regular  basis.  
In addition, in the event that more than 3 patients develop an AE of CTCAE Grade 3 or higher 
in the same system organ class, the DMC Chair will be alerted and may call an ad hoc DMC 
meeting. Further details regarding relevant data and actions will be specified in the separate 
DMC charter. The DMC may call for the study to be placed on hold to further enrollment,  
and the study may be stopped based on a full review of all available clinical safety data. 
 
Part 1 Cohort “Stopping Rules” 
Further enrollment and dose escalation will be placed on hold pending full review of all 
available clinical safety data and discussion with the Investigator if any of the following 
occur: 
Note: subjects already enrolled may continue dosing provided there are no safety issues in 
these subjects. 
• Two or more subjects experience a similar adverse event of CTCAE Grade 2 or higher 
severity (apart from pruritus, ALT or AST elevation; see Table 15-1, Table 15-2 and 
Table 16-1) suspected to be related to the study drug. 
• Two or more subjects experience a similar adverse event that is a CTCAE Grade 3 or 
higher severity regardless of drug causality, unless it is caused by an accident that could 
not reasonably be attributable to the drug. 
• One subject has an adverse event of CTCAE Grade 4 or higher. 
• Two or more subjects with an elevation of serum TBL to greater than 2 × ULN (or 2 × 
baseline if initially elevated) or an increase in aminotransferase enzymes (ALT or AST) as 
described below: 
• In the case of normal baseline transaminases an increase of ALT or AST to 
greater than 3 × ULN. 
• In the case of initially elevated transaminases an increase of ALT or AST to 
greater than 2 × baseline. 
• The Principal Investigator and the Sponsor consider that the number and/or severity and/or 
system organ class of adverse events justify discontinuation of drug administration within 
the cohort. 
• The Sponsor unilaterally requests it. 
Safety reviews will be conducted jointly between medically qualified representatives of the 
Sponsor and Investigator and a joint decision will be made. If a dose level is identified to be 
intolerable, the preceding dose level will be defined as the maximum tolerated dose. 
The severity of adverse events will be graded by the study site Investigator (or his designee) 
based on clinical judgment and captured in the CRF AE page. This information will be used  
to quantify events that may lead to subject’s discontinuation or stopping dose escalation. 


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7.5 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
subjects should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial. 
 
8 
Procedures and assessments 
Subjects should be seen for all visits on the designated day, with the assessments performed as 
per schedule, within the allowed “visit/assessment window” specified in the Site Operations 
Manual. 
Subjects will be seen at the investigational site or at an alternate location to which the 
Investigator has delegated responsibility. The alternate location will have all required ethical 
approvals in place, all staff will be appropriately trained in the protocol and assessments to be 
performed and will be documented on the delegation of duties log. The purpose of this 
flexibility, where available, is to offer patients the option of having their visits performed at a 
more convenient location, as it is anticipated patients may live a significant distance from the 
main Investigational site. Visits where this is an option are outlined in the assessment 
schedule. 


 
 
 
 
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Table 8-1 
Part 1 Assessment schedule 
 
Study Phase 
Screening 
Baseline 
Dosing Period 
Follow Up EOS 
Visit Numbers1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V777 
Study Day(s) 
-84 to -2 
-14 to -1 
1 
72 
142 
212 
28 
29 
56 
84 
Time (post-dose) 
- 
- 
predose 0h 
1h 
2h 
4h 
6h 
8h 
predose 0h 
1h 
2h 
3h 
4h 
6h 
8h 
24h 
- 
- 
Informed consent 
X 
Inclusion/Exclusion Criteria 
S 
S 
Medical history 
X 
X 
Demography 
X 
Alcohol Test and Drug Screen 
S 
S 
Physical Examination 
S 
S 
S 
S 
S 
S 
Hepatitis Screen 
S 
HIV Screen 
S 
Pregnancy test 
X 
X 
X 
X 
X 
X 
Drug dispensing3 
X 
Dose administration (at site)3 
X 
X 
X 
X 
X 
Body height 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG evaluation 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid panel 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
alpha-fetoprotein 
X 
PK blood collection 
X 
X 
X 
X 
X6 
X6 
X4 
X4 
X4 
X 
X 
X 
X 
X 
X 
X6 
X5,6 
X 
Blood type 
X 
VAS (Visual Analog Scale) 
X 
X 
X 
X 
X 
X 
X 
X 
PBC40 
X 
X 
X 
X 
X 
Concomitant therapies 
As required 
Adverse events 
As required 
Serious adverse events 
As required 
Comments 
As required 
Study completion information 
X 


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S = Information remains as source data 
1 Visit structure given for internal programming purposes only 
2 Assessments to performed pre-dose 
3 Daily dosing for 28 days 
4 PK sample to be drawn pre-dose 
5 PK sample to be taken 24 hours post dose on Day 28 
 
 
Note: The intention was to have study visits during the dosing period 7 days apart, with permitted visit windows as 
outlined in the SOM. However it has been noted that the assessment schedule has the visit 3 labelled as Day 1 
rather than Day 0 resulting in 6 days between this and the next visit. Since this error was noted after the study has 
started and patients dosed, the current visit names will remain unchanged, however sites should aim to schedule 
the visits 7 days apart, +/- the permitted visit window. 


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Table 8-2 
Part 2 Assessment schedule 
 
Study Phase 
Screening 
Dosing Period 
EOS 
Unsch- 
eduled 
Visit Numbers 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V777 
V999 
Weeks 
-12 to -2 
1 
2 
3 
5 
9 
13 
17 
>21 
Study Day(s) 
-84 to -14 
1 
8 
15 
29 
57 
85 
113 
>141 
Time (post-dose) 
- 
Baseline 0h 2h 
pre dose 
pre dose 
pre dose 
24h5 
- 
- 
Informed consent 
X 
Inclusion/Exclusion Criteria 
S 
Medical history 
X 
X 
Demography 
X 
Alcohol Test and Drug Screen 
S 
Physical Examination 
S 
S 
S 
S 
S 
Hepatitis Screen 
S 
HIV Screen 
S 
Pregnancy test 
X 
X 
X 
X 
X 
X 
alpha-fetoprotein 
X 
Blood type 
X 
Drug dispensing 
X 
X 
X 
Dose administration at site following completion 
of other assessments 
X 
X 
X 
X 
X 
Body height 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
Pulse rate 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
ECG evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid panel 
X 
X 
X 
X 
X 
X 
X 
Liver function tests 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood collection 
X 
X 
X 
X 
X 
X 
X 
VAS (Visual Analog Scale) 
X 
X 
X 
X 
X 
X 
X 
PBC40 
X 
X 
X 
X 
X 
X 
Telephone follow up 
X 
X4 
Concomitant therapies 
As required 
Adverse events 
As required 
Serious adverse events 
As required 
Comments 
As required 
Study completion information 
X 
X 
Key 
S = Information remains as source data 
EOS = End of Study visit 
4 Telephone follow up call required 30 days post dose, if EoS visit not performed at this stage 
5 To be scheduled approximately 24 hours post Day 84 dose 
 
8.1 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 


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Informed consent must be obtained before conducting any study-specific procedures (i.e., all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents. 
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF. 
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained. 
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval. 
 
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded. 
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
 
8.3 
Efficacy / Pharmacodynamics 
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the Study Operations Manual. Assessments will be performed/samples 
collected at the timepoint(s) defined in the Assessment schedule. 
In order to better define the PD profile, the timing of the sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume  
collected will not exceed those stated in the protocol. 


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8.3.1 
Liver Function Tests 
GGT, Albumin, AST, ALT, ALP, total bilirubin will be assessed. 
The methods for assessment and recording are specified in the laboratory manual and SOM. 
Liver function tests may be completed as part of the blood chemistry panel. 
 
8.3.2 
Patient-Reported Outcome 
PBC 40 
The PBC-40 is a paper-based patient-derived, disease specific quality of life patient reported 
outcome (PRO) measure. It was developed and validated for use in subjects suffering from 
PBC (Jacoby et al 2005). It is designed for self-completion and takes approximately 5 minutes 
to  complete.  It  consists  of  40  questions  arranged  in  8  domains  with  between  3  and   
11 questions in each domain. Each question is scored from 1 to 5 in increasing order of 
severity. The difference in total sum score between each treated group and placebo at Day 28 
will be investigated. 
 
PBC40 itch domain 
The domain specifically relates to cholestatic itch symptomatology. In addition to the 
investigation of the total PBC-40 sum score, the sum scores from the 3 question itch sub-
domain of the PBC40 questionnaire will be determined and used to test for an effect of 
LJN452 relative to placebo. 
 
VAS for Itch and Sleep 
The Global Itch Visual Analogue Scale, a 100 mm visual analogue scale (VAS) will be used 
to assess the severity of patients itch (ranging from 0 = none at all to 10 = the worst 
imaginable itch) and the Sleep Disturbance Visual Analogue Scale will be used to assess the 
impact of nocturnal itch on sleep (from 0 = no sleep loss to 10 = cannot sleep at all).           
The score (distance from left) on the VAS will be recorded for both parameters by the patient 
marking with a line and used to test for an effect of LJN452 over placebo. 
 
