Clinical trial NCT02913105
Conditions: Non-alcoholic Steatohepatitis NASH
Keywords: Non-alcoholic Steatohepatitis NASH Fatty liver disease
Sponsor: Novartis Pharmaceuticals
Start date: 2016-10-24; Completion date: 2018-09-19
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the present study is to assess the effects of LMB763 with respect to safety, tolerability, and on markers of liver inflammation in patients with NASH

Detailed description:

Arms: arm 1: Oral dose once daily for 12 weeks (84 days) arm 2: Oral dose once daily for 12 weeks (84 days)
Interventions: intervention 1: LMB763 intervention 2: Placebo
Intervention descriptions: intervention 1: Hard Gelatin Capsules intervention 2: Hard Gelatin Capsule

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LMB763
CLMB763X2201
A randomized, patient and investigator blinded, 
placebo-controlled, multicenter study to assess the safety, 
tolerability, pharmacokinetics and efficacy of LMB763 in 
patients with non-alcoholic steatohepatitis (NASH)
Document type:
Amended Protocol Version
EUDRACT number:
2016-002833-31
Version number:
v03 (Clean)
Clinical Trial Phase:
II
Release date:
02-Oct-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO & PS) 
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located 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 ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................10
Glossary of terms...............................................................................................................11
Protocol synopsis...............................................................................................................16
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.4
Study purpose ........................................................................................................25
2
Study objectives and endpoints .........................................................................................25
2.1
Primary objectives .................................................................................................25
2.2
Secondary objectives .............................................................................................26
3
Investigational plan ...........................................................................................................28
3.1
Study design...........................................................................................................28
3.2
Rationale of study design.......................................................................................30
3.3
Rationale for dose/regimen, route of administration and duration of treatment....31
3.4
Rationale for choice of comparator .......................................................................32
3.5
Rationale for choice of background therapy..........................................................32
3.7
Risks and benefits..................................................................................................32
3.7.1
Blood sample volumes ..........................................................................33
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4
Population..........................................................................................................................34
4.1
Inclusion criteria ....................................................................................................34
4.2
Exclusion criteria...................................................................................................36
5
Restrictions for Study Patients ..........................................................................................39
5.1
Contraception requirements...................................................................................39
5.2
Prohibited treatment...............................................................................................40
5.3
Dietary restrictions.................................................................................................42
6
Treatment...........................................................................................................................42
6.1
Study treatment......................................................................................................42
6.1.1
Investigational treatment and control drugs..........................................42
6.1.2
Additional study treatment....................................................................42
6.2
Treatment arms ......................................................................................................43
6.3
Treatment assignment and randomization.............................................................43
6.4
Treatment blinding.................................................................................................44
6.5
Treating the patient................................................................................................45
6.6
Permitted dose adjustments and interruptions of study treatment.........................45
6.7
Emergency breaking of assigned treatment code ..................................................49
6.8
Treatment exposure and compliance .....................................................................49
6.9
Recommended treatment of adverse events ..........................................................49
6.10
Rescue medication.................................................................................................50
6.11
Concomitant treatment...........................................................................................50
7
Study completion and discontinuation ..............................................................................50
7.1
Study completion and post-study treatment ..........................................................50
7.2
Discontinuation of study treatment........................................................................50
7.3
Withdrawal of informed consent ...........................................................................51
7.4
Lost to follow-up ...................................................................................................52
7.5
Study Stopping rules..............................................................................................52
7.6
Early study termination by the sponsor .................................................................53
8
Procedures and assessments ..............................................................................................54
8.1
Assessment schedule .............................................................................................54
8.2
Informed consent procedures.................................................................................57
8.3
Patient screening....................................................................................................57
8.4
Patient demographics/other baseline characteristics .............................................57
8.4.1
Hepatitis screen, HIV screen.................................................................58
8.4.2
Alcohol test, Drug screen......................................................................58
8.5
Efficacy / Pharmacodynamics ...............................................................................58
8.5.1
Liver function tests (LFTs) ...................................................................58


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8.5.2
Magnetic Resonance Imaging...............................................................58
8.5.3
Markers of Liver Fibrosis......................................................................59
8.5.4
Fasting Lipids........................................................................................59
8.5.5
Anthropometric Assessments................................................................59
8.5.6
Clinical Outcome Assessments (COAs) ...............................................59
8.6
Safety.....................................................................................................................59
8.6.1
Physical examination ............................................................................59
8.6.2
Vital signs..............................................................................................60
8.6.3
Laboratory evaluations..........................................................................60
8.6.4
Electrocardiogram (ECG) .....................................................................60
8.6.5
Pregnancy assessments..........................................................................61
8.7
Pharmacokinetics...................................................................................................61
9
Safety monitoring ..............................................................................................................63
9.1
Adverse events.......................................................................................................63
9.2
Serious adverse event reporting.............................................................................65
9.2.1
Definition of SAE .................................................................................65
9.2.2
SAE reporting........................................................................................66
9.3
Liver safety monitoring .........................................................................................66
9.4
Renal safety monitoring.........................................................................................70
9.5
Reporting Medication errors including misuse/abuse ...........................................71
9.6
Pregnancy reporting...............................................................................................72
9.7
Early phase safety monitoring ...............................................................................73
10 Data review and database management.............................................................................73
10.1
Site monitoring ......................................................................................................73
10.2
Data collection.......................................................................................................74
10.3
Database management and quality control............................................................74
10.4
Data Monitoring Committee..................................................................................75
10.5
Adjudication Committee........................................................................................75
11 Data analysis......................................................................................................................75
11.1
Analysis sets ..........................................................................................................75
11.2
Patient demographics and other baseline characteristics.......................................75
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11.3
Treatments .............................................................................................................76
11.4
Analysis of the primary variable(s) .......................................................................76
11.4.1
Variable(s).............................................................................................76
11.4.2
Statistical model, hypothesis, and method of analysis..........................76
11.4.3
Handling of missing values/censoring/discontinuations.......................77
11.4.4
Summary statistics of safety..................................................................77
11.4.5
Sensitivity analyses ...............................................................................77
11.5
Analysis of secondary variable(s)..........................................................................77
11.5.1
Efficacy / Pharmacodynamics...............................................................77
11.5.2
Pharmacokinetics ..................................................................................78
11.5.3
Pharmacokinetic / pharmacodynamic interactions................................78
11 5 4
Other assessments
79
11.7
Sample size calculation..........................................................................................79
11 8
Power for analysis of key secondary variables
80
12 Ethical considerations........................................................................................................81
12.1
Regulatory and ethical compliance........................................................................81
12.2
Responsibilities of the investigator and IRB/IEC..................................................81
12.3
Publication of study protocol and results...............................................................81
13 Protocol adherence ............................................................................................................81
13.1
Protocol Amendments ...........................................................................................82
14 References .........................................................................................................................83
15 Appendix 1: The American Heart Association (AHA) Recommended Diet ....................84
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List of tables
Table 5-1
Prohibited medication ...........................................................................41
Table 5-2
Permitted medications if dose is stable for at least 1 month prior to 
randomization........................................................................................41
Table 6-1
Treatment Assignment Numbering – Cohort 1.....................................43
Table 6-2
Treatment Assignment Numbering – Cohort 2.....................................44
Table 6-3
Dosing response to Isolated ALT/AST Elevations ...............................47
Table 9-1
Liver Event Definitions.........................................................................67
Table 9-2
Actions required for Liver Events.........................................................68
Table 9-3
Exclusion of underlying liver disease ...................................................70
Table 9-4
Specific Renal Alert Criteria and Actions.............................................70
Table 9-5
Follow-up of renal events......................................................................71
Table 9-6
Summary of reporting requirements for medication errors...................72
List of figures
Figure 1-1
Coordinated effects of FXR agonism on metabolism...........................21
Figure 3-1
Study design – Cohort 1........................................................................28
Figure 3-2
Study design – Cohort 2........................................................................29


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
Code of Federal Regulation
CK
creatinine kinase
COAR
Clinical Operations, Analytics & Regions
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eSAE
Electronic Serious Adverse Event
FDA
Food and Drug Administration
FXR
Farnesoid X Receptor
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
Hour
HIV
human immunodeficiency virus
i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase


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LFT
Liver function test
LLN
lower limit of normal
LLQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MRI
Magnetic resonance imaging
NASH
Non-alcoholic steatohepatitis
NCDS
Novartis Clinical Data Standards
o.d.
once a day
p.o.
Oral
PA
posteroanterior
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RBC
red blood cell(s)
RDC
Remote Data Capture
REB
Research Ethics Board
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization
WTH
Waist to hip


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Pharmacokinetic definitions and symbols
AUClast
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the time of the last quantifiable concentration [mass x time / 
volume]
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]
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]
Racc
The accumulation ratio
T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax
The time to reach the maximum concentration after drug administration [time]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested 
in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up), which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers 
to be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes any 
placebos, any active controls, as well as approved drugs used outside 
of their indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system.
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any 
background therapy administered to each of the clinical trial subjects, 
regardless of randomization group, rescue medication, active drug 
run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study 
are: a single dose part and a multiple dose part, or a part in patients 
with established disease and in those with newly-diagnosed disease.


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Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal.
Study drug/treatment
Any drug (or combination of drugs) administered to the subject as 
part of the required study procedures; includes investigational drug, 
active drug run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to 
the defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the 
subject and should be used to identify the subject throughout the 
study for all data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 


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Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject 
does not want to participate in the study any longer, 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


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Protocol No. CLMB763X2201
Protocol synopsis
Protocol 
number
CLMB763X2201
Title
A randomized, patient and investigator blinded, placebo-controlled, multicenter 
study to assess the safety, tolerability, pharmacokinetics and efficacy of LMB763 in 
patients with non-alcoholic steatohepatitis (NASH)
Brief title
Study of safety, tolerability, pharmacokinetics and efficacy of LMB763 in patients 
with non-alcoholic steatohepatitis (NASH)
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase 2
Intervention 
type
Drug
Study type
Interventional 
Purpose and 
rationale
This study is designed to assess the safety, tolerability, pharmacokinetics (PK) of, 
and early hepatic response to LMB763 administration for 12 weeks in patients with 
phenotypic non-alcoholic steatohepatitis (NASH). Data from this study will be used 
to support further development of LMB763 in the treatment of patients with NASH.
Primary 
Objective(s)
!
To determine the safety and tolerability of LMB763 during 12 weeks of 
treatment
!
To determine the effect of LMB763 on circulating alanine aminotransferase 
(ALT) levels
Secondary 
Objectives
!
To evaluate the pharmacokinetics (PK) of LMB763 in NASH patients
!
To determine the effect of LMB763 on intrahepatic lipid after 12 weeks of 
treatment
!
To determine the effect of LMB763 on anthropometric assessments after 12 
weeks of treatment
!
To determine the effect of LMB763 on non-invasive markers of liver fibrosis
!
To determine the effect of LMB763 on fasting lipid profile
!
To determine the effect of LMB763 compared with placebo with respect to 
occurrence and impact of potential itch
Study design
This is a non-confirmatory, multicenter, patient and investigator blinded, 
randomized, placebo-controlled, parallel group study in patients with NASH. 
The study will be conducted in two cohorts:
Cohort 1: 
 
Approximately 96 patients will be randomized in a 2:1 ratio to 
receive LMB763 
 or matching placebo. The study will consist of a screening 
period of 45 days, baseline period of 14 days, treatment period of 12 weeks, 
followed up a study completion evaluation approximately 28 days after the final 
drug administration.  
Cohort 2: Approximately 96 patients will be randomized in a 2:1 ratio to receive 
LMB763 
 or matching placebo. The study will consist of a screening period 
of 45 days, baseline period of 20 days, treatment period of 12 weeks, followed up a 
study completion evaluation approximately 28 days after the final drug 
administration.  
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Population
The study population will comprise male and female adult patients with EITHER 
histologic evidence of NASH on liver biopsy within 2 years prior to randomization 
and elevated ALT, OR phenotypic diagnosis of NASH based on elevated ALT, 
Type 2 diabetes mellitus or elevated HbA1c and increased BMI.
Key Inclusion 
criteria
Cohort 1

