Conditions: Primary Bile Acid Diarrhea
Keywords: Primary bile acid diarrhea, FXR agonist, bile acid malabsorption.
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether LJN452 improves the symptoms of bile acid diarrhea and to assess its safety and tolerability profile in patients with primary bile acid diarrhea (pBAD) to guide decision-making regarding further clinical development in this indication.

Detailed description:

Arms:
arm 1: Randomized patients in this arm will receive single oral dose of LJN452 daily for 14 days. There will be a washout period between 7 to 28 days followed by single oral dose of placebo daily for 14 days. arm 2: Randomized patients in this arm will receive single oral dose of placebo daily for 14 days. There will be a washout period between 7 to 28 days followed by single oral dose of LJN452 daily for 14 days.

Interventions: intervention 1: LJN452 intervention 2: Placebo to LJN452
Intervention descriptions: intervention 1: Capsules containing LJN452 intervention 2: Capsules containing placebo to LJN452

Protocol document:
Prot_002.pdf: 
Novartis Institutes for BioMedical Research
LJN452
CLJN452X2202
A double blind, randomized placebo controlled crossover 
multiple dose study of LJN452to assess safety, 
tolerabilityand efficacy in patients with 
primarybileaciddiarrhea (pBAD)
Document type:
Amended Protocol Version
EUDRACT number:
201500319230
Version number:
v02Incorporating amendment 02 (Clean)
Development phase:
II
Release date:
15-Aug-2016
Personal Data
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 Drug Safety 
and Epidemiology Department and notify the Study Lead).
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...........................................................................9
Protocol synopsis...............................................................................................................13
1 Introduction.......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Study purpose........................................................................................................20
2 Study objectives.................................................................................................................21
2.1
Primary objective(s)...............................................................................................21
2.2
Secondary objective(s)...........................................................................................21
3 Investigational plan...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................24
3.3
Rationale of dose/regimen, duration of treatment.................................................24
3.4 
Rationale for choice of comparator.......................................................................25
3.5
Purpose and timing of interim analyses/design adaptations..................................25
3.6
Risks and benefits..................................................................................................25
4 Population..........................................................................................................................26
4.1
Inclusion criteria....................................................................................................26
4.2
Exclusion criteria...................................................................................................27
5 Restrictions for Study Subjects.........................................................................................28
5.1
Contraception requirements...................................................................................29
5.2
Prohibited treatment...............................................................................................29
5.3
Dietary restrictions and smoking...........................................................................29
5.4
General restrictions................................................................................................29
6 Treatment...........................................................................................................................29
6.1
Study treatment......................................................................................................
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6.1.1
Investigational treatment.......................................................................30
6.2
Treatment arms......................................................................................................30
6.3
Permitted dose adjustments and interruptions of study treatment.........................30
6.4
Treatment assignment............................................................................................30
6.5
Treatment blinding.................................................................................................30
6.6
Emergency breaking of assigned treatment code..................................................31
6.7
Treatment exposure and compliance.....................................................................31
6.8
Recommended treatment of adverse events..........................................................31
6.9 
Rescue medication.................................................................................................32
6.10 Concomitant treatment...........................................................................................32
7 Discontinuation and study completion..............................................................................32
7.1
Discontinuation of study treatment........................................................................32
7.2
Study completion and post-study treatment..........................................................33
7.2.1
Lost to follow-up...................................................................................33
7.3
Withdrawal of consent...........................................................................................33
7.4
Study Stopping rules..............................................................................................34
7.5
Early study termination..........................................................................................35
8 Procedures and assessments..............................................................................................36
8.1
Informed consent procedures.................................................................................39
8.2
Patient demographics/other baseline characteristics.............................................39
8.2.1
Demography..........................................................................................40
8.2.2
Medical history/current medical conditions..........................................40
8.3
Efficacy / Pharmacodynamics...............................................................................40
8.3.2
Patient diary..........................................................................................40
8.4
Safety.....................................................................................................................41
8.4.1
Physical examination............................................................................41
8.4.2
Vital signs..............................................................................................41
8.4.3
Height and weight.................................................................................41
8.4.4
Laboratory evaluations..........................................................................42
8.4.5
Pregnancy and assessments of fertility.................................................42
8.4.6
Coagulation Panel.................................................................................43
8.4.7
ECG evaluation.....................................................................................43
8.5
Pharmacokinetics...................................................................................................43
8.5.1 
PK blood collection...............................................................................44
8.6
Other assessments..................................................................................................
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8.6.1
Exploratory Biomarker assessments.....................................................44
9 Safety monitoring..............................................................................................................46
9.1
Adverse events.......................................................................................................46
9.2
Serious adverse event reporting.............................................................................47
9.2.1
Definition of SAE.................................................................................47
9.2.2
SAE reporting........................................................................................48
9.3
Liver safety monitoring.........................................................................................49
9.4
Pregnancy reporting...............................................................................................53
9.5
Early phase safety monitoring...............................................................................53
10 Data review and database management.............................................................................53
10.1 Site monitoring......................................................................................................53
10.2 Data collection.......................................................................................................54
10.3 Database management and quality control............................................................54
10.4 Data Monitoring Committee..................................................................................55
10.5 Adjudication Committee........................................................................................55
11 Data analysis......................................................................................................................56
11.1 Analysis sets..........................................................................................................56
11.2 Subject demographics and other baseline characteristics......................................56
11.3 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................56
11.4 Analysis of the primary variable(s).......................................................................56
11.4.1
Variable(s).............................................................................................56
11.4.2
Statistical model, hypothesis, and method of analysis..........................56
11.4.3
Handling of missing values/censoring/discontinuations.......................57
11.5 Analysis of secondary and exploratory variables..................................................57
11.5.1
Efficacy / Pharmacodynamics...............................................................57
11.5.2
Safety.....................................................................................................57
11.5.3
Pharmacokinetics..................................................................................58
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................58
11.5.5
Other assessments.................................................................................58
11.6 Sample size calculation..........................................................................................59
11.7 Power for analysis of key secondary variables......................................................59
11.8 Interim analyses.....................................................................................................59
12 Ethical considerations........................................................................................................60
12.1 Regulatory and ethical compliance........................................................................
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12.2
Responsibilities of the investigator and IRB/IEC..................................................60
12.3
Publication of study protocol and results...............................................................60
13 Protocol adherence ............................................................................................................60
13.1
Protocol Amendments ...........................................................................................61
14 References .........................................................................................................................62
List of tables
Table 8-1
Assessment Schedule ............................................................................36
Table 9-1
Liver Event and Laboratory Trigger Definitions ..................................50
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers...51
List of figures
Figure 1-1
Co-ordinated effects of FXR on metabolism ........................................16
Figure 1-2
Effect of LJN452 in the chronic treatment rat ANIT model.................17
Figure 3-1
Study design schematic.........................................................................22


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
b.i.d.
twice a day
BA
bile acid
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
CV
coefficient of variation
EC
Ethics committee
EC50
half maximal effective concentration
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
FXR
Farnesoid X-receptor
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
h
Hour
HIV
human immunodeficiency virus
i.v.
Intravenous
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use


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IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LLN
lower limit of normal
LLQ
lower limit of quantification
mg
milligram(s)
ml
milliliter(s)
o.d.
once a day
OECD
Organization for Economic Co-operation and Development
p.o.
Oral
PA
Posteroanterior
pBAD
primary bile acid diarrhea
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RBC
red blood cell(s)
REB
Research Ethics Board
s.c.
Subcutaneous
SAE
serious adverse event
SD
standard deviation
SeHCAT
Selenium Homocholic Acid Taurine
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SHP
Small Heterodimer Partner
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)