8.4 
Safety 
Safety assessments are specified below; methods for assessment and recording are specified in 
the laboratory manual and Site Operations Manual, with the Assessment Schedule detailing 
when each assessment is to be performed. 
 
8.4.1 
Physical examination 
Details on the physical examination will be provided in the Site Operations Manual. 
 
8.4.2 
Vital signs 
• Body temperature 
• Blood pressure (BP) 
• Pulse 


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8.4.3 
Height and weight 
• Height 
• Body weight 
• Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2) 
8.4.4 
Laboratory evaluations 
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted. 
 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured. 
 
Clinical chemistry, including fasted lipid panel 
Sodium, potassium, bicarbonate, creatinine, urea, uric acid, chloride, calcium, alkaline 
phosphatase, total bilirubin, LDH, GGT, AST, ALT, albumin, aPTT, PT/INR, CK, glucose, 
total cholesterol, HDL, LDL, triglycerides, magnesium, phosphate and vitamin D. If the total 
bilirubin concentration is increased above 1.5 times the upper limit of normal, direct and 
indirect reacting bilirubin should be differentiated. 
 
Urinalysis 
Urine test by dipstick e.g., Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin. 
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts. 
 
Special clinical laboratory evaluations 
• Alpha-fetoprotein (performed only at screening) 
• Blood type (performed only at screening) 
Detailed information on special clinical laboratory assessments will be provided in the 
laboratory manual and the SOM. 
 
8.4.5 
Electrocardiogram (ECG) 
PR interval, QRS duration, heart rate, RR, QT, QTc 
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. 


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8.4.6 
Pregnancy 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
Screening followed by a urine pregnancy test at Baseline Visit before study drug 
administration. The urine pregnancy test will be repeated every four weeks up to the follow up 
visit (see Table 8-1 and Table 8-2). The tests will be performed at the clinical center. 
A positive test at Screening and/or Baseline is an exclusion criterion for participating in the 
study. A positive urine pregnancy test after start of study drug requires immediate interruption 
of study drug until serum hCG is performed and found to be negative. If positive, the patient 
will enter the post-treatment follow up period. See also Section 9.5. 
 
8.5 
Pharmacokinetics 
8.5.1 
PK Blood collection and processing 
A complete schedule of blood sampling for pharmacokinetics (including sampling time as 
sampling volumes) can be found in the blood log tables (provided in the SOM) while explicit 
details related to PK blood collection and processing, labeling, and shipment instructions, are 
located in the standalone central laboratory manual. 
All samples will be given a unique sample number (as listed in the SOM). The actual sample 
collection date and time will be entered on the PK blood collection page of the eCRF. 
Sampling problems will be noted in the Comments page of the eCRFs. 
 
8.5.2 
Pharmacokinetic analytical method(s) 
LJN452 will be determined in plasma using a validated LC-MS/MS method. 
 
 
 
 
 


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9 
Safety monitoring 
9.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in 
the study. Therefore, an AE may or may not be temporally or causally associated with the use 
of a medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in 
Section 9.3. 


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Adverse events must be recorded on the Adverse Events CRF for subjects that pass screening 
and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information: 
1. The Common Toxicity Criteria (CTC) AE grade (version 4). If CTC-AE grading does not 
exist for an adverse event, use: 
• 1=mild, 
• 2=moderate, 
• 3=severe 
• 4=life threatening. 
CTC-AE grade 5 (death) is not used, but is collected in other CRFs (e.g., Study 
Completion, Death/Survival). 
2. its relationship to the study treatment (no/yes) 
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
4. whether it constitutes a serious adverse event (SAE) See Section 9.2 for definition of SAE 
5. action taken regarding investigational treatment. 
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: 
• no action taken (i.e., further observation only) 
• study treatment dosage adjusted/temporarily interrupted 
• study treatment permanently discontinued due to this adverse event 
• concomitant medication given 
• non-drug therapy given 
• subject hospitalized/subject’s hospitalization prolonged 
Once an adverse event is detected, it should be followed until its resolution or until it is  
judged to be permanent, throughout the study, and assessment should be made at each visit  
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
study drug, the interventions required to treat it, and whether the AE is ongoing at the end of 
study visit. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or Core Data Sheet (for marketed drugs) or will be 
communicated between IB updates in the form of Investigator Notifications. This information 
will be included in the subject informed consent and should be discussed with the subject 
during the study as needed. 
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 


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9.2 
Serious adverse event reporting 
9.2.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. 
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to Chief Medical Office and Patient Safety as per Section 9.2.2. 


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9.2.2 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last administration of study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence as described below. 
Any SAEs experienced after this should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department, notifying the Clinical Trial Leader. Contact information is listed  
in the Site Operations Manual. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE. 
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
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9.3 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study: 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Appendix 1 for complete definitions of liver laboratory triggers and liver 
events and their required follow up requirements. 
These follow up actions may include: 
• Repeating the LFT* to confirm elevation as defined in Table 15-1, interruption of dosing 
while result is pending 
• Dose reduction (Part 2 only) 
• Discontinuation of the investigational drug 
• Hospitalization of the subject if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution. These 
investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. 
*These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
All follow-up information, and the procedures performed should be recorded as appropriate in 
the CRF, using the Liver Event Checklist as guide, which should be kept as source data. 
 
9.4 
Renal safety monitoring 
Renal events are defined in Appendix 1, with their required follow up requirements. 
 
9.5 
Pregnancy reporting 
To ensure patient safety, each pregnancy in a subject on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. The study drug must be discontinued, though the subject may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The subject may continue all other protocol assessments. 


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Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on an SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
9.6 
Early phase safety monitoring 
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly  
between  medically  qualified  personnel  representing  the   Sponsor   and   Investigator.   
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
The Sponsor will advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if 
possible) of any new, clinically relevant safety information reported from another site during 
the conduct of the study in a timely manner. 
 
10 
Data review and database management 
10.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their  staff. 
During the study Novartis employs several methods of ensuring protocol and  GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed. 


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10.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms  are  complete  and  accurate. 
After final database lock, the investigator will receive a CD-ROM or paper copies of the 
subject data for archiving at the investigational site. 
Data not requiring a separate written record will be defined in the Site Operations Manual and 
assessment schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
CRO working on behalf of Novartis review the data entered into the eCRFs by investigational 
staff for completeness and accuracy and instruct the site personnel to make any required 
corrections or additions. Queries are sent to the investigational site using an electronic data 
query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to the 
CRO working on behalf of Novartis who will make the correction to the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Randomization codes will be tracked using IRT for Part 2. The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO). 
This study will utilize a staggered lock of the clinical database, so that the data can be locked 
after completion of Part 1, or set of Cohorts in Part 1. 
At the conclusion of Part 1 of the study or lock of a set of Cohorts from Part 1, in the event of 
a staggered lock, the occurrence of any emergency code breaks will be determined after return 
of all code break reports and unused drug supplies to Novartis. 
For Part 2, each occurrence of a code break via IRT will be reported to the clinical team and 
monitor. The code break functionality will remain available until study shut down or upon 
request of Novartis. 


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The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement by Novartis 
management. 
All actions described above to lock the database apply to a lock occurring after completion of 
Part 1 (or Cohorts from Part 1) and at the end of the study. Once all necessary actions for 
database lock on the relevant data have been completed and the relevant data has been 
declared to be complete and accurate, it will be locked and the relevant treatment codes will 
be released and made available for data analysis. Any changes to the relevant data after that 
time can only be made by joint written agreement by Novartis management. 
  
 
10.3 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) has been assembled for this compound to monitor 
safety data. This committee is comprised of Novartis personnel not directly involved with the 
study. The DMC will convene as outlined in the DMC Charter. 
Further, the DMC will review available data from Part 1 and approve the planned doses for 
Part 2 prior to the doses being confirmed. 
The DMC will review safety, including AEs and laboratory parameters, on a regular basis.    
In addition, in the event that more than 3 patients develop an AE of CTCAE grade 3 or higher 
in the same system organ class, the DMC Chair will be alerted. Further details regarding 
relevant data and actions will be specified in the separate DMC charter. In addition, adverse 
events, including clinical laboratory data will be continuously reviewed by the Novartis 
medical monitor and as indicated, by the Novartis pharmacovigilance team. 
 
10.4 
Adjudication Committee 
Not required. 


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11 
Data analysis 
11.1 
Analysis sets 
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
Subjects with dose reduction due to ALT/AST will be analyzed according to the treatment 
they received up to the dose reduction in Part 2. 
The safety analysis set will include all subjects that received any study drug. 
The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data. 
The PD analysis set will include all subjects with available PD data and no protocol  
deviations with relevant impact on PD data. 
Details of protocol deviations which warrant exclusion from either the PK or PD analyses data 
sets will be provided in the RAP document Module 3. 
 
11.2 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. 
 
11.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject. 
 
11.4 
Analysis of the primary variable(s) 
The primary efficacy objective is to evaluate the treatment effect of LJN452 over placebo in 
terms of reduction in cholestasis. The primary efficacy endpoint is the fold change in serum 
gamma-glutamyl transferase (GGT) from baseline to Day 28 and Day 85 for Part 1 and Part 2, 
respectively. 
 