Male and female patients 18 years or older (at the time of the screening visit)

Presence of NASH as demonstrated by ONE of the following:
EITHER
1.
Histologic evidence of NASH based on liver biopsy obtained 2 years or less 
before randomization with a diagnosis consistent with NASH, fibrosis level F1, 
F2 or F3, in the absence of a histological diagnosis of alternative chronic liver 
diseases
AND
ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)
OR
2.
Phenotypic diagnosis of NASH based on the presence of ALL THREE of the 
following:

ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND

BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian)  or 
≥23 kg/m2 (in patients with a self-identified Asian race) AND

Diagnosis of Type 2 diabetes mellitus by having either:

HbA1C ≥ 6.5% 
OR

Symptoms of diabetes plus hyperglycemia as indicated by
fasting plasma glucose ≥126 mg/dl (≥ 7.0 mmol/l)
two hour plasma glucose concentration ≥200mg/dl (≥11.1 
mmol/l two hours after 75g anhydrous glucose in an oral 
glucose tolerance test (OGTT)
OR

Drug therapy for Type 2 diabetes mellitus
Cohort 2

Male and female patients 18 years or older (at the time of the screening visit)

Liver fat ≥ 10% at baseline as determined by the reading of the central MRI 
laboratory of locally produced images

Presence of NASH as demonstrated by ONE of the following:
EITHER
3.
Histologic evidence of NASH based on liver biopsy obtained 2 years or less 
before randomization with a diagnosis consistent with NASH, fibrosis level F1, 
F2 or F3, in the absence of a histological diagnosis of alternative chronic liver 
diseases
AND
ALT ≥ 43IU/L (males) or ≥ 28 IU/L (females)
OR
4.
Phenotypic diagnosis of NASH based on the presence of ALL THREE of the 
following:


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
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) AND

BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian)  or 
≥23 kg/m2 (in patients with a self-identified Asian race) AND

Diagnosis of Type 2 diabetes mellitus by having either:

HbA1C ≥ 6.5% 
OR

Symptoms of diabetes plus hyperglycemia as indicated by
fasting plasma glucose ≥126 mg/dl (≥ 7.0 mmol/l)
two hour plasma glucose concentration ≥200mg/dl (≥11.1 
mmol/l two hours after 75g anhydrous glucose in an oral 
glucose tolerance test (OGTT)
OR

Drug therapy for Type 2 diabetes mellitus
Key Exclusion 
criteria
Cohort 1 and 2

Current use of obeticholic acid (OCA)

New initiation of GLP-1 agonists such as liraglutide, exenatide , lixisenatide, 
albiglutide or dulaglutide or DPP4 inhibitors such as sitagliptin, vildagliptin, 
saxagliptin or linagliptin within 3 months of screening

Patients on treatment with the following medicines UNLESS they are on a 
stable dose for at least 1 month before randomization: insulin (no more than
≥25% change in dose), beta-blockers, thiazide diuretics,  fibrates, statins, 
niacin, ezetimibe, vitamin E (if  doses > 200 IU/day; doses > 800 IU/day are 
prohibited), thyroid hormone, psychotropic medications, estrogen or estrogen 
containing birth control. For oral anti-diabetic medications, no more than one 
step up in local prescribing guidelines will be allowed.

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 (approximately 5 times the 
terminal half life) after stopping study medication

Current or history of significant alcohol consumption for a period of more than 
3 consecutive months within 1 year prior to screening (significant alcohol 
consumption is defined as more than 20 g/day in females and more than 30 
g/day in males, on average) and/or a score on the AUDIT questionnaire ≥8 as 
administered by the site as part of the medical history

History of drug or alcohol abuse within the 12 months prior to dosing, or 
evidence of such abuse as indicated by the laboratory assays conducted 
during screening and baseline. Marijuana use is not allowed if it is determined 
to be medically inappropriate by the investigator

Calculated eGFR less than 60 mL/min (using the MDRD formula)

Presence of cirrhosis on liver biopsy or clinical diagnosis

Clinical evidence of hepatic decompensation or severe liver impairment

History or presence of other concomitant liver diseases

History or current diagnosis of ECG abnormalities indicating significant risk of 
safety for patients participating in the study

Patients with contraindications to MRI imaging

For those patients that have had a previous biopsy: Significant weight loss 
(>15%) or change in clinical status (in the opinion of the investigator) since the 
diagnostic liver biopsy


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Study 
treatment
Study treatments are defined as:
!
 LMB763 capsules
!
 LMB763 capsules
!
 LMB763 capsules
!
Matching placebo capsules
Cohort 1: Approximately 96 patients will be randomly assigned in a ratio of 2:1 to 
receive LMB763 
 or matching placebo.
Cohort 2: An additional approximately 96 patients will be randomized in a 2:1 ratio 
to receive LMB763 
 or placebo. 
All patients who have been enrolled into the initial 
 cohort will complete the 
protocol at that dose, however no further patients will be recruited into that cohort 
Efficacy/PD 
assessments
!
Liver function tests (ALT)
!
Magnetic Resonance Imaging (MRI)
!
Anthropometric assessments
!
!
Fasting lipids
!
Visual Analog Scale (VAS) for Itch
Key safety 
assessments
!
Physical examination
!
Vital signs
!
Laboratory evaluations
!
Electrocardiogram
!
Pregnancy assessments
Other 
assessments
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Data analysis
The change from baseline to Week 12 in ALT is the primary efficacy variable.
A Bayesian approach will be used to analyze the change from baseline to Week 12 
in ALT, which is assumed to follow a normal distribution with a known variance for 
each treatment arm. An informative prior for the placebo treatment effect and a 
non-informative prior for the LMB763 treatment effect will be incorporated into the 
analysis. The variance and the informative prior will be based on historical control 
data from studies such as the FLINT trial. Median estimates, credible intervals and 
posterior probabilities that the placebo-adjusted ALT reduction by an LMB763 dose 
is (a) greater than 0 and (b) greater than 19 U/L and/or another cutoff value will be 
provided within the Bayesian framework. As a sensitivity analysis, the posterior 
probabilities will be calculated for varying values of the effective sample size for the 
placebo prior. A further sensitivity analysis using different values of the common 
variance assumed in the likelihood function and the prior may be performed as 
needed. An analysis using SAS PROC MCMC without assuming the variance is 
known in the likelihood function may be performed as well.   
Additionally a repeated measures analysis of covariance (ANCOVA) will be 
performed for change from baseline ALT without using historical placebo control 
data. The model will include effects for treatment, visit, treatment by visit 
interaction, stratification factor (BMI group), baseline, and baseline by visit 
interaction. An unstructured variance-covariance structure will be used to account 
for correlation among multiple measurements from the same patient and variance 
heterogeneity. Point estimates, the associated two-sided 90% confidence intervals 
as well as the p-values for treatment differences will be obtained. The null 
hypothesis of no treatment difference will be tested at the one-sided 0.05 
significance level. Both untransformed and log-transformed ALT will be analyzed. 
For log-transformed ALT analysis the ratio to baseline results obtained by back 
transformation will be reported.
The cohort effect will be explored and a cohort-wise analysis for both the Bayesian 
and ANCOVA approaches may be performed as needed.
If placebo data from in-house studies in a similar patient population become 
available they may be included in an ANCOVA on log-transformed data via 
informative priors.
Key words
Non-alcoholic Steatohepatitis, NASH, 


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1
Introduction
1.1
Background
LMB763 is a potent partial agonist of the bile acid receptor Farnesoid X Receptor (FXR). 
Proposed indications for LMB763 include non-alcoholic steatohepatitis (NASH), cholestatic 
and other hepatic disorders caused by over production and malabsorption of bile acids.
Figure 1-1
Coordinated effects of FXR agonism on metabolism
FXR regulates metabolic pathways through multiple mechanisms in the liver and intestine. 
The processes 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 FGF15/19 from the enterocyte to the 
hepatocyte. In normal physiology, FXR detects increased levels of bile acids 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 FGF15/19. The net result is a decrease in the overall levels of 
bile acids, decrease in gluconeogenesis and lipogenesis in the liver (Redrawn from 
Calkin and Tontonoz 2012).


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Nonalcoholic steatohepatitis (NASH) is a condition characterized by increased fat 
accumulation in the liver and attendant hepatocellular damage and inflammation. NASH is a 
cause of progressive fibrosis and metabolic liver disease, and is a leading cause of cirrhosis 
and hepatocellular carcinoma. Clinical validation of FXR agonism for therapy of NASH has 
been shown in a Phase 2 clinical trial (Neuschwander-Tetri et al 2015) in which a bile acid 
derived FXR agonist lead to improvements in hepatic fibrosis and in some cases resolution of 
NASH. Thus, pharmacological activation of FXR is proposed to be an effective treatment for 
NASH, and LMB763 has a clinical and preclinical profile that supports its use in this 
indication.
This is a First-in-Patient, non-confirmatory Phase 2 study to determine the safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy of LMB763. The most relevant data for 
the present study are summarized in the sections below. For detailed information, please refer 
to the Investigator’s Brochure.
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1.4
Study purpose
This study is designed to assess the safety, tolerability, pharmacokinetics (PK) of, and early 
hepatic response to LMB763 administration for 12 weeks in patients with phenotypic 
non-alcoholic steatohepatitis (NASH). Data from this study will be used to support further 
development of LMB763 in the treatment of patients with NASH.
2
Study objectives and endpoints
2.1
Primary objectives
Primary objectives
Endpoints related to primary objectives
!
To determine the safety and tolerability 
of LMB763 during 12 weeks of 
treatment.
!
Safety endpoints (including vital signs, 
physical examination, laboratory 
measurements, ECG).
!
Adverse events.
!
To determine the effect of LMB763 on 
circulating alanine aminotransferase 
(ALT) levels.
!
Liver function tests (ALT).
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2.2
Secondary objectives
Secondary objectives
Endpoints related to secondary 
objectives
!
To evaluate the pharmacokinetics (PK) of 
LMB763 in NASH patients.
!
PK blood collection and analysis 
(Cmax, Tmax, AUC, Racc, etc.).
!
To determine the effect of LMB763 on 
intrahepatic lipid after 12 weeks of treatment.
!
Percent (%) Liver fat as measured 
by Magnetic Resonance Imaging 
(MRI).
!
To determine the effect of LMB763 on 
anthropometric assessments after 12 weeks of 
treatment.
!
Weight, BMI, waist-to-hip 
(WTH) ratio.
!
To determine the effect of LMB763 on non-
invasive markers of liver fibrosis.
!
Fibroscan® (in a subset of 
patients)
!
Fibrosis biomarker test 
(originally known as Fibrotest®/ 
FibroSure®).
!
To determine the effect of LMB763 on fasting 
lipid profile.
!
Fasting lipid profile.
!
To determine the effect of LMB763 compared 
with placebo with respect to occurrence and 
impact of potential itch.
!
Itch scored on 100 mm visual 
analog scale (VAS) ratings.
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abnormalities are noted, until the patient is deemed to have returned to a satisfactory state of 
health in the opinion of the investigator.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis), adverse event and serious 
adverse event monitoring. 
Refer to the Assessment Schedule for details of safety, PK, and PD assessments.
3.2
Rationale of study design
This randomized, multi-center, patient and investigator blinded, placebo-controlled study is 
designed to assess the safety and tolerability of LMB763 relative to placebo in patients with 
NASH.
Randomization will be initiated at a 2:1 ratio of active to placebo in order to reduce the 
sample size. The statistical power of the study will be bolstered by using historical control 
data from trials like the FLINT study to supplement the placebo arm. Multiple sites are 
necessitated due to the underlying prevalence of NASH defined in publicly available 
recruitment data. No known differences exist in regional criteria for the histopathological 
diagnosis of NASH. Since NASH is more common in those self-identified as Asian at lower 
body mass index (BMI), specific criteria inclusion criteria have been included for this 
population.
In order to maintain the scientific integrity of the study, the investigator and patient will 
remain blinded to their treatment allocation and baseline intra-hepatic lipid content. To allow 
close monitoring of biochemical safety parameters which overlap with efficacy outcomes 
(eg. ALT) and understanding of performance of exploratory biomarkers, the Novartis Clinical 
Trial Team (CTT) will be unblinded throughout the study.
To ensure that no bias is introduced by imbalance in severity of disease across different arms 
of the study, patients will be stratified to active or placebo arms on the basis of BMI.
The duration of 12 weeks of therapy is supported by GLP-toxicology studies of 13 weeks in 
duration and it is also a suitable timeframe to test the chosen primary endpoints in the study. 
In the FLINT trial of a less potent FXR agonist, ALT and GGT levels in the blood dropped as 
early as after 4 weeks of treatment and most of this effect was noted by 12 weeks of therapy 
(Neuschwander-Tetri et al 2015).
To keep dietary intake as consistent as possible, patients participating in this study will be 
instructed to carefully adhere to American Heart Association (AHA) diet or equivalent if there 
is a country specific recommended diet.