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Pharmacokinetic definitions and symbols
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau at steady state [mass x time / 
volume]
Cav,ss
The average steady state plasma (or serum or blood) concentration during 
multiple dosing
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) 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 (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
Racc
The accumulation ratio
Tmax
The time to reach the maximum concentration after drug administration [time]


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Protocol synopsis
Protocol number
CLJN452X2202
Title
A double blind, randomized placebo controlled crossover multiple dose 
study of LJN452 to assess safety, tolerability and efficacy in patients with 
primary bile acid diarrhea (pBAD).
Brief title
To assess safety and tolerability and establish efficacy of LJN452 in 
patients with primary bile acid diarrhea.
Sponsor and Clinical 
Phase
Novartis.
Phase 2
Intervention type
Drug.
Study type
Interventional.
Purpose 
and 
rationale
To assess safety, tolerability and efficacy of LJN452 in patients with pBAD.
Primary Objective(s)

To determine the safety and tolerability of LJN452 in patients with 
pBAD.

To assess the effect of LJN452 on clinical symptoms experienced by 
patients with pBAD.
Secondary 
Objectives

To assess the pharmacokinetics of LJN452 in pBAD patients.

Assess the effect of LJN452 on use of rescue medications during the 
study period.
Study design
This is a multi-center, double blind (patient and investigator blind, sponsor 
open label), randomized placebo controlled, crossover study to assess 
safety, tolerability and efficacy of LJN452 in patients with primary bile acid 
diarrhea (pBAD).
Population
The study population will be comprised of patients with primary bile acid 
diarrhea. Approximately 30 patients will be enrolled in the study and 
randomized, with at least 24 patients expected to complete the study.
Inclusion criteria

A history of diarrheal symptoms for at least 3 months prior to dosing -
Average stool frequency of at least 3 per day when off therapy 
AND
Average stool form of >5 on Bristol Stool Chart.

Previous laboratory or radiological confirmation of bile acid 
malabsorption within the last 5 years with either fecal bile acid loss of 
≥2,000 µmol per 48 hours
OR 
7 day 75Selenium homocholic acid taurine (75SeHCAT) retention.

Age ≥ 18 years.
Exclusion criteria

Patients with other diagnoses leading to diarrhea, including colorectal 
neoplasia, ulcerative colitis, Crohn’s disease, celiac disease, chronic 
pancreatitis, drug-induced diarrhea or active infection 
AND 
Patients who have not been investigated by standard clinical 
assessments to exclude these disorders.

Treatment with bile acid sequestrants (colestyramine, colestipol, 


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colesevelam) for 2 weeks before the first dose of LJN452. A washout of 
14 days for these agents will be allowed before first dosing.

History of extrahepatic biliary obstructive disease or complete biliary 
obstruction.

Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception

A positive Hepatitis B surface antigen or Hepatitis C test result.

History of immunodeficiency diseases, including a positive HIV (ELISA 
and Western blot) test result.
Investigational 
and 
reference therapy

Single oral dose of LJN452 60 μg daily for 14 days.

Single oral dose of placebo to LJN452 0 μg daily for 14 days.
Efficacy/PD 
assessments

Change from baseline in stool frequency and stool form per Bristol Stool 
Chart.
Safety assessments

Safety endpoints include type and frequency of adverse events, serious 
adverse events, and laboratory, vital signs, physical, and ECG 
abnormalities. 
Other assessments

PK.

Use of rescue medication.

Markers of target engagement.
Data analysis
A repeated measures analysis will be done for the two-dimensional 
endpoint: weekly stool frequency and the corresponding average stool form.  
The analysis will include fixed effects for sequence (Drug/Placebo or 
Placebo/Drug), Treatment (Week 1 Drug, Week 2 Drug, Week 1 Placebo, 
Week 2 Placebo), and period (1 or 2). The model will assume an arbitrary 2 
by 2 covariance matrix for the two-dimensional endpoint (frequency, form) 
and a compound symmetry covariance matrix for each individual endpoint. 
Point estimates of the treatment effect on weekly & biweekly stool frequency 
and the corresponding average stool form will be reported together with 
95% simultaneous confidence intervals (confidence ellipsoids).
Key words
Primary bile acid diarrhea, FXR agonist, bile acid malabsorption.


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1
Introduction
1.1
Background
LJN452 is a highly potent agonist of the bile acid receptor Farnesoid X Receptor (FXR), 
which is expressed in liver, intestine and kidney. In the liver, FXR agonism increases 
expression of genes involved in canalicular and basolateral bile acid efflux and bile acid 
detoxifying enzymes while inhibiting basolateral bile acid uptake by hepatocytes and 
inhibiting bile acid synthesis (Calkin and Tontonoz 2012). FXR activation represses bile acid 
synthesis in the liver through induction of Small Heterodimer Partner (SHP), which is a 
negative regulator of Cyp7a1, the rate-limiting enzyme of the neutral bile acid biosynthetic 
pathway (Goodwin et al 2000). Furthermore, FXR agonists increase excretion of bile acids 
through the kidney, increase bile acid binding proteins in the ileum and stimulate 
FGF15/FGF19 expression (a key regulator of bile acid metabolism). Thus, FXR acts as a 
sensor of elevated bile acids and initiates homeostatic responses to control bile acid levels, a 
feedback mechanism that is believed to be impaired in bile acid malabsorption
(Pattni et al 2012, Walters 2014).


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Figure 1-1
Co-ordinated effects of FXR on metabolism
FXR regulates bile acid metabolism through multiple mechanisms in the liver and intestine. 
Theprocesses regulated by FXR are shown in rectangular boxes. Genes are shown with up or down 
arrows to indicate the direction of regulation by FXR agonists. Arrows are used to show the flow of bile 
acids in the enterohepatic circulation or the movement of FGF15 (rodents) or FGF19 (human) from the 
enterocyte to the hepatocyte. In normal physiology, FXR detects increased levels of bileacids and 
responds by decreasing bile acid synthesis and bile acid uptake while increasing bile acid modification 
and secretion in the liver. In the intestine, FXR detects increased bile acid levels and decreases bile 
acid absorption and increases secretion of FGF15 or FGF19. The net result is a decrease in the 
overall levels of bile acids.Adaptedfrom Calkin andTontonoz 2012.
1.1.1
Relevant data summary
The most relevant data for the present study are summarized in thesections below. 
Fordetailed information, please refer to the Investigator
's Brochure.
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C
 
 
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1.2
Study purpose
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The purpose of this study is to determine whether LJN452 improves the symptoms of bile 
acid diarrhea and to assess its safety and tolerability profile in patients with primary bile acid 
diarrhea (pBAD) to guide decision-making regarding further clinical development in this 
indication.