11.4.1 
Variable(s) 
The primary efficacy endpoint is the fold change in serum gamma-glutamyl transferase (GGT) 
from baseline. The Serum GGT values at all time points will be logarithmically transformed 
prior to analysis. The rationale for the log transformation is to achieve more approximate 
normality and to be able to estimate a treatment effect on a ratio scale. Y=log(GGT+0.001) 
will be considered only if there are many observations with GGT result as zero. 


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11.4.2 
Statistical model, hypothesis, and method of analysis 
Changes from baseline for log transformed serum GGT will be analyzed by repeated  
measures analysis of covariance (ANCOVA) with a fixed effect for the treatment, visit, 
treatment*visit interaction, log-transformed baseline as well as log(baseline)*visit interaction. 
The UDCA and pruritus stratification factor will also be included as a fixed effect in the 
ANCOVA model for Part 2 analysis. A saturated covariance structure will be used for 
observations within the same subject. The model will be fitted using SAS Proc Mixed and the 
restricted maximum likelihood scoring method (reml). Two-sided 90% confidence intervals 
for the difference between each LJN452 dose and placebo will be evaluated for each visit. 
This will then be “back-transformed” to the original scale to give a fold change from baseline. 
Dose response may be assessed using appropriate contrasts. The analysis at the 28 day visit 
and 85 day visit will constitute the primary analysis  for  Part  1  and  Part  2,  respectively. 
The analysis will be done for each study part using pooled placebo data within parts 1 and 2, 
respectively. No adjustment for multiplicity will be done. 
 
 
 
Similar analysis as mentioned above can be performed for key LFT parameters. 
Additionally a repeated measures ANCOVA treating all post dose reduction measurements as 
missing will be performed as well. 
 
11.4.3 
Handling of missing values/censoring/discontinuations 
All missing GGT values will be considered missing at random. No imputation or adjustment 
to the primary analysis will be done. 
 
11.4.4 
Supportive analyses 
If it turns out that the primary analysis cannot be fitted because data cannot support  a 
saturated model, a simpler covariance matrix such as the compound symmetric covariance 
structure may be fitted. 
 
11.5 
Analysis of secondary 
 variables 
11.5.1 
Efficacy / Pharmacodynamics 
The secondary efficacy/PD variables are the PBC-40 total score, the PBC-40 itch domain 
subscore, and the VAS scale PRO as well as ALP. 
The difference between LJN452 and placebo will be assessed by Wilcoxon rank sum test for 
change from baseline in total PBC score and itch subdomain score at each visit. A two-sided 
p-value for a  treatment  difference  will  be  reported  with  no  adjustment  for  multiplicity. 
In addition, summary statistics (mean median std min max) will be reported at each applicable 
time point. 


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As an additional secondary end point, a 100 mm visual analogue scale (VAS) will be used to 
assess the severity of patients itch as well as loss of sleep. The score (distance from left) on 
the VAS will be recorded for both parameters by the patient marking with a line. The distance 
marked will be converted to a score between 0 and 10. 
The change from baseline VAS scores for itch and sleep loss will be analyzed by analysis of 
covariance with a baseline covariate, a fixed effect for treatment, visit, and treatment by visit 
interaction as well as visit by baseline interaction. An unstructured covariance matrix will be 
used 90% two-sided confidence intervals for the difference between each LJN452 dose and 
placebo will be presented. The UDCA and pruritus stratification factor will also be included 
as a fixed effect in the model for Part 2 analysis. 
ALP data will be analyzed using the same approach as described in Section 11.4.2. 
Additionally the number and percentage of subjects who have ALP<1.67xULN with > 15% 
reduction from baseline and a normal total bilirubin level will be tabulated by part, treatment 
and visit. 
 
11.5.2 
Safety 
Vital signs 
All vital signs data will be listed by part, treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by part, treatment and visit/time. 
 
ECG evaluations 
All ECG data will be listed by part, treatment, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
 
Clinical laboratory evaluations 
All laboratory data will be listed part, by treatment, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. 
 
Adverse events 
All information obtained on adverse events will be displayed by treatment and subject. 
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system. 


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Other safety evaluations 
Not applicable. 
 
Immunogenicity 
Not applicable. 
 
11.5.3 
Pharmacokinetics 
 
11.5.3.1 Pharmacokinetic parameters 
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol. 
All subjects with at least one period of evaluable pharmacokinetic (PK) parameter data will be 
included in the pharmacokinetic data analysis. 
In Part 1, the pharmacokinetic parameters include (but are not limited to) AUC, Cmax, Tmax 
for LJN452. 
Plasma concentrations will be expressed in ng/mL. All concentrations below the limit of 
quantification or missing data will be labeled as such in the concentration data listings. 
Concentrations below the Limit of Quantification will be treated as zero in summary statistics 
for concentration data only. They will not be considered for calculation of PK parameters 
(with the exception of the pre-dose samples). 
Pharmacokinetic parameters will be determined using the actual recorded sampling times and 
non-compartmental method(s) with Phoenix (Version 6.2 or higher). 
 
11.5.3.2 Statistical methods for pharmacokinetic analyses 
Descriptive statistics of pharmacokinetic parameters will include mean, SD, and CV, min and 
max. When a geometric mean will be presented it will be stated as such. Since Tmax is 
generally evaluated by a nonparametric method, median values and ranges will be given for 
this parameter. 
At day 1 and Day 28, AUC and Cmax will be summarized for each cohort along with 90% 
two-sided confidence intervals computed on the log-scale and back-transformed. All subjects 
with available PK parameters and no protocol deviation excluding them from the PK analysis 
set will be part of this computation. 
If 3 or more cohorts are included in part 1 of the study, then dose-proportionality will be 
explored for PK parameters (AUCtau and Cmax) by fitting a power model (PK parameter = α 
dose β). A natural logarithmic transformation will be applied for the power model, which 
implies to a general linear model to the log transformed PK parameter with a fixed continuous 
log-dose effect. The model becomes  log  (PK  parameter)  =  log(α)  +  β  log(Dose)  +  ε.  
The estimate of the common slope β, which is the exponent in the power model, and the 90% 
confidence interval of the exponent will be obtained. Dose proportionality will be considered if 
the 90% confidence interval for β is completely contained within the pre-specified critical region 
(bL, bU). 


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LJN452 plasma concentration data will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point. Additionally summary statistics may also be provided for the LJN452 plasma 
concentration data with a breakdown by UDCA stratum as appropriate. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values. Pharmacokinetic parameters will be calculated as 
described in Section 8.5 and will be listed by treatment and subject. 
 
11.5.4 
Pharmacokinetic / pharmacodynamic interactions 
The relationship between PK and key primary and/or secondary PD parameters will be 
explored.
 
 
 
 
 


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11.6 
Sample size calculation 
A recently published study of a compound with similar mechanism (Mason et al 2010b; 
Hirschfield et al 2015) on a similar population (study of INT-474 in combination with UDCA 
in patients with PBC) suggests that the treatment difference over placebo at Day 28 is 
approximately -50% with a standard deviation ~ 0.28. In Part 1, with 12 patients per cohort 
randomized to LJN452 or placebo with a randomization ratio of 2:1, there is approximately 
85% probability that the upper limit of a 90% two-sided confidence interval of treatment 
difference between LJN452 versus placebo will exclude 0, if the underlying treatment 
difference is about -50% in terms of percent change from baseline. A total of up to 5 cohorts 
of LJN452 at different dose levels may be studied. Assuming a dropout rate of approximately 
20%, 15 patients per cohort will be enrolled in Part 1, with a total of at least 30 (up to 75) 
patients. 
Part 2 of the study will be conducted on patients currently taking UDCA and UDCA naïve 
patients. A published study (Jones et al 2011) (study of INT-474 as monotherapy in patients 
with PBC) suggests that the effect size of change from baseline in GGT is bigger in naïve 
patients than in the non-responder population studied in Part 1. So, we can assume a treatment 
effect of at least 50% as well as a standard deviation of 0.28. Based on power calculation for 
Part 1, enrolling at least 30 patients to receive an LJN452 dose and 20 patients to receive the 
placebo treatment in Part 2 will provide at least 95% power that a two-sided significance test 
at nominal level 5% will detect a difference (same analysis as in Part 1). A total of 80 patients 
are planned to be randomized to LJN452 or placebo with a 3:3:2 ratio (Dose Level 1:Dose 
Level 2:Placebo). Assuming a dropout rate of approximately 10%, 88 patients will be enrolled 
in Part 2. 
 
11.7 
Power for analysis of key secondary variables 
Data from 30 patients receiving each LJN452 dose and 20 patients receiving placebo in Part 2 
will provide 81% power to detect a 15% treatment difference in change from baseline ALP 
between an LJN452 dose and placebo, based on a 2-sided t-test at the 0.05 significance level 
assuming a standard deviation of 17.8%, obtained from the interim analysis of the first 2 
cohorts in Part 1. 
 