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3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
 
The initial 
dose of 
 LMB763 was chosen on the basis of safety and likely pharmacological 
activity. Preliminary analysis suggested that the mean increases in biomarkers of target 
engagement were higher than anticipated 
 In particular an increase in the 
FXR responsive marker ALP was noted in context of no increase in GGT or 5’NT. No SAEs 
have been attributed to LMB763 
 
 
 
 
 
 
 
The duration of the study is based on findings in 2 published studies relating to obeticholic 
acid (Mudaliar et al 2013; Neuschwander-Tetri et al 2015), which demonstrate that 12 weeks 
will provide sufficient timeframe to assess biochemical changes likely to result from 
improvement to the NASH phenotype. In addition, observations from other studies with 
surgical (Jiménez-Agüero et al 2014), diet (Ryan et al 2013) and pharmacotherapy 
(CLCQ908A2216) also suggest that 12 weeks is an adequate timeframe to test an effect on 
liver fat (Neuschwander-Tetri et al 2015). 
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3.4
Rationale for choice of comparator
Currently there is no licensed pharmacological therapy for patients with NASH. A placebo 
will be used as a comparator in this study to ensure the effects of LMB763 are related to the 
study drug. All patients will be encouraged to adhere to local advice regarding diet and 
exercise regimens.
3.5
Rationale for choice of background therapy
Not applicable
3.7
Risks and benefits
As well as the risks and potential risks described in the Investigators’ Brochure, there may be 
unknown risks to LMB763 which may be serious and unforeseen.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring of safety e.g. liver transaminases, dose reduction steps and stopping rules.
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Women of child bearing potential should be informed that taking the investigational drug may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and must 
agree that in order to participate in the study they must adhere to the contraception 
requirement for the duration of the study. If there is any question that the patient will not 
reliably comply, they should not be entered in the study.
Pruritus and LDL elevations have been noted in clinical trials with a bile acid derived FXR 
agonist, but have not been noted in 
 studies with non-bile acid FXR partial or 
full agonists, LMB763 or LJN452, respectively. Both pruritus and serum lipids will be closely 
monitored in this study.
A maximum of approximately 442.2 mL of blood is planned to be collected from each patient 
as part of the study. Additional samples for monitoring of any safety findings may be required, 
and would be in addition to this volume. Over the course of the 4 to 8 months study period, 
this is not considered to be a concern for this population.
MRI makes use of powerful magnetic fields and radio waves, which are believed to cause no 
direct adverse consequences when used within FDA-approved specifications. No MRI-
contrast will be administered in this study. Thus in principle, MRI scans can be repeated in the 
same patient as often as necessary. The MRI scanning equipment may cause a feeling of 
claustrophobia in susceptible persons; therefore, sensitivity to enclosed spaces should be 
queried at screening.  Refer to eligibility criteria to exclude patients who are not suitable 
candidates for MRI scanning.
Patients participating in this study might have reductions in hepatic fat; it is possible that this 
is a clinical benefit. However, 12 weeks treatment is unlikely to be sufficient to provide 
benefit in reducing hepatic fibrosis. For this reason, liver biopsies are not performed in this 
study. There may be patient benefit in the ancillary dietary and exercise counseling 
accompanying the pharmacologic intervention.
3.7.1
Blood sample volumes
A maximum of approximately 442.2 mL of blood is planned to be collected over a period of 
approximately 22 weeks, from each patient as part of the study. Additional samples required 
for monitoring of any safety findings would be in addition to this volume. This is not 
considered to be a risk for this population.
Timings of blood sample collection are outlined in the Assessment Schedule, Section 8.1
A summary blood log is provided in the Site Operations Manual. Instructions for all sample 
collection, processing, storage and shipment information will be contained in the Central 
Laboratory Manual.
See Section 8.9 regarding the potential use of residual samples. 


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4
Population
The study population will be comprised of male and female adult patients with EITHER 
histologic evidence of NASH on liver biopsy within 2 years prior to randomization and 
elevated ALT, OR phenotypic diagnosis of NASH based on elevated ALT, Type 2 diabetes 
mellitus or elevated HbA1c and increased BMI; full details are outlined in Section 4.1
(Inclusion criteria). 
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 in 
order 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 
and baseline. A relevant record (e.g. checklist) of the eligibility criteria must be stored with 
the source documentation at the study site. 
Provided patients meet all other eligibility criteria, patients with a single lab value outside of 
the allowable range may be considered eligible for enrolment, as long as the abnormal lab 
value is within 10% of the allowable value. ALT and eGFR values must always fall inside the 
allowable range as listed in the inclusion and exclusion criteria.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
Cohort 1
1. Informed consent must be obtained before any assessment is performed
2. Male and female patients 18 years or older (at the time of the screening visit)
3. Presence of NASH as demonstrated by ONE of the following:
EITHER
Histologic evidence of NASH based on liver biopsy obtained within 2 years prior to 
randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, in the 
absence of a histological diagnosis of alternative chronic liver diseases
AND
ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)
OR
Phenotypic diagnosis of NASH based on the presence of ALL THREE of the following:

ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND

BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian)  or 
≥23 kg/m2 (in patients with a self-identified Asian race) AND

Diagnosis of Type 2 diabetes mellitus by having either:

HbA1C ≥ 6.5% 
OR


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
Symptoms of diabetes plus hyperglycemia as indicated by

fasting plasma glucose ≥126 mg/dl (≥ 7.0 mmol/l)

two hour plasma glucose concentration ≥200 mg/dl (≥11.1 mmol/l two 
hours after 75g anhydrous glucose in an oral glucose tolerance test 
(OGTT)
OR

Drug therapy for Type 2 diabetes mellitus (as long as on a stable dose. 
Refer to Section 5.2)
4. . Patients must weigh at least 40 kg (88 lbs) and no more than 150 kg (330 lbs.) to 
participate in the study. Inclusion of patients with higher weights up to 200 kg (440 lbs.) 
may occur if a MRI scanner with a table weight of 200 kg (440 lbs.) is available.
5. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
Cohort 2
6. Informed consent must be obtained before any assessment is performed
7. Male and female patients 18 years or older (at the time of the screening visit)
8. Presence of NASH as demonstrated by ONE of the following:
EITHER
Histologic evidence of NASH based on liver biopsy obtained within 2 years prior to 
randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, in the 
absence of a histological diagnosis of alternative chronic liver diseases
AND
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) at screening
OR
Phenotypic diagnosis of NASH based on the presence of ALL THREE of the following:

ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) at screening AND

BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian) or 
≥23 kg/m2 (in patients with a self-identified Asian race) AND

Diagnosis of Type 2 diabetes mellitus by having either:

HbA1C ≥ 6.5% 
OR

Symptoms of diabetes plus hyperglycemia as indicated by

fasting plasma glucose ≥126 mg/dl (≥ 7.0 mmol/l)

two hour plasma glucose concentration ≥200 mg/dl (≥11.1 mmol/l two 
hours after 75g anhydrous glucose in an oral glucose tolerance test 
(OGTT)
OR

Drug therapy for Type 2 diabetes mellitus (as long as on a stable dose. 
Refer to Section 5.2)


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9. Liver fat ≥ 10% at baseline as determined by the reading of the central MRI laboratory of 
locally produced images. The MRI assessment should only be performed after eligibility 
has been confirmed from all other baseline assessments.
10. Patients must weigh at least 40 kg (88 lbs) and no more than 150 kg (330 lbs.) to 
participate in the study. Inclusion of patients with higher weights up to 200 kg (440 lbs.) 
may occur if a MRI scanner with a table weight of 200 kg (440 lbs.) is available.
11. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
Cohorts 1 and 2
Patients with NASH phenotype fulfilling any of the following criteria are not eligible for 
inclusion in this study:
1. History of severe hypersensitivity to drugs of any kind or sensitivity to those including 
pyrazole (eg celecoxib or stanozolol) or an imidazole ring (eg antifungals including 
ketoconazole, anthelminthics including mebendazole and nitroimidazole antibiotics
including metronidazole).
2. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days 
whichever is longer; or longer if required by local regulations.
3. Current use of obeticholic acid (OCA).
4. New initiation GLP-1 agonists such as liraglutide, exenatide, lixisenatide, albiglutide or 
dulaglutide or DPP4 inhibitors such as sitagliptin, vildagliptin, saxagliptin or linagliptin 
within 3 months of screening.
5. Patients taking medications prohibited by the protocol. See Section 5.2 for further details.
6. Patients on treatment with the following medicines UNLESS they are on a stable dose for 
at least 1 month before randomization: insulin (no more than 25%  change in dose), beta-
blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, vitamin E (if  doses > 200 
IU/day; doses > 800 IU/day are prohibited), thyroid hormone, psychotropic medications, 
estrogen or estrogen containing birth control. For oral anti-diabetic medications, no more 
than one step-up or step-down in local prescribing guidelines will be allowed.
7. History of treated or untreated malignancy of any organ system, other than localized 
basal cell carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 
5 years, regardless of whether there is evidence of local recurrence or metastases.
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.


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9. 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 (approximately 5 times the terminal half life) after stopping 
study medication. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  
In case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient

Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS), or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.
10. Sexually active males will be excluded UNLESS they agree to use a condom during 
intercourse while taking study medication and for 5 days after stopping study medication 
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. Current or history of significant alcohol consumption for a period of more than 3 
consecutive months within 1 year prior to screening (significant alcohol consumption is 
defined as more than 20 g/day in females and more than 30 g/day in males, on average) 
and/or a score on the AUDIT questionnaire ≥8 as administered by the site as part of the 
medical history.
12. Inability to reliably quantify alcohol consumption based upon local study physician 
judgment.
13. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such 
abuse as indicated by the laboratory assays conducted during screening and baseline. 
Marijuana use is not allowed if it is determined to be medically inappropriate by the 
investigator.
14. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y 
gastric bypass).