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2
Study objectives
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)
To determine the safety and 
tolerability of LJN452 in patients 
with primary bile acid diarrhea.
Safety endpoints include type and frequency of 
adverse events, serious adverse events, and 
laboratory, vital signs, physical, and ECG 
abnormalities.
To assess the effect of LJN452 on 
clinical symptoms experienced by 
patients with primary bile acid 
diarrhea.
Changes from baseline in stool frequency and in 
stool form per Bristol Stool Chart.
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary 
objective(s)
To assess the pharmacokinetics of LJN452 in pBAD 
patients.
Tmax, Cmax and AUCtau of 
LJN452.
To assess the effect of LJN452 on use of rescue 
medications during the study period.
Use and type of rescue 
medications.
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3
Investigational plan
3.1
Study design
This is a multi-center, double blind (patient and investigator blind, sponsor open label), 
randomized placebo controlled, crossover study to assess safety,tolerability and efficacy of 
LJN452 in patients with primary bile acid diarrhea (pBAD).In this study approximately 
30patients will be enrolled to have 24 completers.
This is a non-confirmatory trial.
Each patient will undergo a screening period (28 days), run-in period (washing out previous 
treatment effect) (up to 14 days), 2 treatment periods (14 days each), washout period (at least 
7 up to 28 days) between the treatment periods and end of study.
Figure 3-1
Study design schematic
Patients will be assessed for eligibility to enter the study at the screening visit.
Each patient will perform following visits
Screening visit: Day -28 to -2
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During the screening period all patients will undergo screening assessment, which may be 
completed over multiplevisits as per the patient’sconvenience. The screening results will be 
valid for 28 days, if any patientis beyond the screening validity, the patient canbe 
re-screened. Results for all screening assessment must be available before the baseline/Day 1 
pre-dose assessment. 
If the eligibilityis confirmed patientswill be asked to discontinue their sequestrants. 
Patientswill be handed over patient diary to record their daily stool type and frequency using 
Bristol Stool Chart and use of rescue medication (loperamide intake). The patient diary is 
expected to be used by patients’throughoutthe study duration.


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Rescue medication will be loperamide only and patients will be instructed to take 2 mg dose 
only after passage of 4 stools of Bristol Stool Scale Type 6 (Fluffy pieces with ragged edges, a 
mushy stool) or Type 7 (Watery, no solid pieces, entirely liquid). This dose may be repeated 
only after 4 hours have elapsed or passage of 4 further stools of Type 6 or 7 
(whichever occurs first). A total of no more than 16mg of loperamide may be taken in a 
24 hour period. No BA sequestrants should be used by the patients during this study.
Run-in period (Day -7 to -1 or Day -14 to -1)
Patients who have not used bile acid sequestrants for pBAD in the previous week at the time 
of screening will be evaluated for inclusion/exclusion criteria during the screening visit, and if 
found eligible will enter a 1 week run in period (Day -7 to -1) prior to the double blind 
randomized treatment phase.
Eligible patients who are treated with bile acid sequestrants (at least one dose during the 
previous two weeks) will be asked to stop their medication and enter the 2 weeks run -in 
period (Day -14 to -1) of the study. Patients will be allowed to take rescue medication 
(loperamide), which will be recorded as concomitant medication.
Patients will continue to use patient diary to record stool type and frequency along with use of 
rescue medication.
Results for all screening assessment must be available before the baseline/Day 1 pre-dose 
assessment. Screening and run-in visits may be combined for logistic reasons.
After the run-in period, patients will enter the double blind randomized treatment phase.
There will not be a separate baseline visit, but pre-dose assessment on Day 1 will be 
considered as baseline assessment.
Treatment Periods (Day 1-14):
On Day 1, patient will handover stool sample collected before dosing as pre-dose stool sample. 
Pre-dose PK, PD and biomarker samples will be collected before dosing.
In treatment period 1 on Day 1 patients will receive either 60 μg LJN452 or placebo orally 
once daily for 14 days in a 1:1 ratio. Pharmacokinetic (PK), pharmacodynamic (PD) and 
safety samples will be collected on Day 1 for up to 8 hours post dose and on Day 2 pre -dose, 
which corresponds to 24 h after Day 1 dosing. Some PK and PD sample time points on Day 1 
and Day 2 can be optional, see Assessment Schedule.
Patients will be handed over trial medication, to be administered at home enough to cover 
dosing for 14 days in each period. Throughout the 14 days of the treatment period, patients 
will be directed to take study drug at home with water in the morning in a fasting state, 
2 hours prior to the first meal of the day, preferably at the same time of the day.
Following dosing, patients will return to clinic for PK, PD, BM and safety assessment at 
various time points as described in the Assessment Schedule.
The patients will return to the clinic for a series of PK, PD and biomarker sample collections 
on Day 12.


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After 2 weeks of treatment with LJN452 or placebo, patients will undergo a washout of at 
least 7 days, up to a maximum of 28 days. At the end of washout period, patients will return to 
the study site for period 2 of the study. Period 2 will be identical to period 1 except that the 
treatments will be crossed over.
Patient diary will be used to capture stool frequency, consistency and rescue medication. 
Intake of loperamide will be allowed, but will be recorded in the concomitant medication 
section of the CRF.
Study Completion visit:
The patients will return to the site 7 days’±2 days after the last dose to undergo the study 
completion evaluations. Following completion of all assessments, the patients will be 
discharged from the study. If for any reason the patientis withdrawn from the study, the 
patientwill return to the site 7 days after the last dose to undergo the study completion 
evaluations. Following completion of all assessments, the subject will be discharged from the 
study. Safety assessments will include physical examinations, ECGs, vital signs, standard 
clinical laboratory evaluations (hematology, blood chemistry, and urinalysis) adverse event 
and serious adverse event monitoring.
3.2
Rationale of study design
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This randomized, multi-center, double blind (patient and investigator blind, sponsor open 
label), placebo-controlled, cross-over study is designed to assess safety, tolerability and 
efficacy of LJN452 at 60 μg relative to placebo in patients with pBAD, as assessed by a 
reduction in stool frequency and stool type score after 2 weeks of double-blind treatment.
A cross-over design reduces variability as the treatment comparison can be done within 
patient.
Randomization will be maintained at 1:1 ratio over the entire study in order to avoid any 
sequence bias.
Multiple sites will be used to enroll patient in this study due to the underlying prevalence of 
diagnosedpBAD. It is know that differences in criteria exist in the diagnosis of pBAD in 
different regions.
In order to maintain the scientific integrity of the study, investigators and patients will remain 
blinded regarding the allocation of active or placebo. The clinical trial team will be unblinded 
throughout the dosing phase to allow analysis of safety and PK/PDdata.


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3.4
Rationale for choice of comparator
There is no FXR agonist approved drug for treatment of bile acid diarrhea, thus placebo will 
be used as a comparator in this study.
3.6
Risks and benefits
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No more than a transient direct benefit of LJN452 treatment to patients with pBAD is 
anticipated in the short term study.
A maximum of 438 mL of blood is planned to be collected over a period of 8 weeks from 
each patient as part of the study. Additional samples needed for monitoring of any safety 
findings would be in addition to this. This is not considered to be a risk for this population.
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There may be unknown risks of LJN452 which may be serious and unforeseen.
The overall risk to patients with pBAD in this study is expected to be low and will be 
minimized by adherence to the inclusion/exclusion criteria, avoidance of prohibited 
concomitant medications, close clinical monitoring including on-line PK assessments, safety 
reviews and study stopping rules.
The overall risk/benefit assessment of LJN452 is supportive of the conduct of this study in 
patients with pBAD.
4
Population
The study population will be comprised of patients withprimary bile acid diarrhea.
A total of approximately 30 patients will be enrolled in the study and randomized,with at 
least 24 patients expected to complete the study.
The investigator must ensure that all patients being considered for the study meet the
following eligibility criteria. No additional criteria should be applied by the investigator to 
ensure that the study population will be representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at screening. 
Arelevant 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 patient from enrollment into the study.
Replacement patients will be enrolled to replace patients who discontinue the study for 
reasons other than safety.
4.1
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed.
2. A history of diarrheal symptoms for at least 3 months prior to dosing
Average stool frequency of at least 3 per day when off therapy.
AND
Average stool formof >5 on Bristol Stool Chart.
3. Previous laboratory or radiological confirmation within the last 5 years of bile acid 
malabsorption with either:
Evidence of fecal bile acid loss of ≥2,000 µmolper 48 hours.
OR 
7 day 
75Selenium homocholic acid taurine (75
Corporate Confidential Information
SeHCAT) retention of <10%.
4. Age ≥ 18 years
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6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
2. Patients with other diagnoses leading to diarrhea, including colorectal neoplasia, 
ulcerative colitis, Crohn’s disease, celiac disease, chronic pancreatitis, drug-induced 
diarrhea or active infection
AND 
Patients who have not been investigated by standard clinical assessments to exclude these 
disorders.
3. Treatment with bile acid sequestrants (colestyramine, colestipol, colesevelam) for 2 weeks 
before the first dose of LJN452. A washout of 14 days for these agents will be allowed 
before first dosing.
4. Use of drugs or agents of the classes within 1 week prior to dosing or planned use during 
the study period:
Agents that alter GI transit except loperamide, including strong opioids, narcotics, 
anticholinergics.