11.8 
Interim analyses 
Planned interim analyses will take place in Parts 1 and 2 of the study. 
Planned interim analyses will be performed in Part 1; a) when at least 12 patients in Cohort 1 
have completed 4 weeks of dosing and have finished the day 28 post dose assessments; b) 
when the same time point is reached for at least 12 subjects in each cohort of Part 1. 
The purpose of the first interim analysis is to assess patient safety, to evaluate the assumption 
on intra-subject variability of GGT which was used for sample size calculations, and to select 
a dose for the next cohort. An ANCOVA model will be fitted to estimate the change from 
baseline in GGT to day 28 and its variability, and an unblinded sample size re-estimation 
conducted. The results may be used to adjust the size of the next cohort. 


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In the subsequent interim analyses in Part 1, placebo data from all cohorts will be pooled in 
the ANCOVA model to evaluate the treatment difference between each dose level of LJN452 
versus placebo. The model described in the primary analysis section will be fitted, as it is 
indeed the same analysis which will be included in the final study report. 
Unblinded interim analysis results from Part 1 will be reviewed by an internal Novartis 
Interim Analysis Team which may include some CTT members. The Interim Analysis Team 
may communicate interim results to relevant Novartis teams for information, consulting 
and/or decision purposes. The composition of the interim analysis team will be decided before 
the FPFV and a roster of membership maintained in the trial master file. 
The Interim Analysis Team may communicate interim results (e.g., evaluation of PoC criteria 
or information needed for planning/modifying another study) to relevant Novartis teams for 
information, consulting and/or decision purposes. 
No further dissemination of interim results based on un-locked data should occur, in particular 
not with individuals involved in treating the study’s  subjects  or  assessing  clinical  data  
(e.g., ECGs, images, symptoms) obtained in the study. 
In Part 2 of the study an interim analysis is planned when approximately 40 patients have 
completed their Week 8 visit. The purpose of this interim analysis is to review the sample size 
(calculated based on GGT and ALP changes) to assess if it is also adequate to provide precise 
enough  treatment  difference  estimates  in  itch  parameters,  a  key  tolerability  endpoint.   
A blinded sample size re-estimation will be performed and a proposal to increase the sample 
size submitted to the DMC as needed. The DMC will decide whether it is appropriate to 
increase the sample based on an unblinded interim analysis, which will be performed by a 
study independent statistician and programmer with outputs provided to the DMC only. 
Recruitment will continue while the IA is being performed. 
 
11.9 
Interim analyses on locked data 
This study will utilize a staggered lock of the clinical database, so that the data can be locked 
after completion of Part 1, or a set of Cohorts in Part 1. 
Once a Cohort’s data has been locked, treatment codes for the relevant cohort(s) will be 
released and made available for data analysis. 
The results from the locked interim analysis can be communicated beyond Novartis to groups 
including, but not limited to individuals treating the study’s subjects, Health Authorities and 
on clinical registries. 


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12 
Ethical considerations 
12.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
 
12.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
 
12.3 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 


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13 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected  
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators must apply due diligence to avoid protocol deviations. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR. 
 
13.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL 
should be informed and (serious) adverse event reporting requirements (Section 9) followed  
as appropriate. 


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14 
References 
Available upon request. 
Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear 
sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol; 13(4):213-24. 
Carbone M, Mells G, Pells G, et al (2013) Sex and age are determinants of the clinical 
phenotype of Primary Biliary Cirrhosis and response to Ursodeoxycholic acid. 
Gastroenterology; 144:560-569 
Chen F, Ananthanarayanan M, Emre S, et al (2004) Progressive familial intrahepatic 
cholestasis, type 1, is associated with decreased farnesoid X receptor activity. 
Gastroenterology; 756-64. 
Hirschfield G, Mason A, Luketic V, et al (2015) Efficacy of obeticholic acid in patients with 
primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterolgy; 
148(4), 751-761. 
Jacoby A, Rannard A, Buck D, et al (2005) Development, validation, and evaluation of the 
PBC-40, a disease specific health related quality of life measure for primary biliary chirrhosis. 
Gut; 54(11): 1622-1629 
Jones D, Kowdley K, Chapman R, et al (2011) The first new monotherapy therapeutic PBC 
study in a decade? An interventional study evaluating the farnesoid X receptor agonist 
obeticholic acid in PBC. Gut; 60 (Suppl 2). 
Kowdley KV, Luketic VA, Jones DE, et al (2011) The first new monotherapy therapeutic 
PBC study in a decade? An international study evaluating the farnesoid X receptor agonist 
obeticholic acid in PBC. Hepatology; (54): 416A-417A. 
Makishima M, Okamoto AY, Repa JJ, et al (1999) Identification of a nuclear receptor for bile 
acids. Science; 1362-5. 
Mason AL, Luketic VA, Lindor KD, et al (2010a) Farnesoid-x receptor agonists: A new class 
of drugs for the treatment of PBC? An international study evaluating the addition of 
obeticholic acid (INT-747) to ursodeoxycholic acid. Hepatology; 52 (357A). 
Mason AL, Luketic VA, Lindor KD, et al (2010b) Farnesoid-x receptor agonists: A new class 
of drugs for the treatment of PBC? An interventional study evaluating the addition of INT-747 
to ursodeoxycholic acid. Journal of Hepatology; 52 S1-S21. 
Nevens F, Andreone P, Mazzella G, et al (2016) A placebo-controlled trial of obeticholic acid 
in primary biliary cholangitis. N Engl J Med; 375(7):631-43. 
Parks DJ, Blanchard SG, Bledsoe RK, et al (1999) Bile acids: natural ligands for an orphan 
nuclear receptor. Science; 1365-8. 


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Treinen-Moslen M, Kanz MF (2006) Intestinal tract injury by drugs: Importance of metabolite 
delivery by yellow bile road. Pharmacol Ther;112(3):649-67. 
Wang H, Chen J, Hollister K, et al (1999) Endogenous bile acids are ligands for the nuclear 
receptor FXR/BAR. Mol Cell; 543-53. 
Zollner G, Wagner M, Moustafa T, et al (2006) Coordinated induction of bile acid 
detoxification and alternative elimination in mice: role of FXR-regulated organic solute 
transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver 
Physiol;290(5):G923-3. 


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15 
Appendix 1: Liver and Renal events definitions and required 
actions 
The following tables define Liver and Renal events in the study that require specific follow up 
and further action. These actions include discontinuation of study drug, reduction in dose, a 
dose interruption and increased frequency of safety monitoring. Please see Table 15-1 (Liver 
events) and Table 15-2 (Renal events) for further information. 


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Table 15-1 
Liver Triggers and Events: definition and Follow-up Requirements 
 
Criteria 
First Action 
Result 
Second Action 
Result 
Third Action 
ALT or AST 
Potential Hy’s Law 
case defined as: 
ALT or AST > 3 × ULN 
and 
TBL > 2 × ULN 
without notable 
increase in ALP to > 
2 × ULN 
• 
Discontinue study drug 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
-- 
Continue monitoring with Repeat testsa 
until resolution c 
-- 
-- 
ALT or AST 
> 3 × ULN 
and INR > 1.5 
• 
Discontinue study drug 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
-- 
Continue monitoring with Repeat testsa 
until resolution c 
-- 
-- 
ALT or AST 
> 8 × ULN 
• 
Discontinue study drug 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
-- 
Continue monitoring with Repeat testsa 
until resolution c 
-- 
-- 
ALT or AST 
> 2 X Baseline 
AND 
> 3 × ULN 
AND accompanied by 
symptomsb 
• 
Discontinue study drug 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
-- 
Continue monitoring Repeat testsa until 
resolution c 
-- 
-- 


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Criteria 
First Action 
Result 
Second Action 
Result 
Third Action 
ALT or AST 
> 2 X Baseline 
AND 
> 5 to ≤ 8 × ULN 
• 
Repeat testsa within 48 hours of 
notification of result 
• 
HOLD study drug until repeat 
test results available 
• 
Establish causality and complete 
liver event checklist (in SOM) 
 
Part 1 
• 
Discontinue study drug 
• 
Continue monitoring with Repeat 
testsa 2-3 times per week until 
resolution c 
• 
Update liver event checklist 
Part 2 
• 
Reduce dose (Table 6-1). 
• 
Restart study drug at reduced dose 
• 
Repeat testsa 2-3 times a week after 
re-starting study drug 
• 
Update liver event checklist (in 
SOM) 
 
Part 2 
If elevated after re-starting study 
drug, discontinue study drug 
• 
Continue monitoring with Repeat 
testsa until resolution c 
• 
Update liver event checklist 
 
If values normalize, continue with 
reduced dose. 
• 
Repeat testsa two and three weeks 
after re-starting study drug 
If levels remain ≥ 2x Baseline 3 
weeks after dose reduction, 
discontinue study drug 
• 
Continue monitoring with Repeat 
testsa until resolution c 
• 
Update liver event checklist 


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Criteria 
First Action 
Result 
Second Action 
Result 
Third Action 
 