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15. Type I diabetes and uncontrolled diabetes defined as HbAlc ≥ 9.5% within 60 days prior to 
enrollment.
16. Calculated eGFR less than 60 mL/min (using the MDRD formula)
17. Presence of cirrhosis on liver biopsy or clinical diagnosis.
18. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the 
presence of any of the following abnormalities:

Serum albumin < 32 g/L

INR > 1.3

Direct bilirubin > 13 mg/L

ALT or AST > 5 × ULN

Alkaline Phosphatase > 3 × ULN

History of grade 2 or greater esophageal varices, ascites or hepatic encephalopathy

Splenomegaly
19. Platelet count < 120 ×109/L.
20. History or presence of other concomitant liver diseases including, but not limited to:

Hepatitis B or C virus (HCV, HBV) infection

Primary biliary cholangitis (PBC)

Primary sclerosing cholangitis (PSC)

Alcoholic liver disease

Definite autoimmune liver disease or overlap hepatitis

Suspected or confirmed Gilbert's syndrome

Known bile duct obstruction

Suspected or proven liver cancer
21. History of liver transplantation or current placement on a liver transplant list.
22. History of inflammatory bowel disease.
23. Known positivity for Human Immunodeficiency Virus (HIV) infection.
24. History of non-adherence to medical regimens, or patients who are considered by the 
investigator to be unable to reliably comply with the requirements of the study.
25. Chronic use (i.e. > 3 months immediately prior to baseline visit) of high dose Nonsteroidal 
Anti-inflammatory Drugs (NSAIDS) as evaluated by investigator.
26. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
27. Donation or loss of 400 ml or more of blood within eight (8) weeks prior to initial dosing, 
or longer if required by local regulation.


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28. Patients with contraindications to MRI imaging, including:

Brain aneurysm clip

Implanted neural stimulator

Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires

Prosthetic heart valves

Cochlear implant

Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)

Other implanted medical devices (e.g., insulin pumps)

Metal shrapnel or bullets still in the body

Severe claustrophobia

Tattoos (as determined by the Investigator and Imager)

Weight in excess of MRI machine capacity
29. For those patients that have had a previous biopsy: Significant weight loss (>15%) or 
change in clinical status (in the opinion of the investigator) since the diagnostic liver 
biopsy (refer to Inclusion Criterion #3).
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 Patients
Patients must be informed and reminded of the restrictions outlined in this section throughout 
the study.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and must 
agree that in order to participate in the study they must adhere to the contraception 
requirements specified in Section 4.2 (Exclusion criteria). If there is any question that the 
patient will not reliably comply, they should not be entered or continue in the study.
Sexually active males should be reminded of the requirement to wear a condom for the 
following reasons:

To prevent pregnancy in a female partner
AND

To prevent  delivery of investigational drug via seminal fluid to their partner
If there is any question that the patient will not reliably comply, the patient should not be 
entered or continue in the study. Male patients should be informed that if a female partner 
becomes pregnant while he is enrolled in the study, contact with the female partner will be 
attempted to request her consent to collect pregnancy outcome information. Please refer to 
exclusion criteria (Section 4.2) for details of contraception requirements for the study.


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5.2
Prohibited treatment
Medications or herbal remedies that may have a significant impact on LMB763 metabolism 
by inhibiting UGT1A1 are prohibited in the study from the first dosing until end of study 
evaluations have been completed. These include (but not limited to): atazanavir, gemfibrozil, 
indinavir, itraconazole, ketoconazole, manidipine and zafirlukast and Silybum marianum (milk 
thistle) and Valeriana officinalis (valerian). The non-selective UGT inhibitors diclofenac, 
probenecid and valproic acid are also prohibited.
Should a patient have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g. analgesia following dental surgery, etc.), the sponsor 
should be advised, as administration of any concomitant medication may require the patient to 
be replaced. Decisions regarding replacements will be discussed with the sponsor on a 
case-by-case basis.
There is a potential for LMB763 to increase exposure of drugs metabolized by CYP2C8 
(including repaglinide, pioglitazone and rosiglitazone) and those dependent on export by 
BCRP (potentially glyburide (glibenclamide), atorvastatin, rosuvastatin and pitavastatin). 
Careful attention should be paid to the drug interaction sections of the prescribing information 
for these compounds.
Patients on medications specified in Table 5-2 can be included if these medications are 
deemed by the investigator to be:

Medically necessary, and 

Dose has been stable for at least 1 month prior to randomization, and 

Dose is believed to remain stable for the duration of the double-blind treatment period. 
No new use of these medications is allowed after entering the study, with the exception of 
drugs to control medically significant elevations in LDL-cholesterol which have been 
confirmed upon repeat testing.
A ‘stable’ dose of insulin is defined as being within 25% of the current dose. A stable dose of 
oral anti-diabetic medications is defined as up to one step-up or step-down in local prescribing 
guidelinesfrom the dose at randomization. For all other medications listed in Table 5-2, the 
definition of stable will be left to investigator discretion.


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An overview of the prohibited medication is given in Table 5-1, and the summary of 
permitted medications if on a stable dose is presented in Table 5-2.
Table 5-1
Prohibited medication
Medication
Prohibited 
Specific UGT1A1 inhibitors: atazanavir, 
gemfibrozil, indinavir, itraconazole, ketoconazole, 
manidipine, and zafirlukast 
Any use from first drug intake to end-of-study visit
Herbal remedies inhibiting UGT1A1: Silybum 
marianum (sylamarin, milk thistle) and Valeriana 
officinalis (valerian)
Any use from first drug intake to end-of-study visit
Non-selective UGT inhibitors: diclofenac, 
probenecid, valproic acid 
Any use from first drug intake to end-of-study visit
Vitamin E
Doses >800 IU/day 
GLP-1 agonists such as liraglutide, exenatide , 
lixisenatide, albiglutide or dulaglutide or DPP4 
inhibitors such as sitagliptin, vildagliptin, 
saxagliptin or linagliptin  
Newly initiated use within 3 months prior to 
screening
Table 5-2
Permitted medications if dose is stable for at least 1 month prior to 
randomization
Medication
Oral anti-diabetic medications such as metformin, sulfonylureas (including glyburide (glibenclamide), 
meglitinides (such as repaglinide) and thiazolidinediones (including pioglitazone and rosiglitazone))*
Insulin (within 25% of the dose at randomization)**
Beta-blockers and thiazide diuretics 
Fibrates, statins*, niacin, ezetimibe***
Vitamin E****
Thyroid hormone 
Psychotropic medications (phenothiazines or second generation antipsychotics) 
Estrogen or estrogen containing birth control
Notes: *There is a potential for LMB763 to increase exposure of drugs metabolized by CYP2C8 
(including repaglinide,) and those dependent on export by BCRP (potentially glyburide (glibenclamide), 
atorvastatin, rosuvastatin and pitavastatin). Careful attention should be paid to the drug interaction 
sections of the prescribing information for these compounds. For oral anti-diabetic medications, one 
step up in local prescribing guidelines from the dose at randomization will be allowable; **Unless 
adjustment is required due to intercurrent illness; ***Unless adjustment is required to treat medically 
significant increases in LDL that have been confirmed upon repeat testing; ****Only applicable for 
patients taking >200 IU/day; 


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5.3
Dietary restrictions
On study visit days, all patients will fast (i.e. no food or liquid except water) for at least 
6 hours prior to administration of study treatment and will continue to fast for at least 1 hour 
thereafter. No fluid intake apart from the fluid given at the time of drug intake is allowed from 
1 h before until 1 h after dosing.
Alcohol consumption is to be strongly discouraged, and should not exceed 20 g/day in females and 
30 g/day in males. Alcohol should be avoided for 8 hours prior to time of drug intake. 
Patients can drink water ad libitum however, to ensure adequate hydration patients should 
have a fluid intake of at least 240 mL every 4 hours during waking hours in addition to fluid 
taken with meals and medication.
To keep the dietary intake as consistent as possible, patients participating in this study will be 
counseled regarding appropriate exercise and diet per local standards, e.g. instruction to 
carefully adhere to American Heart Association (AHA) diet or equivalent if there is a country 
specific recommended diet (see Appendix 1).
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for patient numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drugs
The investigational drug, LMB763and matching placebo, will be prepared by Novartis and 
supplied to the Investigator site as single blinded patient packs to be dispensed by the 
unblinded pharmacist at the investigator site. Study treatments are defined as:

 LMB763 capsules

 LMB763 capsules

 LMB763 capsules

Matching placebo capsules
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.


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6.2
Treatment arms
Patients will be assigned to one of the following two treatments in a ratio of 2:1. Study 
treatments are defined as:
Cohort 1:
!
LMB763 
 (1 × LMB763 
 capsule)
!
Matching placebo (1 × Matching placebo capsule)
Cohort 2:
!
LMB763 
(2 × LMB763 
 capsules)
!
Matching placebo (2 × Matching placebo capsules)
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual patients by way of a randomization 
number. Randomization numbers will be assigned in ascending, sequential order to eligible 
patients (see Site Operations Manual for details).
The randomization number is only used to identify which treatment the patient has been 
randomized to receive. The Patient number assigned to a patient at screening remains the 
unique identifier for the patient throughout the study.  For information on patient numbering, 
please see ‘Patient numbering’ section in the Site Operations Manual.
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 patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of treatment arms to randomization numbers. 
These randomization numbers are linked to the different treatment arms.
Randomization will be stratified by BMI at baseline (<30 kg/m 2 or ≥ 30 kg/m2 for patients 
with an Asian race, or <35 kg/m2 or ≥ 35 kg/m2 for all other patients). The race will be based 
on the race the patient self-reports as captured on the demography eCRF.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of patients. 
Table 6-1 provides general details of the numbering of patients for randomization into each 
cohort:
Table 6-1
Treatment Assignment Numbering – Cohort 1
Race
BMI (kg/ m2)
Randomization Numbers
Asian
<30
5101-5292
Asian
≥30
5301-5492
Non-Asian
<35
5501-5692
Non-Asian
≥35
5701-5892
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Table 6-2
Treatment Assignment Numbering – Cohort 2 
Race
BMI (kg/ m2)
Randomization Numbers
Asian
<30
9101-9292
Asian
≥30
9301-9492
Non-Asian
<35
9501-9692
Non-Asian
≥35
9701-9892
6.4
Treatment blinding
This is a patient and investigator-blinded study. Patients and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
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.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment (LMB763 or placebo) 
throughout the study.
Unblinding a single patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site (see Section 6.7).
Drug product will be supplied as single blinded patient packs, so an unblinded pharmacist 
(or appropriately trained site personnel) who is independent of the study team will be required 
in order to maintain the blind. This unblinded pharmacist will receive a randomization number 
and treatment allocation from the IRT system, and will then dispense the appropriate 
medications to the patient. Appropriate measures must be taken by the unblinded pharmacist 
to ensure that the treatment assignments are concealed from the rest of the site staff.
Note that the IRT system will not be used for any drug accountability or dispensing 
procedures. IRT is only used for enrollment tracking in this study.
Sponsor staff
The sponsor will remain unblinded to the treatment assignment of all patients to allow for 
continuous unblinded safety monitoring throughout the study. 
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors will be unblinded through review of source documentation compiled 
by the unblinded pharmacist, which details treatment allocation to individual patients. 
The unblinded monitors will also be able to review the treatment allocation provided to the 
unblinded pharmacist via the IRT system. 
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project 
while the study is ongoing.
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6.5
Treating the patient
Study medication will be self-administered by the patient orally once daily (refer to 
Section 3.1 for 12 weeks (84 days). On visit days, treatment will be administered at the site. 
All study treatment will be administered under fasted conditions (no food or drink for at least 
6 hours). On Day 1 (V3) and Day 42 (V7), a meal will be provided at least 4 hours post-dose. 
See the Site Operations Manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Safety and tolerability
In the event of a significant safety/tolerability concern which does not meet study stopping 
criteria (Section 7.5), and is not related to ALT and/or AST elevations, temporary interruption 
and dose adjustments are permitted as follows in order to allow the patient to continue on 
study treatment:

Cohort 1: Reduction in dose frequency to every alternate day

Cohort 2: Reduction in dose
 
Investigators must use their medical judgment in regards to what they deem as the best 
interest of the patient.
Significant isolated ALT and/or AST increase
In the event of a significant ALT and/or AST elevation, temporary interruption and dose 
reduction is permitted in order to allow the patient to continue on study treatment. 
The guidance for the modification of study treatment is outlined below and in Table 6-3; this 
will allow an evaluation of whether such dose reductions are useful in patient management. 
The ability to reduce the dose is clinically relevant as data generated after dose reduction will 
provide further information regarding the tolerability and safety of LMB763.
If the patient has symptoms or other LFT abnormalities, in particular elevations of bilirubin 
and/or PT/INR and/or ALP), refer to Section 9.3 and Table 9-2 for appropriate actions. 
Triggers related to ALT and/or AST elevation are described in Table 9-1. A significant ALT 
and/or AST increase is defined as (i) in the presence of symptoms or other liver function 
abnormalities > 3 × ULN, AND in the case of elevated baseline > 2 × Baseline value; (ii) in
the absence of symptoms or other liver function abnormalities ALT and/or AST elevation > 5 
× ULN AND in the case of elevated baseline > 2 × Baseline value. All cases with ALT 
and/or AST elevation > 3 × ULN will be captured as a liver event per Table 9-1 and 
instructions for further assessment detailed in Table 9-2. Patients who experience significant 
isolated ALT and/or AST elevations will be instructed to return to the clinic within 48 -72 
hours for an additional laboratory evaluation to confirm these results, as defined in Table 6-3. 
The laboratory tests to be repeated are ALT, AST, GGT, alkaline phosphatase, total bilirubin, 
and albumin (LFT) and PT/INR. 
The guidance for the modification of study treatment is outlined below in Table 6-3.