Corporate Confidential Information
Any medication that could interfere with the interpretation of the study (thyroxine 
replacement is a permissible exception).
5. History of extrahepatic biliary obstructive diseaseor complete biliary obstruction.
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
Evidence of urinary obstruction or difficulty in voiding at screening.
8. 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.
9. 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.
10. Sexually active males must use a condom during intercourse while taking drug and for 5 
days after stopping LJN452 and should not father a child in this period. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid.
11. Significant mental and physical illness other than pBAD which has not resolved within 
two (2) weeks prior to initial dosing.
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 5 days after stopping of LJN452. Highly effective contraception 
methods include:

Total abstinence from heterosexual intercourse (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), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug.  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 months 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 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 be stable on the same pill for a 
minimum of 3 months before taking investigational drug.
13. A positive Hepatitis B surface antigen or Hepatitis C test result.
14. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) 
test result.
15. 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 treatment day 1 visit, the patients 
must be informed and reminded of the restrictions.


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5.1
Contraception requirements
Please refer to exclusion criteria (Section 4) for details of contraception requirements for the 
study.
5.2
Prohibited treatment
No medication or herbal remedies likely to have an impact on LJN452 metabolism will be 
allowed from the first dosing until end of study evaluations have been conducted. 
 
 Administration of acetaminophen (no more than 1000 mg in a single dose and no 
more than 4000 mg per day) is acceptable, but must be documented.
A full list of prohibited medications will be provided in the SOM.
5.3
Dietary restrictions and smoking
Patient must avoid high fat foods during the study and adhere to a diet that is similar across 
both periods of the cross-over design.
All patients 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 (i.e. no food and liquid except water) for 
at least 2 hours thereafter.
Food intake will be monitored regularly throughout the study using a patient diaryand will be 
included in the clinical database. 
Patients can drink water ad libitumin addition to fluid taken with meals and medication.
On PK days Day 1 and Day 12, no breakfast will be provided. Meals should be similar in 
caloric content and distribution for all patients on the day of dosing.
5.4
General restrictions
No strenuous physical exercise (e.g. weight training, aerobics, football) until after Study 
Completion evaluation.
6
Treatment
6.1
Study treatment
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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.


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6.1.1
Investigational treatment
The investigational drug, LJN452 10 µg (0.01 mg), and matching placebo will be prepared
and supplied by Novartis as single blinded packs to be dispensed by the unblinded pharmacist 
at the investigator site according to the randomization schedule.
6.2
Treatment arms
Patients will be assigned to the 2 treatment sequence (Drug/Placebo or Placebo/Drug) in a 
ratio of 1:1. The number of patients enrolled may change based on data from interim analyses.
Study treatments are defined as:

A: Single oral dose of LJN452 60 μg daily for 14 days (administered as LJN452 6 x 10 μg 
capsules).

B: Single oral dose of placebo to LJN452 0 μg daily for 14 days (administered as placebo 
to LJN452 6 x 0 μg capsules).
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments by the investigator and/or interruptions other than for safety 
reasons are not permitted.
In case of notable adverse events, safety concerns and/or based on pharmacokinetic data 
review during the study, the following changes to the administered dose may be considered by 
the sponsor in consultation with the investigator:

Administration of a dose below the starting dose.

Administration of a dose higher than the starting dose not exceeding the exposure cap.
These changes must be recorded on the Dosage Administration Record CRF.
6.4
Treatment assignment
Randomization numbers will be assigned in ascending, sequential order to eligible patients 
(see Site Operations Manual for details). The investigator will enter the randomization 
number on the CRF.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. 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 randomization scheme for patients 
will be reviewed and approved by a member of the Novartis IIS Randomization Group.
6.5
Treatment blinding
This is a double blind study: Patients, investigator staff, and persons performing the 
assessments will remain blinded to the identity of study treatments according to the 
specifications provided in the Site Operations Manual.
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.


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Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study with the following exceptions: 
Unblinded pharmacist or authorized designee at site, and the sponsor clinical trial team.
The Interim Analysis Team may communicate interim analysis results (e.g. information 
needed for planning/modifying another study) to relevant Novartis teams for information, 
consulting and/or decision purposes.
The sponsor clinical trial team will remain unblinded throughout the study.
Unblinding to the investigator and patient will only occur in the case of patient emergencies 
(see Section 6.6) and at the conclusion of the study or after IAs.
6.6
Emergency breaking of assigned treatment code
Emergency unblinding should only be undertaken when it is essential to treat the patient 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
investigator site(s) 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 patient, 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.
6.7
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
patients treated with LJN452, as detailed in Section 8.5.
6.8
Recommended treatment of adverse events
Expression of ALP is induced by FXR activation. Hence LJN452 is expected to increase 
circulating levels of ALP in a dose dependent manner and this will not necessarily indicate 
liver injury. Elevation of ALP should be interpreted in light of other tests, such as ALT, AST, 
and total bilirubin levels. Please see specific stopping rules and response to abnormal lever 
enzyme tests.
Medication used to treat adverse events must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.


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6.9
Rescue medication
Use of rescue medication (loperamide) will be allowed and must be recorded on the patient 
diary/Concomitant medications/Significant non-drug therapies CRF after start of study drug.
Rescue medication will be loperamide only and patients will be instructed to take 2 mg dose 
only after passage of 3 stools of Bristol Stool Scale Type 6 (fluffy pieces with ragged edges, a 
mushy stool) or Type 7 (watery, no solid pieces, entirely liquid). This dose may be repeated 
only after 4 hours have elapsed or passage of 4 further stools of Type 6 or 7 
(whichever occurs first). A total of no more than 16 mg of loperamide may be taken in a 
24 hour period. No BA sequestrants should be used by the patients during this study.
6.10
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
Patients may voluntarily discontinue study treatment for any reason at any time.
Discontinuation of study treatment will be at the discretion of the Investigator, under the 
following circumstances:

Any protocol deviation that results in a significant risk to the patient’s safety.

If continuation in the study is deemed detrimental to the patient’s well-being.
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
Individual patient withdrawal
Patients may voluntarily discontinue study treatment for any reason at any time.
Study treatment must be discontinued and the patient withdrawn from the study if the patient 
withdraws consent.
The study treatment must be discontinued and the patient’s withdrawal from the study should 
be at the investigator’s discretion if the following occur:

Pregnancy.