Part 1 
• 
Restart study drug at assigned dose 
level 
• 
Repeat testsa 2-3 times a week after 
re-starting study drug 
• 
Update liver event checklist 
Part 2 
• 
Maintain assigned dose level 
• 
Restart study drug at assigned dose 
level 
• 
Repeat testsa 2-3 times a week after 
re-starting study drug 
• 
Update liver event checklist 
 
Both Parts 
If elevated after re-starting study 
drug, discontinue study drug 
 
Both Parts 
• 
Continue study drug at assigned 
dose level 
ALT or AST 
> 2 X Baseline 
AND 
≤ 5 × ULN 
(patient is 
asymptomatic) 
• 
Repeat testsa within 48 hours of 
notification of result 
 
Part 1 
• 
Discontinue study drug 
Part 1 
• 
Continue monitoring with Repeat 
testsa 2-3 times per week until 
resolution c 
• 
Update liver event checklist 
Part 2 
• 
Repeat testsa visit within 48 hours 
• 
HOLD study drug until repeat test 
results available 
• 
Complete liver event checklist 
 
Part 2 
A. Reduce dose (Table 6-1). 
• 
Restart study drug at reduced dose 
• 
Repeat testsa 2-3 times a week after 
re-starting study drug 
B. If elevated after re-starting study 
drug, discontinue study drug 
• 
Continue monitoring with Repeat 
testsa until resolution c 
• 
Update liver event checklist 


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Criteria 
First Action 
Result 
Second Action 
Result 
Third Action 
 
Part 2 
• 
Maintain assigned dose level 
 
Both Parts 
• 
Maintain assigned dose level 
Alkaline phosphatase 
ALP (isolated) 
> 2 × ULN if normal 
baseline or 
>2 x baseline if 
elevated before drug 
exposure (in the 
absence of known 
bone pathology) 
• 
Repeat testsa within 48 hours of 
notification of result 
 
Both Parts 
• 
Monitor LFT within 1 to 4 weeks or 
at next visit 
• 
Establish causality and complete 
liver event checklist (in SOM) 
- 
Total bilirubin 
> 2 × ULN if normal 
baseline or 
>2 x baseline if 
elevated before drug 
exposure 
(in the absence of 
known Gilbert 
syndrome) 
• 
Repeat testsa within 48 hours of 
notification of result 
• 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
 
Both Parts 
• 
Discontinue study drug 
• 
Initiate close monitoring (evaluate 2- 
3 times a week with repeat testsa) 
• 
Hospitalize if clinically appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
Both Parts 
• 
Continue monitoring with Repeat 
testsa until resolution c 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
• 
Repeat testsa within a week of 
notification of result 
 
Both Parts 
If elevation from baseline is confirmed, 
initiate close observation of the patient 
i.e. evaluate 2-3 times a week with 
repeat testsa 
Both Parts 
• 
Repeat testsa within 1 to 4 weeks or 
at next visit 


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Criteria 
First Action 
Result 
Second Action 
Result 
Third Action 
Jaundice 
• 
Discontinue study drug 
• 
Initiate close monitoring 
(evaluate 2-3 times a week with 
repeat testsa ) 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
Both Parts 
• 
Continue monitoring with Repeat 
testsa until resolution c 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study drug interruption 
or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality and complete 
liver event checklist (in SOM) 
Both Parts 
Investigator discretion 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; the non-infectious hepatitis; the benign, malignant and 
unspecified liver neoplasms 
a Repeat tests: Physical examination and PT/INR and LFT: Liver function test: ALT, AST, GGT, alkaline phosphatase, total bilirubin, and albumin (see Section 6.2.1); 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at three subsequent monitoring visits at least 2 weeks apart, 
(3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, and (5) death. 
 
 
Elevation confirmed or persisting, i.e. remain > 90% of the original elevated level 
 
 
Decreasing elevation, i.e. decrease to ≤ 90 % of the original elevated level. 


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Table 15-2 
Renal events: definition and follow up requirements 
Renal Event 
Actions 
1. Hold study medication 
2. Confirm increase after 24-48h of notification of the 
value 
Serum creatinine ≥ 2 x BL or ≥1.5 mg/dL 
 
 
 
Serum creatinine increase 
25 – 49% compared to baseline during 
normal hydration status 
Serum creatinine increase ≥ 50 % 
compared to baseline 
 
 
 
 
 
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold compared to baseline 
Albumin-creatinine ratio (ACR) ≥ 30 mg/g 
or ≥ 3 mg/mmol; 
New dipstick proteinuria ≥ 1+ 
Protein-creatinine ratio (PCR) >ULN 
New dipstick glucosuria ≥ 1+ not due to 
diabetes 
3. If confirmed, permanently discontinue study 
medication 
4. Follow up until resolution or stabilization of laboratory 
abnormality(ies) 
Confirm 25% increase after 24-48h of notification of the 
value 
Follow up within 2-5 days 
Confirm ≥ 50 % within 24-48 hours after receipt of the 
abnormal value 
If confirmation of abnormal value is not possible in this 
timeframe study drug must be withheld until further 
evaluation is possible 
Consider drug interruption 
Consider patient hospitalization / specialized treatment 
Confirm value after 24-48h of notification of the value 
Perform urine microscopy 
Consider drug interruption / discontinuation 
 
 
 
Blood glucose (fasting) 
Perform serum creatinine, ACR 
New dipstick hematuria not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF 
Monitor patient regularly (frequency at investigator’s discretion) until one of the following: 
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline) 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 


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16 
Appendix 2: Pruritus event definitions and required actions 
The following table defines options for management of different CTCAE grades of pruritus. 
These include: concomitant medication administration; study drug interruption or withdrawal 
of study drug. 
 
Table 16-1 Pruritus event definitions and required actions 
Pruritus Event 
Actions 
CTCAE Grade 1 
Mild or localized; topical intervention 
indicated 
CTCAE Grade 2 
Intense or widespread; intermittent; skin 
changes from scratching (e.g., edema, 
papulation, excoriations, lichenification, 
oozing/crusts); oral intervention indicated; 
limiting instrumental ADL 
CTCAE Grade 3 
Intense or widespread; constant; limiting 
self-care ADL or sleep; oral corticosteroid 
or immunosuppressive therapy indicated 
Treat with concomitant medication according to 
Investigator’s discretion 
No option for drug interruption 
 
Treat with concomitant medication according to 
Investigator’s discretion 
No option for drug interruption 
 
Treat with concomitant medication according to 
Investigator’s discretion 
Option for drug interruption of up to 1 week 
 

SAP_001.pdf: 
Biostatistics & Statistical Programming /  
Novartis Institutes for BioMedical Research 
Tropifexor (LJN452) 
Study CLJN452X2201 / NCT02516605
A multi-part, randomized, double-blind, placebo-controlled 
study to assess the safety, tolerability and efficacy of 
tropifexor (LJN452) in patients with Primary Biliary 
Cholangitis 
RAP Module 3: Detailed Statistical Methodology 
Author(s): 
,  Trial Statistician (
) 
, Trial Statistician (Novartis) 
Document type: 
RAP Module 3: Detailed Statistical Methodology 
Document status: 
Final – Amendment 1
Release Date:  
  October 4, 2018 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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RAP Module 3 Amendment 1 
 
CLJN452X2201 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 3 
1 
Introduction to RAP documentation .................................................................................... 4 
1.1 
Scope ........................................................................................................................ 4 
1.2 
Changes to RAP documentation (M3) ..................................................................... 4 
2 
Study objectives and design ................................................................................................ 5 
2.1 
Study objectives ....................................................................................................... 5 
2.1.1 
Primary Objectives .................................................................................. 5 
2.1.2 
Secondary Objectives .............................................................................. 5 
 
 5 
2.2 
Study design and treatment ...................................................................................... 5 
3 
First interpretable results (FIR) ........................................................................................... 8 
4 
Interim analyses ................................................................................................................... 8 
5 
Statistical methods: Analysis sets ...................................................................................... 10 
6 
Statistical methods for Pharmacokinetic (PK) parameters ................................................ 11 
6.1.1 
Variables ............................................................................................... 11 
6.1.2 
Descriptive analyses .............................................................................. 11 
6.1.3 
Statistical model, assumptions and hypotheses ..................................... 12 
6.1.4 
Model checking procedures .................................................................. 12 
6.1.5 
Graphical presentation of results ........................................................... 12 
6.1.6 
Pharmacokinetic / pharmacodynamic interactions ................................ 13 
7 
Statistical methods for Pharmacodynamic (PD) parameters ............................................. 13 
7.1 
Primary objective ................................................................................................... 13 
7.1.1 
Variables ............................................................................................... 13 
7.1.2 
Descriptive analyses .............................................................................. 13 
7.1.3 
Statistical model, assumptions and hypotheses ..................................... 13 
7.1.4 
Handling of missing values/censoring/discontinuations ....................... 14 
7.1.5 
Model checking procedures .................................................................. 14 
7.1.6 
Graphical presentation of results ........................................................... 14 
7.1.7 
Supportive analyses ............................................................................... 14 
7.2 
Secondary objectives ............................................................................................. 15 
7.2.1 
Variables ............................................................................................... 15 
7.2.2 
Descriptive analyses .............................................................................. 15 
7.2.3 
Statistical model, assumptions and hypotheses ..................................... 15 
7.2.4 
Model checking procedures .................................................................. 15 
7.2.5 
Graphical presentation of results ........................................................... 15 