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If the additional laboratory evaluation confirms a significant increase of ALT and/or AST 
values, the dose frequency will be reduced to every alternate day (cohort 1), or the dose will 
be reduced 
(cohort 2); the investigator and site personnel will remain blinded 
to the identity of treatment. The investigator must document the patient's dose frequency 
reduction in source documents.  
If the additional laboratory evaluation does not confirm the significant increase of ALT or 
AST values, the patient will continue with the assigned/original treatment.
If the additional laboratory evaluation shows a higher elevation of ALT and/or AST 
(e.g. > 8 x ULN) as compared to the original elevation (e.g. > 5 x ULN but < 8 x ULN), the 
guidance for this higher elevation (e.g. > 8 x ULN) should be followed.
Actions should be based on whichever of AST and ALT has a higher multiple of ULN or 
baseline value. In order to allow for variation in laboratory results, persisting elevation is 
defined as the value remaining at ≥90% of the original elevated value. When there is a marked 
difference in multiple of ULN between ALT and AST, medical judgment should be applied to 
distinguish between persisting and decreasing. If at any time the repeat testing shows levels in 
a higher category, the guidance for the higher category should be followed.
Only one cycle of dose frequency/dose reduction is allowed. If, despite being on a reduced 
dose, a patient has persistent or new significant ALT and/or AST elevations, the patient must 
be discontinued from study treatment (refer to Section 7.2). After discontinuation for a liver-
related event, LFT and clinical monitoring should continue until the event is resolved (refer to 
Section 9.3). Increasing the dose to the original level is not permitted.


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Table 6-3
Dosing response to Isolated ALT/AST Elevations
ALT and/or AST
increase
First Action
Result
2nd  Action
Result
3rd Action
> 2 x baseline 
AND  ≤5 x ULN
Repeat tests1
within 48-72 
hours
Elevation2 of ALT 
and/or AST 
confirmed
Initiate close observation of 
patient. Repeat tests1 within 
48 – 72 hours
Persistent elevation2
of ALT and/or AST for 
1 week
Cohort 1: Reduce Dose frequency to alternate 
day dosing
Cohort 2: Reduce LMB763 dose
 
Continue close observation of patient with minimum 
twice weekly testing1 (once weekly if stable) until 
ALT and AST <3x ULN (or 2x baseline if elevated 
before drug exposure).
If ALT and AST levels remain ≥3x ULN three  weeks 
after dose reduction, discontinue study treatment
Decreasing ALT and 
AST3
Continue assigned study treatment as per 
protocol
Decreasing ALT 
and AST3
Continue assigned study 
treatment as per protocol
--
--
> 2 x baseline 
AND >5 x ULN 
but ≤ 8 x ULN  
Repeat tests1 in 
48 hours
Elevation2 of ALT 
and/or AST 
confirmed
Cohort 1: Reduce Dose 
frequency to alternate day 
dosing
Cohort 2: Reduce LMB763 
dose 
 
Initiate close observation of 
patient. Repeat tests1 within 
48 – 72 hours
Persistent elevation2
of ALT and/or AST
Discontinue study treatment
Decreasing ALT and 
AST3
Continue with reduced dose frequency or 
reduced dose
Continue close observation of patient with minimum 
twice weekly testing1 (once weekly if stable) until 
ALT and AST < 3 x ULN and < 2 x baseline.
If ALT and AST levels remain ≥3 x ULN three weeks 
after dose reduction, discontinue study treatment
Decreasing ALT 
and AST3
Continue assigned study 
treatment as per protocol
--
--
>2 × baseline 
AND >8 × ULN 
Discontinue 
study treatment
--
--
--
--


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1Tests: A physical examination should be performed and recorded in source documents. PT/INR, ALT, AST, GGT, alkaline phosphatase, total bilirubin, and albumin; 
these repeats must be performed using the central laboratory if possible and captured via the unscheduled lab CRF. If this is not possible, then the repeats can be 
performed at a local laboratory to monitor the safety of the patient. If tests are performed at local laboratory, results will be captured in source documents only.
2Persistent: either ALT and/or AST remain > 90% of the original elevated level 
3Decreasing: both ALT and AST levels decrease to ≤ 90 % of the original elevated level. Medical judgement should be applied if there is a marked difference between 
ALT and AST multiples


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6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. 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. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the study monitor for the site and the Study Team that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will need to 
provide: 

protocol number

study drug name (if available)

patient number
In addition, the investigator must provide information to inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable to ensure that un-blinding 
can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given patient 
and whether the patient can continue in the study.
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
patients treated with LMB763, as detailed in Section 8.7.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
6.9
Recommended treatment of adverse events
Treatment of AEs may be considered at the discretion of the Investigator. Medication used to 
treat AEs must be recorded on the Concomitant medications/Significant non-drug therapies 
CRF.


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6.10
Rescue medication
Use of rescue medication is not allowed during the study.
6.11
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
Study completion and discontinuation
7.1
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 Study Completion 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.
All patients should have a safety follow-up call conducted 30 days after last visit. 
The information collected is kept as source documentation. All SAEs reported during this 
time period must be reported as described in Section 9.2 and the Site Operations Manual.  
Documentation of attempts to contact the patient should be recorded in the source 
documentation.
7.2
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Individual patient withdrawal:
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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Individual treatment discontinuation:
Study treatment must be discontinued and the patient withdrawn from the study if the patient 
withdraws consent.
Study treatment must be discontinued if the following occur:

Pregnancy.

Hypersensitivity (CTCAE grade 2 or higher) reaction to LMB763 requiring intervention.

Adverse events, abnormal laboratory values or abnormal test result that indicate a safety 
risk to the patient, in the opinion of the investigator

An adverse event that is a CTCAE Grade 3 and believed to be related to the study drug 
(apart from liver and renal events - see below).

A liver safety event as defined in Section 9.3 (Liver safety monitoring) with ALT, AST, 
total bilirubin and/or alkaline phosphatase elevations mandating study treatment 
discontinuation. Please refer to Section 9.3 (Liver safety monitoring), Table 9-1 and 
Table 9-2 for further instructions and monitoring.

A renal safety event as defined in Section 9.4  with serum creatinine elevations mandating 
study treatment discontinuation. Please refer to Section 9.4  for further instructions and 
monitoring.

Any protocol deviation that results in a significant risk to the patient’s safety in the 
opinion of the investigator.

If continuation in the study is deemed detrimental to the patient’s well-being in the 
opinion of the investigator.
The appropriate personnel from the study site and Novartis (including the CTT, medically 
qualified representatives of the Sponsor, and the investigator) will assess whether study 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.
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. Where possible, they should return for follow up assessments at the end of 
study visit. If they fail to return for assessments for unknown reasons, every effort 
(e.g. telephone, e-mail, letter) should be made to contact them. 
7.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent from the study is defined as 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 contacts and

Does not allow analysis of already obtained biologic material.


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In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
7.4
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 cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred. 
7.5
Study Stopping rules
The severity of adverse events will be graded by the study site Investigator (or 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 dose arms or the study.
Study Stopping Rules
The study will be placed on hold to further enrollment, no new patients may be dosed, 
however dosing of those without safety concerns may continue. The study may be stopped 
based on a full review of all available clinical safety data and discussion with the Investigators 
if any of the following occur:

One patient on study drug experiences any adverse event that is CTCAE Grade 4 or higher 
that is classified as related to study drug.

Two or more patients on study drug experience a similar adverse event that is a CTCAE
Grade 3 or higher other than ALT elevation.

The Principal Investigator and the Sponsor consider that the number and/or severity of 
adverse events justify discontinuation of the study.

The Sponsor unilaterally requests it.
Safety reviews for study stopping will be conducted jointly between medically qualified 
representatives of the Sponsor and Investigator and a joint decision will be made.


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7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
patients must 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
8.1
Assessment schedule
Assessment Schedule
EPOCH
SCREENING
Treatment
Visit Name
Screening
Baseline25
Treatment
EOS2
Visit Numbers1
1
2
101
1023
1033
1043
105
1063
1073
199
Study Day(s)
-60 to -15
-14/-20 to -1
1
7
-2 +2
14
-2 +2
28
-2 +2
42
-2 +2
56
-2 +2
84
-2 +2
112
-2 +2
Time (post-dose)
-
-
0h3
1h
2h
4h4
6h
-
-
-
0h3
1h
2h
4h4
6h
-
-
-
Informed consent5
X
X
Inclusion / Exclusion criteria
X
X
Medical history/current medical conditions
X
X
Demography
X
Alcohol Test and Drug Screen 
X
X
Hepatitis and HIV Screen
X
Pregnancy test7
X
X
X 
X
X
X
X
Physical examination
X
X
X
X
X
X
Body height
X
Body weight
X
X
X
X
X
X
X
Waist and Hip circumference
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
Blood Pressure and Pulse Rate8,9
X
X
X
X
X
X
X
ECG evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Blood chemistry
X
X
X 
X
X
X
X
X
X
X
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EPOCH
SCREENING
Treatment
Visit Name
Screening
Baseline25
Treatment
EOS2
Visit Numbers1
1
2
101
1023
1033
1043
105
1063
1073
199
Study Day(s)
-60 to -15
-14/-20 to -1
1
7
-2 +2
14
-2 +2
28
-2 +2
42
-2 +2
56
-2 +2
84
-2 +2
112
-2 +2
Time (post-dose)
-
-
0h3
1h
2h
4h4
6h
-
-
-
0h3
1h
2h
4h4
6h
-
-
-
Urinalysis
X
X
X
X
X
X
X
Fasting lipid panel10
X
X
X
X
X
X
X
X
X
X
Coagulation Panel11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X17
X
X
X
X
X
X
X
Fibroscan18,19
X
X
X
X
VAS (Visual Analog Scale)21
X
X
PK blood collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Type
X
Dose administration
X22
MRI23
X
X
X17
Concomitant therapies
X24
(Serious) adverse events
As required
Comments
As required
Study completion information
X
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1 Visit structure given for internal programming purpose only
2 If a patient withdraws from the study, or if study medication is discontinued for any reason, the patient should be scheduled for a subsequent visit at which time all 
assessments at the EOS visit should be performed.
3 Assessments to be performed pre-dose
4 A meal will be provided 4 hours post dose.
5 Informed consent must be provided by all patients before any screening procedures are performed. The pharmacogenetic assessment is optional and requires a 
separate informed consent to be signed
7 Serum pregnancy tests will be performed at Screening and end of study; urine tests may be used at other timepoints. 
8 At screening and baseline, if vital signs are out-of-range, the investigator may obtain two additional readings, so that up to three (3) consecutive assessments are made, 
each after at least 30 minutes, and with the patient seated quietly during the five (5) minutes preceding the assessment. At least the last reading must be within the 
ranges provided in order for patients to qualify.
9 Blood pressure and pulse rate will be measured in a sitting position at all visits.
10 Lipid panel includes total cholesterol, LDL, HDL (including subfractions HDL-1, HDL-2, and HDL-3), and Triglycerides. Direct LDL will also be measured pre-dose at 
V101, V105, V107, and EOS (V199). Additional analyses of LDL sub-fraction and ApoC3 at these timepoints may be performed if notable changes in LDL or triglycerides, 
respectively, are observed. 
11
22 Patients will be provided with a supply of study medication to self-administer once daily for 12 weeks (Day 2 to Day 84). Study medication will be administered by site 
personnel on all visit days. Patients should bring all used and unused medications, and diaries, to each visit.
23 MRI of the abdomen, including liver; see Imaging manual for further instructions.
24 A thorough review of any concomitant medications (including medication name, dose, unit, frequency, and route) should be performed at every visit.
25 Baseline period is 14 days for Cohort 1, and 20 days for Cohort 2. 
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8.2
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the patient agrees to future research.  
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an 
Investigator Notification or an Aggregate Safety Finding. New information might require an 
update to the informed consent and then must be discussed with the patient.
Ensure patients are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Patient screening
In general it is permissible to re-screen a patient if he/she fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis. 
Information on what data should be collected for screening failures is outlined in the 
Site Operations Manual.
8.4
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all patients.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
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8.4.1
Hepatitis screen, HIV screen
All patients will be screened for HIV, Hepatitis B and C. See the Site Operations Manual for details.
8.4.2
Alcohol test, Drug screen
All patients will be screened substances of abuse and cotinine. See the Site Operations 
Manual for details.
8.5
Efficacy / Pharmacodynamics
Efficacy of LMB763 will be assessed based on the following assessments:

Liver function tests (ALT)

Magnetic Resonance Imaging (MRI)

Anthropometric assessments

Markers of liver fibrosis

Fasting lipids

Visual Analog Scale (VAS) for Itch
Pharmacodynamic samples will be collected at the timepoints defined in the 
Assessment schedule. Follow instructions outlined in the central laboratory manual regarding 
sample collection, numbering, processing and shipment. 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. Pharmacodynamic (PD) samples will be obtained and evaluated in all 
patients at all dose levels.
8.5.1
Liver function tests (LFTs)
ALT, AST, GGT, ALP (total), total bilirubin, and albumin will be assessed as indicated in the 
Assessment Schedule. The effect on circulating ALT levels is the primary efficacy variable 
for this study. 
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reactive bilirubin will be quantified.
ALP isoenzymes and 5’NT will also be measured but will not form part of the screening 
requirements or safety data set.
The methods for assessment and recording are specified in the laboratory manual. Some of the 
liver function tests may be completed as part of the blood chemistry panel.
8.5.2
Magnetic Resonance Imaging
Patients will undergo magnetic resonance imaging twice during the course of the study 
(Baseline and End of Treatment) to quantitate liver fat. Optional exploratory MRI based 
assessments will be performed in a subset of patients to evaluate the effect of LMB763 on 
other MRI related endpoints as outlined in Section 8.1 (Assessment schedule).
All patients 
who discontinue prematurely must have an end of treatment MRI assessment.


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8.5.3
Markers of Liver Fibrosis

Fibroscan® (Optional): will be performed where available to assess liver stiffness (in kPa). 
If Fibroscan is unavailable, alternative technology to assess liver stiffness may be 
considered upon consultation with the sponsor

Enhanced liver fibrosis Test (ELF) panel: the following will be assessed: hyaluronic acid 
(HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of 
procollagen type III (PIIINP)

Fibrosis biomarker test (originally called Fibrotest®/ Fibrosure®): the following will be 
assessed: α2-macroglobulin, apolipoprotein A1, total bilirubin, haptoglobin, GGT, and 
ALT

Additional fibrosis markers may be assessed, including but not limited to collagen neo-
epitopes, FIB4, APRI and NAFLD scores
Additional information is provided in the site operations manual and central laboratory 
manual. These markers will be assessed as indicated in Section 8.1 Assessment schedule.
8.5.4
Fasting Lipids
Blood samples will be collected for a fasting lipid panel, including total cholesterol, 
HDL-cholesterol and LDL-cholesterol, triglycerides, free glycerol and free fatty acids as per 
Section 8.1 (Assessment schedule). Lipid measurements should be collected under fasted 
conditions. Detailed information will be provided in the central laboratory manual.
8.5.5
Anthropometric Assessments
Height, body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes), 
and waist and hip circumference in centimeters (cm), will be measured as indicated in 
Section 8.1 (Assessment schedule). Details of these assessments will be provided in the site 
operations manual.
8.5.6
Clinical Outcome Assessments (COAs)
Visual Analog Scale (VAS)
10 cm visual analogue scale (VAS) will be used to assess the severity of patients itch 
(ranging from 0 = no itch at all to 10 = the worst imaginable itch). The score (distance from 
left) on the VAS will be recorded by the patient marking with a line and used to test for an 
effect of LMB763 over placebo.
The scale will be completed by patients as indicated in Section 8.1 (Assessment schedule).
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule (Section 8.1) detailing when each 
assessment is to be performed.
8.6.1
Physical examination
See the Site Operations Manual for details.


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8.6.2
Vital signs

Body temperature

Blood pressure (BP)

Pulse 
8.6.3
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials and 
platelet count will be measured.
Coagulation parameters including APTT, PT, and INR will also be assessed; methods for 
assessment and recording are provided in the central laboratory manual. 
Clinical chemistry
Sodium, potassium, creatinine, BUN/urea, uric acid, serum phosphate, chloride, albumin, 
calcium, alkaline phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, CK, glucose, 
total cholesterol, triglycerides. 
Liver function tests are outlined in Section 8.5.1. 

Homeostasis model assessment (HOMA)-IR will also be derived, but will not be part of 
the safety dataset
Urinalysis
Dipstick measurements for specific gravity, albumin, protein, glucose and blood will be 
performed. Microscopy, WBC, RBC and sediments will also be assessed in case of an 
abnormal dipstick test.
8.6.4
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
site operations manual.
PR interval, QRS duration, heart rate, RR, QT, QTc will be assessed.
The Fridericia QT correction formula (QTcF) (calculated with the RR interval expressed in 
seconds) should be used for clinical decisions.
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.


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8.6.5
Pregnancy assessments 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
Screening Visit followed by a urine pregnancy test at Baseline Visit and before study drug 
administration. The urine pregnancy test will be repeated every four weeks up to the follow up visit 
where a serum pregnancy test will be repeated. See the Assessment Schedule, Section 8.1, for 
timing of the protocol required pregnancy testing; additional pregnancy testing may be 
performed to meet local requirements. 
A positive test at Screening Visit and/or Baseline Visit is an exclusion criterion for 
participating in the study. A positive pregnancy test after start of study drug requires 
immediate interruption of study drug until serum β-hCG is performed and found to be 
negative. If positive, the patient will enter the post-treatment follow up period.
If additional pregnancy testing is needed per local requirements, those additional results will 
be kept as source documentation only.
8.7
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment schedule, Section 8.1. 
Follow instructions outlined in the central laboratory manual regarding sample collection, 
numbering, processing and shipment. See Section 8.9 regarding the potential use of residual 
samples.
Concentrations will be expressed in mass per volume units. Concentrations below the LLOQ 
will be reported as “zero” and missing data will be labeled as such in the Bioanalytical Data 
Report.
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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 until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
The occurrence of adverse events must 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 finding, laboratory 
test finding, 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 and kidney related events are 
included in Section 9.3 and Section 9.4, respectively. 
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Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. the Common Toxicity Criteria (CTC) AE grade (version 4.0 or higher) for the adverse 
event. If CTC-AE grading does not exist for an adverse event, use:

1 = mild,

2 = moderate,

3 = severe

4 = life threatening* (see Section 9.2 for definition of a serious adverse event (SAE))
*Note: There may be cases where a CTCAE with a grade of 4 (life-threatening) may 
not necessarily be an SAE (e.g. certain laboratory abnormalities in the absence of 
meeting other seriousness criteria).

CTC-AE grade 5 (death) is not used, but is collected as a seriousness criteria and also 
collected in other CRFs (e.g. Study Completion, Death/Survival).
2. its relationship to the study treatment 

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness 
criteria have been met  
5. Action taken regarding investigational treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). Once an adverse event is detected, it must 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 investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the subject, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.


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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study  and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
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 it were more severe (see Annex IV, ICH-E2D Guideline).
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 (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.


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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 [after the last study visit] must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Note: SAEs reported by patients deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the 
Site Operations Manual.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must 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 study 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 study 
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.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to 
Novartis within 24 hours of the investigator learning of its occurrence/receiving follow-up 
information.
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.


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Please refer to Table 9-1 for complete definitions of liver events.
Table 9-1
Liver Event Definitions
Definition/ threshold
Liver laboratory triggers

ALT or AST ≥2× baseline value

1.5 × ULN < TBL 2 × ULN
Liver events

ALT or AST > 3 × 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*
*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
TBL: total bilirubin; ULN: upper limit of normal 
Follow-up of liver events
Every liver event defined in Table 9-2 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below and in Section 6.6. Additional details on 
actions required in case of liver events are outlined in Table 9-2. 

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and GGT) to confirm 
elevation within 48-72 hours. These liver chemistry repeats should always be performed 
using the central laboratory, with the results provided via the standard electronic transfer.  
If results will not be available from the central laboratory within 24 hours, then the repeats 
can also be performed at a local laboratory to monitor the safety of the patient. Should this 
occur, a sample should also be sent to the central laboratory for analysis. If a liver event is 
subsequently reported, any local liver chemistry tests previously conducted that are 
associated with this event should have results maintained in source documents. The result 
from the central laboratory will be provided via the standard electronic transfer. 

If the initial elevation is confirmed, close observation of the patient will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Dose adjustment, interruption and/or discontinuation of the investigational drug (refer to 
Section 6.6 (Permitted dose adjustments and interruptions of study treatment) and  
Section 7.2 (Discontinuation of study treatment), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event


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
Thorough follow-up of the liver event should include:

Repeating liver chemistry tests two or three times weekly. Testing should include 
PT/INR ALT, AST, ALP, and GGT. If total bilirubin is elevated > 2 x ULN, 
fractionation into direct and indirect bilirubin is required. To rule out muscular origin 
of transaminase elevations, CPK should be measured along with liver chemistry tests. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject is asymptomatic. 
Retesting should be continued up to resolution. 

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Exclusion of underlying liver disease, as specified in Table 9-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
Table 9-2
Actions required for Liver Events
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN and > 2 
× baseline value

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and > 2 
× baseline value 
and INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 5 × ULN and > 2 
× baseline value 
but ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation is confirmed, refer to 
Table 6-3
Refer to Table 6-3
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and > 2 
× baseline value,
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality
Refer to Table 6-3
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 to ≤ 5 × ULN if 
normal baseline or
>2 x baseline if 
elevated before 
drug exposure
(patient is 
asymptomatic)

Repeat LFT within 48-72 hours

If elevation is confirmed, refer to 
Table 6-3
Refer to Table 6-3
Investigator discretion
ALP (isolated)
> 2 × ULN if 
normal baseline
(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
TBL (isolated)
> 2 × ULN if 
normal baseline 
(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 from baseline 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 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.