Intolerable or clinically significant diarrhea.

Hypersensitivity reaction to LJN452.


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
An increase in aminotransferase enzymes (ALT or AST) of greater than 3 x ULN AND 
EITHER symptoms such as anorexia, fatigue, right upper quadrant abdominal pain or 
tenderness, fever, rash and/or eosinophilia OR elevation of serum TBL to greater than 
2 x ULN OR INR>1.5.

Medically significant (>8 x ULN) ALT or AST elevation.

An AE with a CTCAE rating of Grade 3 or higher regardless of drug causality, unless it is 
caused by elevation of ALT (as above) or an accident that could not reasonably be 
attributable to the drug.

An AE with a CTCAE rating of Grade 2 or higher considered to be due to study drug, 
unless it is caused by elevation of ALT (as above).

An elevation of ALP or GGT of >2.5 x ULN considered to be due to study drug or >5 × ULN 
regardless of drug causality.
Patients 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 patient will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. Study completion is defined as when the last 
patient 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.
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the Study Completion visit, including a final post-study safety contact at the 30-day point. 
Documentation of attempts to contact the patient should be recorded in the source 
documentation.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. All patients who 
complete the study will return to their standard of care after the end of study visit.
7.2.1
Lost to follow-up
For patients 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 patient, e.g. dates of 
telephone calls, registered letters, etc. A patient should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.


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Withdrawal of consent occurs only when a patient 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 patient 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 patient 
are not allowed unless safety findings require communicating or follow-up.
7.4
Study Stopping rules
The study will be placed on hold and may be stopped or amended based on full review of all 
available clinical safety data and discussion with the Investigator if any of the following occur:

Two or more patients on study drug experience a similar adverse event that is a CTCAE 
Grade 3 or higher apart from ALT elevation (see below).

One patient on study drug experiences any adverse event that is CTCAE Grade 4 or higher 
apart from ALT elevation (see below) other than an accident that is not related to study 
drug).

Two or more patients with an increase in aminotransferase enzymes (ALT or AST) of 
greater than 3 x ULN AND EITHER symptoms such as anorexia, fatigue, right upper 
quadrant abdominal pain or tenderness, fever, rash and/or eosinophilia OR elevation of 
serum total bilirubin to greater than 2 x ULN OR INR >1.5.

Two or more patients on study drug experience an elevation of ALP or GGT of >5 × ULN 
or one patient on study drug experiences an elevation of ALP or GGT of >20 × ULN. 

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 discontinuation of the study.
Safety reviews will be conducted jointly between medically qualified representatives of the 
Sponsor and Investigator and a joint decision will be made. 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 patient’s discontinuation or stopping of the study.
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. If a patient withdrawal occurs for any reason, the 
Investigator must make every effort to determine the primary reason for a patient’s 
withdrawal from the study and record this information on the Study Completion CRF.


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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, 
patients should be seen as soon as possible and treated as a prematurely withdrawn patient. 
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 patient’s interests.
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


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8
Procedures and assessments
Patients 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.
Table 8-1
Assessment Schedule
Study Phase Screening
Run-in
Treatment Period 1 / Washout / Period 2
EOS
Visit Numbers1
V15
V25
V3
V4
V5
V62
V777
Visit Numbers
V7
V8
V9
V10
Study Day(s)
-28 to -2
-14 to -1
1
2
7±2
12
43±2
Time (post-dose)
-
-
0h
1h
2h
4h
5h
6h
8h
0h
-
0h
1h
2h
4h
5h
6h
8h
-
Informed consent
X
Inclusion / Exclusion criteria
X
Medical history/current medical conditions
X
Physical examination
X
X
X
X
Demography
X
Hepatitis screen
X
HIV screen
X
Alcohol Test and Drug Screen 
X
Pregnancy test
X3
X4
X4
X3
Body height
X
Body weight
X
X
X
X
Body temperature
X
X
X
X
Blood Pressure and Pulse Rate
X
X
X
X
ECG evaluation
X
X
X
X
Coagulation Panel6
X
X
X
X
Blood chemistry
X7
X
X8,18 X8,18 X8,18 X8,18 X8,18
X8,18
X8,18
X9
X
X8
X8
X8
X8
X8
X8,18
X
Hematology
X
X
X
X


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Study Phase Screening Run-in
Treatment Period 1 / Washout / Period 2
EOS
Visit Numbers1
V15
V25
V3
V4 
V5
V62
V777
Visit Numbers
V7
V8 
V9
V10
Study Day(s) -28 to -2 -14 to -1
1
2 
7±2
12
43±2
Time (post-dose)
- 
-
0h 1h 2h 4h 5h 6h 
8h 
0h
-
0h 1h 2h 4h 5h 6h 
8h
-
Urinalysis
X
X
X
X
Drug dispensation
X
Drug administration record10
X
X 
X
Stool Collection11
X12
X12
X
Patient diary
X 
X 
X
X
X
X 
X19
X
X
X
X X18
X18
X18
X18
X18
X18
X18
X 
X 
X 
X 
X 
X 
X18
X
X
PK blood collection
X X18
X18
X18
X18
X18
X18
X18
X 
X 
X 
X 
X 
X 
X18
X15
X
Adverse events
As required
Serious adverse events
As required
Concomitant therapies
As required
Comments
Study completion information
X
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1Visit structure given for internal programming purpose only
2Minimum 7 days and up to 28 days washout starting after last dose in period 1.
3Serum pregnancy test.
4Urine pregnancy test can be performed and results will be required before dosing. A positive urine pregnancy test should be confirmed with a serum pregnancy test.  
5Visit 1 and visit 2 can be combined
6
Panel includes Activated partial thromboplastin time (aPTT), fibrinogen (Fbg), prothrombin time (PT), international normalized ratio (INR, transformed by PT), and 
thrombin time (TT)
7Alpha fetoprotein measured in screening visit only
8Measure total bile acids only.
9LFT assessments(GGT, ALP, AST, ALT).Blood sample can be collected at homeor workper investigators discretions.
10Patients shall be dosed till Day 14 in each period.
11Stool analysis may include fecal occult blood, microbiome and bile acids. Samples will be collected once on the day of assessment. All bowel movements will be 
recorded daily with the exact time, daily frequency and consistency (using the Bristol stool chart) in the patient diary. Diary will also capture food intake.
12Morning stool sample preferable collected before dosing or within 2 hours of dosing.
13
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BM plasma will be collected to assess bile acid multiplex.


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8.1
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
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 patientsource 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 partnersof 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.
The study includes an optional scintigraphic clonic transit assessment in a US center only 
which requires a separate signature if the patient agrees to participate. As part of this protocol 
only Investigators in US will present this option to the patient. The process of obtaining 
consent should be exactly the same as described above for the main informed consent.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Patient demographics/other baseline characteristics
Corporate Confidential Information
Patient demographic and baseline characteristic data will be collected on all patients.
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.