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CLJN452X2201 
 
 
 16 
8 
Statistical methods for safety and tolerability data ............................................................ 16 
8.1.1 
Variables ............................................................................................... 16 
8.1.2 
Descriptive analyses .............................................................................. 16 
8.1.3 
Graphical presentation of results ........................................................... 17 
 
 17 
 
List of tables 
Figure 2-1 
Study design ............................................................................................ 6 
Figure 2-2 
Study design Part 1.................................................................................. 7 
Figure 2-3 
Study design Part 2.................................................................................. 8 
Table 5-1 
Protocol deviation codes and analysis sets............................................ 10 
 


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1 
Introduction to RAP documentation 
1.1 
Scope 
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLJN452X2201”. 
Module 3 (M3) provides the description of the statistical methodology used to analyze the 
data, TFL shells details the presentation of the data, including shells of summary tables, figures 
and listings, and Module 8 (M8) contains programming specifications e.g. for derived variables 
and derived datasets, to support the creation of CSR outputs. 
1.2 
Changes to RAP documentation (M3) 
Refer to corresponding guidances and NIBR RAP Addendum template for detailed information 
on the requirements of documenting changes to RAP documentation. 
For the statistical methodology (M3), any major changes to the statistical methodology should 
be reflected in the RAP M3 documentation via version control (M3 amendment) (new document 
version to be approved by the trial team as the original module). 
Such major changes could include (but are not limited to): 
• change in statistical methodology 
• substantial change in (derivation of) main endpoint 
• substantial change in study design (e.g. protocol amendment introducing new multiple-
dose cohorts in a so far single-dose trial) 
Such changes may also require a protocol amendment to ensure consistency. In addition they 
need to be mentioned (high-level) in the CSR (section for changes to planned analysis). 
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file / note 
in RAP Addendum or within the CSR itself.  
 
 
 Corrections of typographical errors or modification of 
spelling (from English to American, for example) do not need to be incorporated into the RAP 
M3 documentation. 
 
 
 
This RAP M3 Amendment 1 is to reflect the following changes: 
• 
The addition of a deviation code leading to exclusion from the PD analysis set in 
Table 5-1. 
• 
The addition of the time by log-transformed baseline term in the repeated measures 
analysis model in Section 7.1.3. 
• 
The changes to the study design in protocol amendment 5. 


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CLJN452X2201 
 
2 
Study objectives and design 
2.1 
Study objectives 
2.1.1 
Primary Objectives 
• To determine the effect of LJN452 on cholestatic markers (Liver function tests, 
specifically GGT) in patients with Primary Biliary Cholangitis (PBC). More specifically, 
in Part 2 to determine the dose-response relationship of LJN452 on GGT following 12 
weeks of treatment 
• To determine the safety and tolerability of daily dosing of LJN452 in patients with PBC 
2.1.2 
Secondary Objectives 
• To evaluate the pharmacokinetics (PK) of LJN452 in patients with PBC 
• To evaluate the change in overall disease specific quality of life from PBC40 
• To determine the change in the itch domain of PBC40 questionnaire 
• To evaluate the change in itch based on 100 mm visual analog score (VAS) 
• Part 2: To determine the dose-response relationship of LJN452 on ALP in patients with 
PBC following 12 weeks of treatment 
2.2 
Study design and treatment 
This is a randomized, double-blind, placebo-controlled, multi-part study to assess safety, 
tolerability and efficacy of LJN452 in patients with Primary Biliary Cholangitis (PBC). 
Part 1 uses an escalating multiple dose design in PBC patients with incomplete biochemical 
response to, but still taking, ursodeoxycholic acid (UDCA). 
Part 2 is a parallel group, 12-week study to assess the safety, tolerability and efficacy of two 
doses of LJN452 compared to placebo in PBC patients with an incomplete biochemical 
response to, but still taking, UDCA or those not taking UDCA. The two LJN452 doses for Part 
2 will be selected based on safety, tolerability and efficacy data from Part 1. 


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RAP Module 3 Amendment 1 
 
CLJN452X2201 
 
Once approximately 40 patients from Part 2 have completed 8 weeks of treatment, an interim 
analysis will be conducted to re-assess the sample size for Part 2. Figure 2-1 shows how Parts 
1 and 2 are connected. 
Figure 2-1 
Study design 
 
Part 1 
A minimum of 2 and maximum of 5 cohorts of approximately 15 patients with PBC with 
incomplete biochemical response, but still taking UDCA treatment will be enrolled into Part 1, 
with the aim of a minimum of 12 patients per cohort completing. Patients withdrawing for 
reasons other than AEs may be replaced throughout the study. Patients withdrawing from a 
cohort may not be enrolled in a subsequent cohort. 
Figure 2-2 shows the study design of Part 1. At the beginning of Part 1, a screening visit will 
take place, where a patient's eligibility to enter the study will be assessed. Eligible patients will 
be admitted to the study site and re-evaluated for inclusion / exclusion criteria during the 
baseline visit. All baseline safety evaluation results must be available and reviewed prior to first 
dosing. 
Cohort 1  
28 Day treatment 
Cohort 1  
Follow up 
Cohort 2  
28 Day treatment 
Cohort 2  
Follow up 
Cohort 3 etc  
28 Day treatment 
Cohort 3 etc  
Follow up 
Dose 
Escalation 
Meeting 
Dose 
Escalation 
Meeting 
Part 1: Multiple (1 to 5) cohorts; 4 weeks treatment 
Part 2: Parallel design, 2 dose levels,12 weeks treatment 
Two dose levels approved by DMC 
Day 28 data available 
Dose Level 1 12 week treatment 
Follow up 
Dose Level 2 12 week treatment 
Follow up 
Placebo 12 week treatment 
Follow up 


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RAP Module 3 Amendment 1 
 
CLJN452X2201 
 
Figure 2-2 
Study design Part 1 
Study Day             
 
1 
7 
14 
21 
28 
29 
56 
84 
Study visit           
 
 
 
 
 
 
 
 
 
Screening 
BL 
4 week treatment period 
Follow up               EOS 
 
BL = Baseline assessments  
EOS = End of Study visit 
 = Study visit  = Optional study visit 
Patients will be asked to arrive at the study site approximately 2 hours prior to dosing on Day 1. 
Patients in Cohort 1 will be randomized in a 2:1 ratio to receive the starting dose of 0.03 mg 
LJN452 or placebo. Safety assessments will be performed for 4 hours post dose and 
pharmacokinetic 
 assessments will be performed for up to 8 hours post first dose. 
Prior to discharge, the patients will be given a supply of LJN452 or placebo and instructed to 
take first thing in the morning with water, prior to eating every day. 
Patients will then return on Days 7, 14 and 21 for safety, pharmacokinetic 
 
assessments and dosing. Patients will be asked to return to the study site on Day 28, for the final 
dosing visit, when safety, pharmacokinetic 
 assessments will be performed. 
Patients will be asked to return to the study site for an optional ambulatory visit on Day 29, 
where 24 hour post dose pharmacokinetic 
 assessments will be performed. 
Patients are asked to return to the study site on approximately Day 56 for follow up assessments. 
An end of study visit will take place at approximately Day 84. 
A dose escalation review and an interim analysis are planned when at least 12 patients have 
completed dosing and Day 28 assessments in Cohort 1. The main purpose of the interim analysis 
will be to evaluate the observed variability in GGT levels and, if needed, consider a sample size 
re-estimation. 
Additional cohorts will follow the same schedule as Cohort 1. Further cohorts may be added 
depending on emerging safety and PK/PD data. Additional interim analyses may be performed 
after a minimum of 12 patients in each cohort finish dosing and Day 28 assessment. The sponsor 
will be unblinded and the Clinical Trial Team may be unblinded when all subjects in a cohort 
have completed 28 day of study hence at the time of the planned IAs. 
Part 2 
Approximately 88 patients with PBC, with an incomplete biochemical response to, but still 
taking, UDCA or those not currently taking UDCA are planned to be recruited into Part 2, with 
the aim that 80 will complete the study. Patients who participated in Part 1 may be recruited to 
Part 2, provided they meet all required eligibility criteria and have not received study 
medication within 3 months of Randomization (or longer if required by local regulations). 