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Table 9-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, gGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended actions and follow-up assessments are 
listed in Table 9-4 and Table 9-5, respectively. 
Table 9-4
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Serum creatinine increase 50 % 
compared to baseline
Confirm 50 % within 24-48 hours after receipt of the 
abnormal value
If confirmation of abnormal value is not possible in this 
timeframe study drug must be withheld until further 
evaluation is possible
Consider drug interruption 
Consider patient hospitalization / specialized treatment
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold
Albumin-creatinine ratio (ACR) ≥ 30 mg/g 
or ≥ 3 mg/mmol;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR) ≥ 150 mg/g 
or ≥15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 


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Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 9-5
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data load. 
Review and record possible contributing factors 
to the renal event (co-medications, other co-
morbid conditions) and additional diagnostic 
procedures (MRI etc) in the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium, 
potassium, phosphate, calcium), bicarbonate 
and uric acid

Urine output
Monitor patient regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline or 
protein-creatinine ratio within 50% of baseline)
or

Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level with 
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause 
rather than tubular toxicity.
9.5
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.


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All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Drug Safety and Epidemiology. As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-6
summarizes the reporting requirements.
Table 9-6
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose 
Administration (DAR) CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent 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.
Pregnancy must be recorded on the 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 study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
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 outcomes should 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. 


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9.7
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 (email) 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 (email) (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 ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
The investigator must maintain source documents for each 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 patient (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 patientswill be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
After database lock, the investigator will receive 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.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis (or a designated CRO) will review the data entered into the CRFs 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 are 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 
Novartis (or a designated CRO) who will make the correction to the database. The signed 
copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes will be tracked using an Interactive Response Technology (IRT). 
The system will be supplied by a vendor, who will also manage the database. The database 
will be sent electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.


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The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment received.
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that 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
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
patient. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens and any 
other relevant information will be listed by treatment group and patient.
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11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and patient.
11.4
Analysis of the primary variable(s)
The primary objective of this study is to assess the safety and tolerability of LMB763 as well 
as the efficacy of LMB763 on ALT in NASH patients during 12 weeks of treatment. 
Safety/tolerability data will be summarized. Further details are provided in Section 11.4.4.
11.4.1
Variable(s)
Change from baseline to Week 12 in ALT is the primary efficacy variable. ‘Baseline’ is 
defined as the mean of ALT levels at baseline (V2) and pre-dose (V101) visits.
11.4.2
Statistical model, hypothesis, and method of analysis
A Bayesian approach will be used to analyze the change from baseline to Week 12 in ALT, 
which is assumed to follow a normal distribution with a known variance for each treatment 
arm. An informative prior for the placebo treatment effect and a non-informative prior for the 
LMB763 treatment effect will be incorporated into the analysis. The variance and the 
informative prior will be based on historical control data from studies such as the FLINT trial 
(Neuschwander-Tetri et al 2015). Median estimates, credible intervals and posterior 
probabilities that the placebo-adjusted ALT reduction by an LMB763 dose is (a) greater than 
0 and (b) greater than 19 U/L and/or another cutoff value will be provided within the Bayesian 
framework. As a sensitivity analysis, the posterior probabilities will be calculated for varying 
values of the effective sample size for the placebo prior. A further sensitivity analysis using 
different values of the common variance assumed in the likelihood function and the prior may 
be performed as needed. An analysis using SAS PROC MCMC without assuming the 
variance is known in the likelihood function may be performed as well.    
Additionally a repeated measures analysis of covariance (ANCOVA) will be performed for 
change from baseline ALT without using historical placebo control data. The model will 
include effects for treatment, visit, treatment by visit interaction, stratification factor 
(BMI group), baseline, and baseline by visit interaction. An unstructured variance-covariance 
structure will be used to account for correlation among multiple measurements from the same 
patient and variance heterogeneity. Point estimates, the associated two-sided 90% confidence 
intervals as well as the p-values for treatment differences will be obtained. The null 
hypothesis of no treatment difference will be tested at the one-sided 0.05 significance level. 
Both untransformed and log-transformed ALT will be analyzed. For log-transformed ALT 
analysis the ratio to baseline results obtained by back transformation will be reported
The cohort effect will be explored and a cohort-wise analysis for both the Bayesian and 
ANCOVA approaches may be performed as needed.
If placebo data from in-house studies in a similar patient population become available they 
may be included in an ANCOVA on log-transformed data via informative priors.


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11.4.3
Handling of missing values/censoring/discontinuations
Assuming missing at random, a patient with missing value at a visit will still contribute to the 
estimation of the treatment effect at that particular visit as the likelihood-based repeated 
measures ANCOVA borrows information from non-missing values of this patient and other 
patients.
11.4.4
Summary statistics of safety
Vital signs
All vital signs data will be listed by treatment group, 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 group, 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 group, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group 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. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body system.
Other safety evaluations
Not applicable.
11.4.5
Sensitivity analyses
If more than 10% of the data for the Bayesian analysis on the change from baseline to Week 
12 in ALT are missing then the Last Observation Carried Forward (LOCF) approach and/or 
another method may be used to impute missing data and the Bayesian analysis re-conducted. 
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
Log-transformed ratio to baseline % liver fat and fasting lipid profiles (total cholesterol, HDL, 
LDL, triglycerides) as well as change from baseline % liver fat, weight, BMI, WTH ratio will 
be analyzed using the same repeated measures ANCOVA described in Section 11.4.2 with 


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log-transformed baseline in lieu of baseline as a covariate for lipid parameters. Fibroscan® 
(in a subset of patients), ELF and fibrosis biomarker test data will be analyzed similarly and 
the log-transformation applied prior to the analysis as needed. For parameters with only one 
post-treatment measurement an ANCOVA with treatment as a classification factor and 
baseline (or log-transformed baseline if applicable) as a covariate will be employed. For % 
liver fat, if historical placebo control data in a similar patient population are identified in the 
literature or become available from in-house studies later on then they may be incorporated 
into a Bayesian analysis as described for ALT.   
11.5.2
Pharmacokinetics
LMB763 plasma concentration data will be listed by patient and visit/sampling time point. 
Descriptive summary statistics will be provided by visit/sampling time point, including the 
frequency (n, %) of concentrations below the LLOQ and reported as zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values. Pharmacokinetic parameters will be calculated as 
described in Section 8.7 and will be listed by patient.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): Cmax, Tmax, AUClast, AUCtau, Racc, T1/2, Vz/F and CL/F from the plasma 
concentration-time data. The linear trapezoidal rule will be used for AUC calculation. 
Regression analysis of the terminal plasma elimination phase for the determination of T1/2 
will include at least 3 data points after Cmax. If the adjusted R2 value of the regression 
analysis of the terminal phase is less than 0.75, no values will be reported for T1/2, AUCinf 
and CL/F.
An assessment of dose proportionality of LMB763 exposure will be conducted using Cmax
and AUC. An Analysis of Variance (ANOVA) with dose as the classification factor will be 
performed on log-transformed dose-normalized parameters. A comparison between the 2 
doses will be made within the ANOVA framework. The ratio of geometric means and the 
associated 90% confidence interval (CI) will be obtained by back-transforming the least 
squares mean treatment difference and the corresponding 90% CI in the log domain to the 
original scale.
11.5.3
Pharmacokinetic / pharmacodynamic interactions
The relationship between LMB763 PK parameters (Cmax and AUCtau) and key PD 
parameters (including, but not limited to FGF19, C4, ALP, Cholesterol (total LDL and HDL)) 
may be explored using a graphical approach and descriptive statistics may be provided. 
Additional statistical analysis such as ANOVA or regression may be performed, if necessary. 
Modeling approach may also be used to explore the PK/PD interactions. 


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11.5.4
Other assessments
Change from baseline itch VAS measurements will be analyzed using the same repeated 
measures ANCOVA described in Section 11.4.2.
11.7
Sample size calculation
A mean decrease of 11 U/L from baseline to Week 12 in ALT was observed in the placebo 
group (N=142) of the FLINT trial. Historical placebo control data from trials such as the 
FLINT study will be used when analyzing ALT data from the current study by including prior 
information in a Bayesian approach.
Data from 54 patients in an LMB763 dosing arm and 54 placebo patients (placebo data from 
the current study supplemented by historical placebo control data), will provide approximately 
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76% power to detect a 19 U/L placebo-adjusted reduction from baseline ALT. The sample 
size calculation was done using a one-sided test at the 0.05 significance level, assuming a 
standard deviation of 41.16 U/L which was derived from the FLINT trial. A placebo-adjusted 
19 U/L reduction in ALT corresponds to a 30 U/L decrease if the mean reduction induced by 
the placebo treatment is 11 U/L as reported in the FLINT study.
The corresponding power without using any historical placebo control data will be 61% if 54 
patients in a LMB763 dosing arm and 27 patients in the placebo arm complete the study.
To make allowance for potential dropouts approximately 96 patients will be enrolled in the 
each dosing cohort. All patients who have been enrolled into the initial 
 cohort will 
complete the protocol at that dose, however no further patients will be recruited into that 
cohort 
11.8
Power for analysis of key secondary variables
Data from a total of 81 patients (54 from an LMB763 dosing arm and 27 placebo patients) 
will provide 52% and 82% power to detect a 1.64% and 2.46% difference in absolute change 
from baseline % liver fat between the 2 treatments, respectively, based on a one-sided test at 
the 0.05 significance level. It is assumed the standard deviation equals to 4.02%, derived from 
the summary results in a recently completed Novartis study that enrolled non-alcoholic fatty 
liver disease patients with baseline liver fat >10% as measured by MRI. Since the observed 
overall mean baseline % liver fat in that study is 16.39%, a placebo-adjusted absolute 
decrease of 1.64% and 2.46% corresponds to a relative reduction of 10% and 15%, 
respectively.  
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed 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 must 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
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 is an 
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investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and health authorities, where required, it cannot be 
implemented.
13.1
Protocol Amendments
Any change 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.
Amendments that are intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
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 reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References 
Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear 
sterol-activated receptors LXR and FXR. Nat. Rev. Mol. Cell Biol. p. 213-24.
Jiménez-Agüero R, Emparanza JI, Beguiristain A, et al (2014) Novel equation to determine 
the hepatic triglyceride concentration in humans by MRI: diagnosis and monitoring of 
NAFLD in obese patients before and after bariatric surgery. BMC Med. p. 137
Mudaliar SU, Henry RR, Sanyal AJ, et al (2013) Efficacy and safety of the farnesoid X 
receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver 
disease. Gastroenterology p. 574-82.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al (2015) Farnesoid X nuclear receptor 
ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet p. 956-65.
Patel YA, Imperial JC, Muir AJ, et al Liver Forum’s Data Standardization Working Group
(2017) Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: 
Recommendations From the Liver Forum. Gastroenterology. 153(3):621-625.
Ryan MC, Itsiopoulos C, Thodis T, et al (2013) The Mediterranean diet improves hepatic 
steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 
p. 138-43.