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8.2.1
Demography
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, predominant ethnicity.
8.2.2
Medical history/current medical conditions
Relevant medical history and current medical conditions will be recorded on the CRF until 
signature of the informed consent.
Where possible, diagnoses and not symptoms will be recorded.
Any event or change in the subject’s condition or health status occurring prior to informed 
consent will be reported in the Relevant medical history / Current medical conditions section 
of the CRF.
8.3
Efficacy / Pharmacodynamics
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the Site 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.
8.3.1
Patient-Reported Outcome - IBS-QOL
The IBS-QOL is a self-reported quality-of-life measure specific to Irritable Bowel Syndrome 
(IBS) that can be used to assess the impact of IBS and its treatment. The IBS-QOL was 
developed using a needs based model. The IBS-QOL consists of 34 items, each with a 
five-point response scale.
The individual responses to the 34 items are summed and averaged for a total score and then 
transformed to a 0-100 scale for ease of interpretation with higher scores indicating better IBS 
specific quality of life. There are also eight subscale scores for the IBS-QOL 
(Dysphoria, Interference with Activity, Body Image, Health Worry, Food Avoidance, 
Social Reaction, Sexual, Relationships).
The IBS-QOL is designed to be self-administered, and takes an average of 10 minutes to 
complete. The IBS-QOL can be interviewer-administered if necessary.
The transformation formula used for the IBS-QOL total and scale scores is:
Score = (The sum of the items - lowest possible score/Possible raw score range)*100
8.3.2
Patient diary
Patient diary will be used to capture stool frequency, consistency and rescue medication. 
Intake of loperamide or equivalent will be allowed, but will be recorded in the concomitant 
medication section of the CRF.


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8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule detailing when each assessment is 
to be performed.
8.4.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and/or pelvic exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded the CRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History CRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event 
must be appropriately recorded on the Adverse Event CRF.
8.4.2
Vital signs
8.4.2.1
Blood Pressure and Pulse Rate
Vital signs include blood pressure (BP) and pulse measurements. After the patient has been 
supine for approximately 5 minutes systolic and diastolic BP will be measured once using a 
validated BP device, with an appropriately sized cuff.
The CRF should contain the BP measurements. 
8.4.2.2
Body temperature
Oral body temperature will be obtained at specified times during the study.
8.4.3
Height and weight
8.4.3.1
Body height
Height in centimeters (cm) in indoor clothing, but without shoes) will be measured.
8.4.3.2
Body weight
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2


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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 untilthe change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
8.4.4.1 Hematology
Basophils, Eosinophils, Hematocrit, Hemoglobin, Lymphocytes, Monocytes, Neutrophils, 
Platelets, Erythrocytes, Leukocytes
8.4.4.2 Blood chemistry
Alkaline Phosphatase, Alanine Aminotransferase, Amylase, Aspartate Aminotransferase, 
Creatine Kinase, Gamma Glutamyl Transferase, Lactate Dehydrogenase, Triacylglycerol 
Lipase, Triglycerides, Urea, Albumin, Bicarbonate, Bilirubin, Blood Urea Nitrogen, Calcium, 
Cholesterol, Chloride, Creatinine, Glucose, Potassium, Magnesium, Phosphate, Protein, 
Sodium, HDL Cholesterol, LDL Cholesterol, Alpha Fetoprotein, Urate, Cholesterol/HDL-
Cholesterol Ratio, Direct Bilirubin, Indirect Bilirubin, Lipids
8.4.4.3 Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelialcells and sediments, and allow proper assessments. Required assessments are 
specified in the protocol.
Casts, Occult Blood, pH, Specific Gravity, Ketones, Glucose, Protein, Bilirubin, Nitrite, 
Leukocytes, Sodium/Potassium Ratio, Appearance, Color, Osmolality, Turbidity
8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have regular urine pregnancy 
tests during the study. A positive urine pregnancy test requires immediate interruption of 
study drug until serum β-hCG is performed and found to be negative.
8.4.5.1 Pregnancy test
Corporate Confidential Information
Pregnancy tests are required of all female patients regardless of reported 
reproductive/menopausal status. Follicle stimulating hormone will be estimated for 
postmenopausal females at screening only.
Serum pregnancy tests will be performed at screening and initial baseline. Urine pregnancy 
tests may be used at other visits.A positive urine pregnancy test should be confirmed with a 
serum pregnancy test.  
When performed at screening and baseline,the result of this test must be received before the 
patient may be dosed.


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8.4.6
Coagulation Panel
A blood sample will be taken to analyze the following parameters: PT, INR, APTT and TT.
8.4.7
ECG evaluation
A standard 12-lead ECG will be performed with the patient ina supine position. Interpretation 
of the tracing must be made by a qualified physician and documented on the ECG and in the 
ECG section of the CRF. Each ECG tracing should be labeled with the
study number
patient initials
patient number
date
and kept in the source documents at the study site. Clinically significant abnormalities should 
be recorded on the relevant medical history CRF page prior to informed consent signature and 
on the Adverse Events page thereafter. Clinically significant findings must be discussed with 
the sponsor.
The CRF will contain:
date and time of ECG
heart rate
PR interval
QT interval
QTcF interval
QRS duration
Original ECG tracings, appropriately signed, will be archived at study site.
8.5
Pharmacokinetics
Corporate Confidential Information
A complete schedule of blood sampling for pharmacokinetics (including sampling time as 
sampling volumes) can be found in the blood log tables, while explicit details related to PK 
blood collection and processing, labeling, and shipment instructions, see Site Operations 
Manual (SOM).
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.


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8.5.1
PK blood collection
For details on PK blood collection and processing, labeling, and shipment instructions, see 
laboratory manual.
The exact clock time of dosing, as well as actual sample collection date and time will be 
entered on the PK blood collection summary page of the CRF. Sampling problems will be 
noted in the relevant field of the CRF.
Corporate Confidential Information
8.6
Other assessments


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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 patient or 
clinical investigation patient 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 patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient 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 
patient and identifying adverse events. Alert ranges for liver related events are included in 
Section 9.3.
Adverse events must be recorded on the Adverse Events CRF for patients 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 [study] treatment(select as appropriate).


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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

patient hospitalized/patient’s hospitalization prolonged
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, 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 the outcome.
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 patient informed consent and should be discussed with the patient 
during the study as needed.
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’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.
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 bile acid malabsorption diarrhea

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
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
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 patient or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the patient 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 DS&E as per Section 9.2.2.
9.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following 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 
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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.
SAEs (initial and follow-up) that are recorded electronically in the Electronic Data Capture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug 
Safety & Epidemiology immediately after investigator signature or 24 hours after entry, 
whichever occurs first. Study site personnel must also inform the Clinical Trial Leader.
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 
patient 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 
regulatory requirements in participating countries.
9.3
Liver safety monitoring
To ensure patient 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 Table 9-1 and Table 9-2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed in in Table 9-2.


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For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation.
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. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug (refer to Section 7.1, if appropriate

Hospitalization of the patient 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. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF, including the liver 
event overview CRF pages.
Table 9-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
Liver laboratory 
triggers
3 x ULN < ALT / AST ≤ 5 x ULN
1.5 x ULN < TBL ≤2 x ULN
Liver events
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN 
[mainly conjugated fraction] without notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity *


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Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more 
than 2 weeks, discontinue the 
study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN accompanied 
by symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 3 to ≤ 5 × ULN
(patient is asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit


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Criteria
Actions required
Follow-up monitoring
TBL (isolated)
> 2 × ULN (in the 
absence of known Gilbert 
syndrome)

Repeat LFT within 48 hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study drug 
interruption or discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
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
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
cResolution 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.


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9.4
Pregnancy reporting
To ensure patient safety, each pregnancy in a patient 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 patient 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 patient may continue all other protocol assessments. 
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.
9.5
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). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, 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 patient 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.