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RAP Module 3 Amendment 1 
 
CLJN452X2201 
 
Figure 2-3 
Study design Part 2 
Study visit           
 
TC 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
 
 
             12 week treatment period 
Follow up  
BL 
 
 
EOS 
 
BL = Baseline assessments (performed pre-dose Day 1) 
 = Study visit 
TC = Telephone Contact 
EOS = End of Study visit 
A screening visit will take place, where patient's eligibility to enter the study will be assessed. 
Eligible patients will be asked to arrive at the study site approximately 2 hours prior to dosing 
on Day 1 to perform Baseline assessments. 
Patients will be randomized in a 3:3:2 ratio to receive either LJN452 Dose level 1, LJN452 
Dose level 2 or placebo. Following drug administration, safety, pharmacokinetic 
 
assessments will be performed at 2 hours post dose. 
Prior to discharge, the patients will be given a supply of LJN452 or placebo and instructed to 
take their dose first thing in the morning with water, prior to eating every day. 
Patients will then return at weeks 3, 5, 9 and 13 for safety, tolerability, pharmacokinetic 
 
 assessments. A telephone contact will be made one week after start of dosing to 
check their progress and check they have no questions. 
Patients will be asked to return to the study site in week 17 for follow up assessments and to 
complete their end of study assessments. 
3 
First interpretable results (FIR) 
First interpretable results (FIR) will be provided for this trial. 
The study FIR template (mock slides) can be found in CREDI in the study RAP folder. 
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list. 
4 
Interim analyses 
The first interim analysis will be performed when at least 12 patients in Cohort 1 have 
completed 4 weeks of dosing at 0.03 mg and Day 28 post dose assessments. The purpose of this 
interim analysis is to assess patient safety, to evaluate the assumption on intra-subject variability 
of GGT, which was used for sample size calculations, and to select a dose for the next cohort. 
An ANCOVA model will be fitted to estimate the change from baseline in GGT and its 
variability, and an unblinded sample size re-estimation conducted. The results may be used to 
adjust the size of the next cohort. 
Doses in subsequent cohorts of Part 1 will be decided based on accumulated information 
collected from all previous cohorts including safety, PK and PD data. 


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Additional interim analyses will be performed when at least 12 patients in subsequent cohorts 
of Part 1 have completed 4 weeks of dosing and Day 28 assessments. Placebo data from all 
cohorts will be pooled in the ANCOVA model to evaluate the treatment difference between 
each dose level of LJN452 versus placebo. The model described in the primary analysis section 
will be fitted, as it is indeed the same analysis which will be included in the final study report. 
 
Results from Part 1 will be used to select the doses for Part 2, which may be initiated prior to 
the completion of Part 1. Part 2 will not be initiated if the estimated change from baseline in 
GGT at Day 28 is smaller than 20% at the highest dose level of LJN452 in Part 1. 
Unblinded interim analysis results from Part 1 will be reviewed by an internal Novartis Interim 
Analysis Team which may include some CTT members. The Interim Analysis Team may 
communicate interim results to relevant Novartis teams for information, consulting and/or 
decision purposes. The composition of the interim analysis team will be decided before the 
FPFV and a roster of membership maintained in the trial master file. 
The Interim Analysis Team may communicate interim results (e.g., evaluation of PoC criteria 
or information needed for planning/modifying another study) to relevant Novartis teams for 
information, consulting and/or decision purposes. 
No further dissemination of interim results based on un-locked data should occur, in particular 
not with individuals involved in treating the study’s subjects or assessing clinical data (e.g., 
ECGs, images, symptoms) obtained in the study. 
In Part 2 of the study, an interim analysis is planned when approximately 40 patients have 
completed their Week 8 visit. The purpose of this interim analysis is to review the sample size 
(calculated based on GGT and ALP changes) to assess if it is also adequate to provide precise 
enough treatment difference estimates in itch parameters, a key tolerability endpoint. A blinded 
sample size re-estimation will be performed and a proposal to increase the sample size 
submitted to the DMC as needed. The DMC will decide whether it is appropriate to increase 
the sample size based on an unblinded interim analysis, which will be performed by a study 
independent statistician and programmer with outputs provided to the DMC only. Recruitment 
will continue while the IA is being performed. 
This study will utilize a staggered lock of the clinical database, so that the data can be locked 
after completion of Part 1, or a set of Cohorts in Part 1. 
Once a Cohort’s data has been locked, treatment codes for the relevant cohort(s) will be released 
and made available for data analysis. 
The results from the locked Part 1 interim analysis can be communicated beyond Novartis to 
groups including, but not limited to individuals treating the study’s subjects, health Authorities 
and reported on clinical registries. 
Additional interim analyses 
 may be conducted to support decision 
making concerning the current clinical study, the sponsor’s clinical development projects in 
general or in case of any safety concerns.  
No dose escalation is planned in Part 2. 


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DMC 
In Part 2, in addition to frequent review of the emerging study data by the study team, the DMC 
will review safety, including AEs and laboratory parameters, on a regular basis. In addition, in 
the event that more than 3 patients develop an AE of CTCAE Grade 3 or higher in the same 
system organ class, the DMC Chair will be alerted and may call an ad hoc DMC meeting. 
Further details regarding relevant data and actions will be specified in the separate DMC 
charter. The DMC may call for the study to be placed on hold to further enrollment, and the 
study may be stopped based on a full review of all available clinical safety data. 
The DMC charter contains specific details and outputs for the DMC are contained in a separate 
document. 
5 
Statistical methods: Analysis sets 
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
Subjects with dose reduction due to ALT/AST will be analyzed according to the treatment they 
received up to the dose reduction in Part 2. 
The safety analysis set will include all subjects that received any study drug and experienced 
no protocol deviations with relevant impact on safety data. 
The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data. 
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data. 
The analysis sets and protocol deviation codes are related as follows: 
Table 5-1 
Protocol deviation codes and analysis sets 
Category    
   Deviation code 
Text description of deviation 
Data exclusion 
Subjects are excluded from all (safety) analysis in case of these 
PDs:  
Exclude subject completely 
from all (safety) analysis 
sets 
I01 
ICF not obtained 
Yes 
S02 
Subject did not receive any study drug 
Yes 
Subjects are excluded from PK analysis in case of these PDs:  
Exclude subject from PK 
analysis set  
I01 
ICF not obtained 
Yes 
S02 
Subject did not receive any study drug 
Yes 
Subjects are excluded from PD analysis in case of these PDs: 
Exclude subject from PD 
analysis set 
I01 
ICF not obtained 
Yes 
S02 
Subject did not receive any study drug 
Yes 


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Category    
   Deviation code 
Text description of deviation 
Data exclusion 
I03 
Diagnosis of PBC not demonstrated 
Yes 
I07 (Part 1) 
Additional inclusion criterion for Part 1 not met 
Yes 
I08 (Part 2) 
Additional inclusion criterion for Part 2 not met 
Yes 
D01 
Withdrawal criteria met but subject not 
discontinued 
Yes 
Subjects are excluded from PK and PD analysis in case of these 
PDs: 
Exclude subject from PK 
and PD analysis sets 
I01 
ICF not obtained 
Yes 
S02 
Subject did not receive any study drug 
Yes 
I03 
Diagnosis of PBC not demonstrated 
Yes 
I07 (Part 1) 
Additional inclusion criterion for Part 1 not met 
Yes 
I08 (Part 2) 
Additional inclusion criterion for Part 2 not met 
Yes 
D01 
Withdrawal criteria met but subject not 
discontinued 
Yes 
If updates to this table are needed, an amendment to RAP M3 needs to be implemented prior to 
DBL. 
6 
Statistical methods for Pharmacokinetic (PK) parameters 
All subjects with at least one period of evaluable pharmacokinetic (PK) parameter data will be 
included in the pharmacokinetic data analysis. 
6.1.1 
Variables 
In Part 1, the pharmacokinetic parameters include (but are not limited to) AUC, Cmax, Tmax 
for LJN452. 
Plasma concentrations will be expressed in ng/mL. All concentrations below the limit of 
quantification or missing data will be labeled as such in the concentration data listings. 
Concentrations below the Limit of Quantification will be treated as zero in summary statistics 
for concentration data only. They will not be considered for calculation of PK parameters (with 
the exception of the pre-dose samples). 
6.1.2 
Descriptive analyses 
Descriptive statistics of pharmacokinetic concentration and parameters will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax where median, minimum and maximum will be 
presented. Concentrations below LLOQ will be treated as zero in summary statistics and for PK 
parameter calculations. A geometric mean will not be reported if the dataset includes zero 
values. Pharmacokinetic parameters will be listed by treatment and subject. 


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At Day 1 and Day 28, AUC and Cmax will be summarized for each cohort along with 90% 
two-sided confidence intervals computed on the log-scale and back-transformed. All subjects 
with available PK parameters and no protocol deviation excluding them from the PK analysis 
set will be part of this computation. 
LJN452 plasma concentration data will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Additionally summary statistics may also be provided for the LJN452 plasma concentration 
data with a breakdown by UDCA stratum as appropriate. 
6.1.3 
Statistical model, assumptions and hypotheses 
If 3 or more cohorts are included in Part 1 of the study, then dose-proportionality will be 
explored by fitting a power model to log(AUCtau) and log(Cmax). The model will specify a 
linear regression in log AUC (resp. log Cmax) regressed onto log dose level. This analysis will 
be done at Day 28 only. 
Dose proportionality will be assessed on pharmacokinetic parameters AUCtau and Cmax on 
Day 28. 
The pharmacokinetic parameters will be used to explore the relationship between dose and 
pharmacokinetic parameters using the power model on the log scale: 
ln(PKij) = μ + β ln(Dosej) 
with β denoting the slope and Dosej denoting the total dose. 
An estimator for the slope including the 90% confidence interval will be obtained based upon 
the log-transformed observations. This estimator and confidence interval will then be 
“back-transformed” to the original scale. 
For exploratory information, PK dose proportionality will be considered across the whole dose 
range if the 90% confidence interval (βL, βU) for the slope βj is completely contained within a 
pre-specified critical region (bL, bU), where the two limits bL, bU are derived as follows: 
bL = 1 + ln(θL)/ln(r)  and  bU = 1 + ln(θU)/ln(r) 
with r=ratio of doses (highest dose/lowest dose), θL=0.8, θU=1.25 being the standard 
bioequivalence limits. 
Graphical representation of dose proportionality will be explored. 
6.1.4 
Model checking procedures 
The quality of the fit of the power model to assess dose-proportionality will be assessed by 
comparing the linear sub-model against a saturated model with a different mean level at each 
concentration. In case of evidence of lack-of-fit, alternative models will be explored. 
6.1.5 
Graphical presentation of results 
Arithmetic mean (SD) plasma concentration data will be plotted across time, with separate line 
types for each population. 