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The investigator must maintain source documents for each patient 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 
patient'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 patients will be disclosed.
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 database lock, the investigator will receive a CD-ROM or paper copies of the patient 
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.
10.3
Database management and quality control
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 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.


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Laboratory samples will be processed centrally and the results will be sent electronically to a 
designated CRO.
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The data will be sent electronically to a 
designated CRO. In case the electronic diary is not used then the patients will enter data in 
paper diary. These diaries will be handed over to site and site personnel will enter data in the 
clinical database or send them to the designated CRO to enter data in the clinical database.
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis.
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 between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head.
DNA samples:
To maximize confidentiality, all samples and the information associated with the samples will 
be double-coded to prevent the exposure of the patient’s information and identity. 
This double-coding process allows Novartis to go back and destroy the sample at the patient’s 
request.  In addition, sample information is stored in one secured database while genetic data 
is stored in an independent secured database.
The use of DNA to search for biomarkers of disease and drug action is exploratory. Any 
results from this DNA study will not be placed in the patient’s medical records.
10.4
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 and include one or more Novartis physician with expertise in the indication. The DMC will 
convene as outlined in the DMC Charter to review an event or combination of events that fulfil 
the study stopping rules defined in Section 7.4.
In addition, adverse events, including clinical laboratory data will be continuously reviewed 
by the Novartis Clinical trial team, including the study physician, on an ongoing basis as data 
become available from the Electronic Data Capture system.
10.5
Adjudication Committee
Not required.


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11
Data analysis
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with available PK data and no protocol deviations 
with relevant impact on PK data.
The PD analysis set will include all patients with available PD data and no protocol deviations 
with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence 
(drug followed by placebo or vice-versa) and patient. Summary statistics will be provided for 
all patients, as well as for each treatment sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and patient.
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 sequence and patient.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary analysis variables are: a) stool frequency, b) and stool form assessed by the 
Bristol stool chart.
11.4.2
Statistical model, hypothesis, and method of analysis
A repeated measures analysis will be done for the two-dimensional endpoint: weekly stool 
frequency and the corresponding average stool form. The analysis will include fixed effects 
for sequence (Drug/Placebo or Placebo/Drug), Treatment (Week 1 Drug, Week 2 Drug, Week 
1 Placebo or Week 2 Placebo), and period (1 or 2). The model will assume an arbitrary 2 by 2 
covariance matrix for the two-dimensional endpoint (frequency, form) and a compound 
symmetry covariance matrix for each individual endpoint. Point estimates of the weekly & 
biweekly treatment effect on stool frequency and form will be reported together with 95% 
simultaneous confidence intervals (confidence ellipsoids).
Baseline weekly stool frequency and the corresponding average stool form will be analyzed 
similarly using the method described above to assess unequal carryover effects.


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11.4.3
Handling of missing values/censoring/discontinuations
Missing values will be assumed missing at random. No imputation of missing values will be 
done for any analyses.
11.5
Analysis of secondary and exploratory variables
The number and percentage of subjects using loperamide will be tabulated by treatment. Total 
weekly loperamide use (in mg) will be summarized by treatment and visit (including baseline). 
The stool index, calculated as [weekly stool frequency*mean stool form]+loperamide use 
[weekly mg*3], will also be summarized and analyzed using a linear mixed effects model 
including sequence, period and treatment as fixed effects and subject nested within sequence 
as a random effect.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatmentsequence, patient, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatmentsequence, patient 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 by treatmentsequence, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. Baselines will be the last available measurement in each treatment 
period post washout and prior to dosing.
Adverse events
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All information obtained on adverse events will be displayed by treatment and patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. An adverse event starting in one period 
and continuing into the next period is counted only in the onset period. A patient with 
multiple adverse events within a body system and treatment period is only counted once 
towards the total of this body system and treatment.


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11.5.3
Pharmacokinetics
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
All patients with at least one period of evaluable pharmacokinetic (PK) parameter data will be 
included in the pharmacokinetic data analysis.
The following pharmacokinetic parameters and other appropriate parameters may be 
determined for LJN452:
AUClast, AUCtau, Cmax, Cmin, Cav,ss, Tmax, CL/F, Racc (accumulation ratio = 
AUCtau,ss/AUCtau,day 1) may be assessed from plasma concentration-time data.
non-compartmental method(s) with Pheonix (Version 6.3 or higher).
11.5.4
Pharmacokinetic / pharmacodynamic interactions
The relationship between PK and key PD parameters (for example, change in stool frequency) 
may be explored, if needed.
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11.5.5
Other assessments
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11.6
Sample size calculation
11.7
Power for analysis of key secondary variables
No assessment of power for the secondary objectives has been done.
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11.8
Interim analyses
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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, patient recruitment 
procedures (e.g. advertisements) and any other written information to be provided to patients. 
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.
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 patients 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.


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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 patients 
may be implemented immediately, 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 patient 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; 213-24.
Goodwin B, Jones SA, Price RR, et al. (2000) A regulatory cascade of the nuclear receptors 
FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell; 517-26.
Pattni SS, Brydon WG, Dew T, et al. (2012) Fibroblast growth factor 19 and 7α-hydroxy-4-
cholesten-3-one in the diagnosis of patients with possible bile acid diarrhea. Clin Transl 
Gastroenterol; e18.
Walters JR (2014) Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and 
therapy. Nat Rev Gastroenterol Hepatol; 426-34.
Walters JR, Johnston IM, Nolan JD, et al. (2015) The response of patients with bile acid 
diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment. Pharmacol. Ther; 
54-64.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LJN452
CLJN452X2202
A double blind, randomized placebo controlled crossover
multiple dose study of LJN452 to assess safety,
tolerability and efficacy in patients with primary bile acid 
diarrhea (pBAD)
Statistical Analysis Plan (SAP)
Document type: 
SAP Documentation –NIBR 
Document status:
Final
Release date:
14-Aug-2016
Number of pages:
12
Personal Data
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................3
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary objectives...................................................................................5
1.3.2
Secondary objectives...............................................................................5
1.4
Study design and treatment......................................................................................6
2 First interpretable results (FIR)...........................................................................................6
3 Interim analyses...................................................................................................................7
4 Statistical methods: Analysis sets........................................................................................7
5 Statistical methods for Pharmacokinetic (PK) parameters..................................................8
5.1
Variables..................................................................................................................8
5.2
Descriptive analyses................................................................................................8
5.2.1
Graphical presentation of results.............................................................9
6 Statistical methods for Pharmacodynamic (PD) parameters...............................................9
6.1
Primary objective.....................................................................................................9
6.1.1
Variables.................................................................................................9
6.1.2
Descriptive analyses................................................................................9
6.1.3
Statistical model, assumptions and hypotheses.......................................9
7 Statistical methods for safety and tolerability data............................................................10
7.1
Primary objective...................................................................................................10
7.1.1
Variables...............................................................................................10
7.1.2
Descriptive analyses..............................................................................11
7.1.3
Graphical presentation..........................................................................11
List of tables
Figure 1-1
Study design............................................................................................
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6
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Table 4-1
Protocol deviation codes and analysis sets..............................................7


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1
Introduction 
1.1
Scopeof document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial CLJN452X2202.
The Statistical analysisplan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v02(incorporating 
Amendment 2) approved by the SRC on 09August2016. 
1.3
Study objectives
1.3.1
Primary objectives
To determine the safety and tolerability of LJN452 in patients with primary bile acid 
diarrhea(pBAD)
To assess the effect of LJN452 on clinical symptoms experienced by patients with 
pBAD
1.3.2
Secondary objectives
To assess the pharmacokinetics of LJN452 in pBAD patients