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Overlaying individual plasma concentration-time profiles will be generated. 
6.1.6 
Pharmacokinetic / pharmacodynamic interactions 
The relationship between PK (dose, concentration or PK parameter such as Cmax and AUC on 
Day 28) and key PD parameters (absolute and change from baseline to Day 28) including the 
primary endpoint GGT, the secondary efficacy/PD variables (PBC-40 total score, PBC-40 itch 
domain subscore, and the VAS scale PRO),
 
 
will be explored by graphic exhibition. 
7 
Statistical methods for Pharmacodynamic (PD) parameters 
Analysis will be done for Part 1 and Part 2 separately unless specifically mentioned. 
7.1 
Primary objective 
The primary efficacy objective is to evaluate the treatment effect of LJN452 over placebo in 
terms of reduction in cholestasis. The primary efficacy endpoint is the fold change in serum 
gamma-glutamyl transferase (GGT) from baseline to Day 28 and Day 85 for Part 1 and Part 2, 
respectively. 
7.1.1 
Variables 
The primary efficacy endpoint is the fold change in serum GGT from baseline. 
The serum GGT values at all time points will be logarithmically transformed prior to analysis. 
The rationale for the log transformation is to achieve more approximate normality and to be 
able to estimate a treatment effect on a ratio scale. Y=log(GGT+0.0001) will be considered only 
if there are many observations with GGT result as zero. 
The change from baseline will be calculated as the difference between each of the 
log-transformed post-dose serum GGT values and the log-transformed baseline serum GGT 
value. This change from baseline will then be “back-transformed” to give a fold increase from 
baseline. 
Baseline will be latest available pre-dose measurement. 
7.1.2 
Descriptive analyses 
Unless stated otherwise, summary statistics for PD variables will include sample size (n), mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. A geometric mean will not be reported if the dataset includes zero values. 
Summary statistics will be reported by treatment at each applicable time point for the original 
data and also the change from baseline or fold increases from baseline or percent change from 
baseline, as appropriate. 
7.1.3 
Statistical model, assumptions and hypotheses 
Log-transformed changes from baseline for serum GGT will be analyzed by repeated measures 
analysis of covariance (ANCOVA) for each Part 1 and Part 2 separately. The model will include 


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treatment as a fixed effect, time as a repeated effect, the treatment by time interaction, the time 
by log-transformed baseline interaction and log-transformed baseline as a continuous covariate. 
The UDCA and pruritus stratification factor will also be included as a fixed effect in the 
ANCOVA model for the Part 2 analysis. A saturated covariance structure will be used for 
observations within the same subject. The model will be fitted using SAS Proc Mixed and the 
restricted maximum likelihood scoring method (reml). Two-sided 90% confidence intervals for 
the difference between each LJN452 dose and placebo will be evaluated for each visit. This will 
then be “back-transformed” to the original scale to give a fold change from baseline. Dose 
response may be assessed using appropriate contrasts. The analysis at the Day 28 (Visit 7) and 
day 85 (Visit 7) will constitute the primary analysis for Part 1 and Part 2, respectively. 
The analysis will be done for each study cohort using pooled placebo data within Parts 1 and 2, 
respectively. No adjustment for multiplicity will be done. 
Additionally an exploratory analysis on the combined data from Part 1 and Part 2 may be 
performed using a similar approach and the correlation between measurements taken in Part 1 
and Part 2 from the same subject will be accounted for as appropriate. 
Similar analysis as mentioned above can be performed for key LFT parameters. 
In Part 2, there is the option of reducing the dose level for the individual subject. If for any 
subject the dose is reduced during the study, any data after the dose reduction will be set to 
missing. A repeated measures ANCOVA treating all measurements obtained post dose 
reduction as missing will be performed as well for Part 2 only. 
7.1.4 
Handling of missing values/censoring/discontinuations 
All missing GGT values will be considered missing at random. No imputation or adjustment to 
the primary analysis will be done. 
7.1.5 
Model checking procedures 
Residual plots will be produced and presented within the SAS OUTPUT listing. Residual plots 
will be checked and data transformations will be applied if necessary. 
In the case of convergence issues of the primary model, alternative covariance structures will 
be considered and compared using standard fit statistics (AIC). 
7.1.6 
Graphical presentation of results 
Arithmetic mean (±SD) of serum GGT levels and key LFT parameters, and fold change from 
baseline in serum GGT levels and key LFT parameters will be plotted across time. 
Adjusted means and 90% CI from the repeated measures analysis of fold change from baseline 
in serum GGT levels and key LFT parameters will be plotted across time. 
Placebo adjusted fold change from baseline and 90% CI will be plotted across time. 
7.1.7 
Supportive analyses 
If it turns out that the primary analysis cannot be fitted because data cannot support a saturated 
model, a simpler covariance matrix such as the compound symmetric covariance structure may 
be fitted. 


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7.2 
Secondary objectives 
7.2.1 
Variables 
The secondary efficacy/PD variables are the PBC-40 total score, the PBC-40 itch domain 
subscore, and the VAS scale PRO as well as ALP (alkaline phosphatase). 
The change from baseline will be calculated as the difference between each of the post-dose 
values and the baseline value. 
Baseline will be latest available pre-dose measurement. 
7.2.2 
Descriptive analyses 
See section 7.1.2. 
7.2.3 
Statistical model, assumptions and hypotheses 
The difference between each LJN452 dose and placebo will be assessed by Wilcoxon rank sum 
test for change from baseline in total PBC score and itch subdomain subscore at each visit. A 
two-sided p-value and 90% CI for each treatment difference will be reported with no adjustment 
for multiplicity. In addition, summary statistics (mean, median, SD, minimum, maximum) will 
be reported at each applicable time point. 
As an additional secondary end point, a 100mm visual analogue scale (VAS) will be used to 
assess the severity of patients’ itch as well as loss of sleep. The score (distance from left) on the 
VAS will be recorded for both parameters by the patient marking with a line. The distance 
marked will be converted to a score between 0 and 10. 
The change from baseline in VAS scores for itch and sleep loss will be analyzed by repeated 
measures analysis of covariance. The model will include treatment as a fixed effect, time as a 
repeated effect, the treatment by time interaction, the visit by baseline interaction and baseline 
as a continuous covariate. An unstructured covariance matrix will be used. Two-sided 90% 
confidence intervals for the difference between each LJN452 dose and placebo will be presented 
for each visit. The UDCA and pruritus stratification factor will also be included as a fixed effect 
in the model for the Part 2 analysis. Missing values will not be imputed. 
ALP data will be analyzed using the same approach as described in Section 7.1.3. 
Additionally, the number and percentage of subjects who have ALP<1.67xULN with >15% 
reduction from baseline and a normal total bilirubin level will be tabulated by part, treatment 
and visit. 
7.2.4 
Model checking procedures 
See section 7.1.5. 
7.2.5 
Graphical presentation of results 
Arithmetic mean (±SD) of the absolute levels and change from baseline in secondary variables 
will be plotted across time. 
Box plots will be provided for change from baseline VAS and PBC scores. 


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Adjusted means and 90% CI from the repeated measures analysis of change from baseline in 
VAS scores for itch and sleep will be plotted across time. 
Placebo adjusted change from baseline and 90% CI will be plotted across time. 
8 
Statistical methods for safety and tolerability data 
8.1.1 
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information. 
8.1.2 
Descriptive analyses 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) 
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject. 
Vital signs 
All vital signs data will be listed by part, cohort, treatment, subject, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by part, cohort, treatment and visit/time. 
ECG evaluations 
All ECG data will be listed by part, cohort, treatment, subject and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by part, cohort, treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by part, cohort, treatment, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by part, 
cohort, treatment and visit/time. 


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The following special clinical laboratory evaluations will be listed and summarized by part, 
cohort, treatment and visit/time: 
• Fasting lipid panel 
• Alpha-fetoprotein (Listed only) 
• Blood type (Listed only) 
Adverse events 
All information obtained on adverse events will be displayed by part, cohort, treatment and 
subject. 
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment. 
Pregnancy test 
All pregnancy test results for women will be listed by part, cohort, subject and visit 
Immunogenicity 
Not applicable. 
8.1.3 
Graphical presentation of results 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created. 


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