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To assess the effect of LJN452 on use of rescue medications during the study period


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1.4
Study design and treatment
This is a multi-center, double blind (patient and investigator blind, sponsor open label),
randomized placebo controlled, crossover study to assess safety, tolerability and efficacy of
LJN452 in patients with pBAD. In this study approximately 30 patients will be enrolled to 
have 24 completers. 
This is a non-confirmatory trial.
Figure 1-1
Study design
In treatment period 1 on Day 1 patients will receive either 60 μg LJN452 or placebo orally
once daily for 14 days in a 1:1 ratio. Pharmacokinetic (PK), pharmacodynamic (PD) and
safety samples will be collected on Day 1 for up to 8 hours post dose and on Day 2 pre-dose,
which corresponds to 24 h after Day 1 dosing.
Patients will be handed over trial medication, to be administered at home enough to cover
dosing for 14 days in each period. Throughout the 14 days of the treatment period, patients
will be directed to take study drug at home with water in the morning in a fasting state,
2 hours prior to the first meal of the day, preferably at the same time of the day.
After 2 weeks of treatment with LJN452 or placebo, patients will undergo a washout of at
least 7 days, up to a maximum of 28 days. At the end of the washout period, patients will 
return to the study site for period 2 of the study. Period 2 will be identical to period 1 except 
that the treatments will be crossed over.
The randomization will be maintained at a 1:1 ratio over the entire study in order to avoid any
sequence bias.
2
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. 


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3 
Interim analyses 
4
Statistical methods: Analysis sets
For patientsfor which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
For patients for which the actual sequence of treatments received does not match the 
randomized sequence of treatments, the actual sequence will be used for analysis involving a 
sequence component (e.g. ANOVAs with a sequence effect) if the actual sequence is one of 
the sequences planned in the study design. If the actual sequence is not one of the sequences 
planned in the study design, the randomized sequence will be used for analysis involving a 
sequence component but data points from periods in which the patienthas not received the 
randomized treatment will be excluded from the analysis. 
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with available PK data and no protocol deviations 
with relevant impact on PK data.
The PD analysis set will include all patients 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 4-1 
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Patientsare excluded from all (safety)analysis in case of these 
PDs: 
Exclude patientcompletely 
from all analysis sets
I01
ICF not obtained
Yes
S01
Subject did not receive any study drug
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Yes


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Category
Deviation code
Text description of deviation
Data exclusion
Patients are excluded from PK analysis in case of these PDs: 
Exclude patient from PK 
analysis set 
S01
Subject did not receive any study drug
Yes
I01
ICF not obtained
Yes
Patients are excluded from PD analysis in case of these PDs:
Exclude patient from PD 
analysis set
S01
Subject did not receive any study drug
Yes
   I01
ICF not obtained
Yes
Patients are excluded from PK and PD analysis in case of these 
PDs:
Exclude patient from PK and 
PD analysis sets
S01
Subject did not receive any study drug
Yes
I01
ICF not obtained
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
The following and other appropriate pharmacokinetic parameters may be determined using 
the actual recorded sampling times and non-compartmental method(s) with Phoenix 
WinNonlin (Version 6.3 or higher): AUClast, AUCtau, Cmax, Cmin, Cav,ss, Tmax, CL/F, 
Racc (accumulation ratio = AUCtau,ss/AUCtau,day 1).
5.2
Descriptive analyses
LJN452 concentration data will be listed by patient and visit/sampling time point. Descriptive 
summary statistics will be provided by visit/sampling time point.
Pharmacokinetic parameters will be calculated as described in Section 5.1 of the protocol and 
will be listed by patient and visit. 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.


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5.2.1
Graphical presentation of results
Arithmetic mean (SD) and geometric mean (95% CI) plasma concentration data will be 
plotted across time.
Overlaying individual plasma concentration-time profiles will be generated.
Individual plasma concentration-time profiles will be generated.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
To assess the effect of LJN452 on clinical symptoms experienced by patients with pBAD.
6.1.1
Variables 
The primary analysis variables are: a) stool frequency, b) and stool form assessed by the 
Bristol stool chart.
6.1.2
Descriptive analyses
Summary statistics (including median and IQR) of the stool frequencyand averagestool form
(weekly and biweekly) for each treatment as well asthe difference and % change between the 
2 treatmentswill be provided by visit.Baseline data will be summarized by treatment and 
visit. The number and percentage of patientswith each stool form will be provided by 
treatment and visit. The stool frequency and stool form data will be listed by treatment 
sequence, patient and visit. 
6.1.3
Statistical model, assumptions and hypotheses
Arepeated measures analysis will be done for thetwo-dimensional endpoint: weekly stool 
frequency and the corresponding average stool form. The analysis will include fixed effects 
for sequence (Drug/Placebo or Placebo/Drug), Treatment (Week 1 drug, Week 2 drug, Week 
1 placeboor Week 2 Placebo), and period (1 or 2).The model will assume an arbitrary 2 by 2 
covariance matrix for the two-dimensionalendpoint (frequency, form) and a compound 
symmetry covariance matrix for each individual end point. Point estimates of the weekly & 
biweekly treatment effect on stool frequency and the corresponding average stool form will be 
reported together with 95% simultaneous confidence intervals (confidence ellipsoids).
6.1.3.1 Handling of missing values/censoring/discontinuations
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Missing values will be assumed missing at random. No imputation of missing values will be 
done for any analyses.


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6.1.3.2 Graphical presentation of results
Boxplots to visualize treatment differences instool frequency and stool formwill be created.
6.1.3.3 Supportive analysis
Baseline weekly stool frequency and the corresponding average stool form will be analyzed 
using the same method as described in Section 6.1.3to assess unequal carryover effects.
The number and percentage of subjects using loperamide will be tabulated by treatment. Total 
weekly loperamide use (in mg) will be summarized by treatment and visit(including baseline). 
The stool index, calculated as [weekly stool frequency*mean stool form]+loperamide use 
[weekly mg*3], will also be summarized and analyzed using a linear mixed effects model 
including sequence, period and treatment as fixed effects and subject nested within sequence 
as a randomeffect.
7
Statistical methods for safety and tolerability data
7.1
Primary objective
To determine the safety and tolerability of LJN452 in patients with pBAD.
7.1.1
Variables 
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Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as patientdemographics, baseline characteristics, and 
treatment information.


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7.1.2
Descriptive analyses
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
patient. Summary statistics will be provided for all patients, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and patient.
Treatment
Data for study drug administration and concomitant therapies will be listed by treatment 
sequence and patient.
Vital signs
All vital signs data will be listed by treatment sequence, patient, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment sequence, patient 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 by treatment sequence, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a patient with any abnormal values. Summary statistics will be provided by 
treatment and visit/time. Baselines will be the last available measurement in each treatment 
period post washout and prior to dosing.
Log-transformed lipid (total Cholesterol, LDL, HDL, triglycerides) and LFT (GGT, ALP, 
AST, ALT) data will be analyzed using a mixed effects model including sequence, period, 
and treatment as fixed effects and subject nested within sequence as a random effect.
Adverse events
All information obtained on adverse events will be displayed by treatment and patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. An adverse event starting in one period 
and continuing into the next period is counted only in the onset period. A patient with 
multiple adverse events within a body system and treatment period is only counted once 
towards the total of this body system and treatment.
7.1.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (lab parameters) will be created.


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