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Protocol No. CLMB763X2201
15
Appendix 1: The American Heart Association (AHA) 
Recommended Diet
Optimization of nutrition-related practices can result in a marked triglyceride-lowering effect 
that ranges between 20% and 50%. These practices include weight loss, reducing simple 
carbohydrates at the expense of increasing dietary fiber, eliminating industrial-produced trans 
fatty acids, restricting fructose and saturated fatty acids, implementing a Mediterranean-style 
diet, and consuming marine-derived omega-3 PUFA.
AHA recommends the following:
Eat a variety of fruit and vegetable servings every day. Dark green, deep orange, or yellow 
fruits and vegetables are especially nutritious. Examples include spinach, carrots, peaches, 
and berries. Eat a variety of grain products every day. Include whole-grain foods that have 
lots of fiber and nutrients. Examples of whole grains include oats, whole wheat bread, and 
brown rice. Eat fish at least 2 times each week. Oily fish, which contain omega-3 fatty acids, 
are best for your heart. These fish include tuna, salmon, mackerel, lake trout, herring, and 
sardines. Stay at a healthy weight by balancing the amount of calories you eat with the 
activity you do every day. If you want to lose weight, increase your activity level to burn 
more calories than you eat. 
Eat foods low in saturated fat and cholesterol. Try to choose the following foods:

Lean meats and meat alternatives like beans or tofu

Fish, vegetables, beans, and nuts

Nonfat and low-fat dairy products

Polyunsaturated or monounsaturated fats, like canola and olive oils, to replace 
saturated fats, such as butter 
Read food labels and limit the amount of trans fat you eat. Trans fat is found in many 
processed foods made with shortening or with partially hydrogenated or hydrogenated 
vegetable oils. These foods include cookies, crackers, chips, and many snack foods. 
Limit sodium intake to less than 2,300 mg of sodium a day (about one teaspoon). Choose and 
prepare foods with little or no salt.  
Limit alcohol intake to 2 drinks a day for men and 1 drink a day for women. 
Limit drinks and foods with added sugar.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LMB763
CLMB763X2201
A randomized, patient and investigator blinded, placebo-
controlled, multicenter study to assess the safety, 
tolerability, pharmacokinetics and efficacy of LMB763 in 
patients with non-alcoholic steatohepatitis (NASH)
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 1
Release date:
09 November 2018
Number of pages:
20
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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 ........................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1. Primary objective(s).......................................................................................5
1.3.2. Secondary objective(s)...................................................................................5
1.4
Study design and treatment......................................................................................7
2
First interpretable results (FIR) ...........................................................................................8
4
Statistical methods: Analysis sets........................................................................................9
5
Statistical methods for Pharmacokinetic (PK) parameters................................................10
5.1
Variables................................................................................................................10
5.2
Descriptive analyses ..............................................................................................11
5.3
Statistical model, assumptions and hypotheses .....................................................11
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................11
6.1
Primary objective...................................................................................................11
6.1.1
Variable.................................................................................................11
6.1.2
Descriptive analyses..............................................................................11
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.1.4
Model checking procedures ..................................................................12
6.1.5
Sensitivity analysis................................................................................13
6.1.6
Supportive analysis ...............................................................................13
6.2
Secondary objectives .............................................................................................13
6.2.1
Variables ...............................................................................................13
6.2.2
Descriptive analyses..............................................................................13
6.2.3
Statistical model, assumptions and hypotheses.....................................14
7
Statistical methods for safety and tolerability data............................................................15
7.1
Variables................................................................................................................15
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7.2
Descriptive analyses ..............................................................................................16
7.3
Graphical presentation...........................................................................................16
10 Derivations ........................................................................................................................18
10.1.1
HOMA-IR .............................................................................................18
10.1.2
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®.......18
10.1.3
FIB-4 .....................................................................................................18
10.1.4
APRI......................................................................................................18
10.1.5
Disease scores and diagnostic algorithms.............................................19
11 Reference list.....................................................................................................................19
Appendix 1: Parameter names for biomarkers ..................................................................20
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................10


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1
Introduction 
1.1
Scope of document
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol (V03) is available at the time of finalization of Statistical Analysis Plan
Amendment 1.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To determine the safety and tolerability 
of LMB763 during 12 weeks of 
treatment.

Safety endpoints (including vital signs, 
physical examination, laboratory 
measurements, ECG).

Adverse events.

To determine the effect of LMB763 on 
circulating alanine aminotransferase 
(ALT) levels.

Liver function tests.
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To evaluate the pharmacokinetics 
(PK) of LMB763 in NASH patients.

PK blood collection and analysis 
(Cmax, Tmax, AUC, Racc, etc.).

To determine the effect of LMB763 
on intrahepatic lipid after 12 weeks 
of treatment.

Percent (%) Liver fat as measured by 
Magnetic Resonance Imaging (MRI).

To determine the effect of LMB763 
on anthropometric assessments after 
12 weeks of treatment.

Weight, BMI, waist-to-hip (WTH) 
ratio.

To determine the effect of LMB763 
on non-invasive markers of liver 
fibrosis.

Fibroscan® (in a subset of patients)

Enhanced liver fibrosis panel (ELF) 
and fibrosis biomarker test 
(originally known as 
Fibrotest®/FibroSure®).

To determine the effect of LMB763 
on fasting lipid profile.

Fasting lipid profile.


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!
To determine the effect of LMB763 
compared with placebo with respect 
to occurrence and impact of potential 
itch.
!
Itch scored on 100 mm visual analog 
scale (VAS) ratings.
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!
Mean (SE) plots of key secondary parameters (Percent liver fat as measured by 
MRI, Weight, Fibroscan®, ELF panel, fasting lipid profile and itch as assessed on 
the VAS scale) per treatment (overlaying) and over time.
4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. All 
placebo subjects will be pooled. Subjects with dose frequency/dose change due to AE will be 
analyzed according to the treatment they received up to the dose frequency/dose change.
All patients that received at least one dose of study drug will be included in the safety data 
analysis “safety population”.
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The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
All patients with evaluable PD parameter data and no major protocol deviations impacting PD 
data will be included in the PD data analysis “PD population”.
For the End of Study (EOS) visit only data from study completers will be included in the 
summary/analysis tables/figures. 
The data exclusion for each analysis set based on protocol deviation codes will be captured in 
the following table, which will be completed in a SAP amendment prior to DBL as needed.
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
protocol deviations: 
Exclude subject completely 
from all (safety) analysis 
sets
Subjects are excluded from PK analysis in case of these 
protocol deviations: 
Exclude subject from PK 
analysis set 
Subjects are excluded from PD analysis in case of these 
protocol deviations:
Exclude subject from PD 
analysis set
Subjects are excluded from PK/PD analysis in case of these 
protocol deviations:
Exclude subject from 
PK/PD analysis sets
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
The following pharmacokinetic parameters will be determined for each analyte using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
6.2 or higher): Cmax, Tmax, AUClast, AUCtau, Racc, T1/2, Vz/F and CL/F from the plasma 
concentration-time data.


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5.2
Descriptive analyses
LMB763 and LMB763 metabolites 
 plasma concentrations will be listed 
by treatment, subject, and visit/sampling time point. Descriptive summary statistics will be 
provided by treatment and visit/sampling time point. Summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, maximum, 
and the frequency (n, %) of concentrations below the LLOQ. 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. Graphical methods will be employed to 
show mean and individual concentration-time profiles.
Pharmacokinetic parameters will be listed by treatment and subject and summarized by 
treatment with descriptive statistics as listed above. Since Tmax is generally evaluated by a 
nonparametric method, only median, minimum, and maximum will be reported. 
5.3
Statistical model, assumptions and hypotheses
Dose proportionality
An exploratory assessment of dose proportionality for LMB763 and LMB763 metabolites 
 will be conducted. Log-transformed dose-normalized Day 1 and Day 42 
AUC and Cmax will be analyzed separately using an Analysis of Variance (ANOVA) with dose 
as the classification factor. A comparison between the 2 doses will be made within the ANOVA 
framework. The ratio of geometric means and the associated 90% confidence interval (CI) will 
be obtained by back-transforming the least squares mean treatment difference and the 
corresponding 90% CI in the log domain to the original scale.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
One of the primary objectives of this study is to assess the efficacy of LMB763 in NASH 
patients during 12 weeks of treatment.
6.1.1
Variable
Change from baseline in ALT is the primary efficacy variable. Baseline is defined as the mean 
of ALT levels at Baseline (V2) and pre-dose (V101) visits. 
6.1.2
Descriptive analyses
The absolute and change from baseline as well as percent change from baseline ALT 
measurements will be listed by treatment, subject and visit/time and descriptive statistics will 
be provided by treatment and visit/time. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum as 
appropriate. 
Mean (SE) absolute and change from baseline ALT as well as geometric mean ratio to baseline 
ALT (90% CI) over time will be plotted by treatment. 
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6.1.3
Statistical model, assumptions and hypotheses
Bayesian approach
A Bayesian approach will be used to analyze the change from baseline to Week 12 in ALT, 
which is assumed to follow a normal distribution with a known variance for each treatment arm. 
An informative prior for the placebo treatment effect and a non-informative prior for the 
LMB763 treatment effect will be incorporated in the analysis. The variance and the informative 
prior will be based on historical control data from external and/or internal studies such as the 
FLINT trial (Neuschwander-Tetri et al 2015). Median estimates, 90% credible intervals and 
posterior probabilities that the placebo-adjusted ALT reduction by an LMB763 dose is (a) 
greater than 0 and (b) greater than 19 U/L and/or another cutoff value will be provided within 
the Bayesian framework.
The cohort effect will be explored and a cohort-wise analysis may be performed as needed.
If placebo data from in-house studies in a similar patient population become available they may 
be included in an ANCOVA on log-transformed data via informative priors.
Repeated measures approach
A repeated measures analysis of covariance (ANCOVA) will be performed for change from 
baseline ALT. The model will include effects for treatment, visit, treatment by visit interaction, 
stratification factor (BMI group), baseline, and baseline by visit interaction. The BMI group 
will have the following 2 strata: low BMI (Asian <30 and Non-Asian<35) and high BMI (Asian 
≥30 and Non-Asian≥35). An unstructured variance-covariance structure will be used to amount
for correlation among multiple measurements from the same patient and variance heterogeneity.
If the unstructured covariance causes model convergence issues other simpler covariance
structures will be considered. Point estimates, the associated two-sided 90% confidence interval 
as well as the p-values for treatment differences (including LMB 50 mg vs LMB 100 mg) will 
be obtained. The null hypothesis of no treatment difference will be tested at the one-sided 0.05 
significance level. Both untransformed and log-transformed ALT will be analyzed, with log-
transformed baseline in lieu of untransformed baseline as a covariate when log-transformed 
ALT is analyzed. For log-transformed ALT analysis the ratio to baseline results obtained by 
back transformation will be reported.
Additionally a repeated measures ANCOVA treating all post dose adjustment measurements as 
missing will be performed as well if the number of patients with dose adjustment is not small
(for example, >20%).
The cohort effect will be explored and a cohort-wise analysis may be performed as needed.
6.1.4
Model checking procedures
Assuming missing at random, a patient with missing value at a visit will still contribute to the 
estimation of the treatment effect at the particular visit as the likelihood-based repeated 
measures ANCOVA borrows information from non-missing values of this patient and other 
patients.


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6.1.5
Sensitivity analysis
As a sensitivity analysis the Bayesian analysis in Section 6.1.3 will be repeated with varying 
values of the effective sample size for the placebo prior. A further sensitivity analysis using 
different values of the common variance assumed in the likelihood function and the prior may 
be performed as needed. A Bayesian analysis without assuming the variance is known in the 
likelihood function may be performed as well.
If more than 10% of the data for the Bayesian analysis on the change from baseline to Week 12 
in ALT are missing then as a sensitivity analysis the Last Observation Carried Forward (LOCF) 
approach and/or another method may be used to impute missing data and the Bayesian analysis 
re-conducted.
6.1.6
Supportive analysis
The subgroup of subjects in Cohort 2, meeting the Cohort 1 ALT inclusion criterion (ALT ≥ 60 
IU/L (males) or ≥ 40 IU/L (females)), may also be analyzed separately, if enough subjects meet 
the criterion. The analyses may include, but not limited to, the same descriptive and inferential 
analyses described in Sections 6.1.2 and 6.1.3 respectively. Additionally a repeated measures 
ANCOVA with 4 levels for the treatment effect (100 mg LMB, placebo to 100 mg LMB, 50 
mg LMB, placebo to 50 mg LMB) may be performed to compare LMB to placebo within each 
cohort.
6.2
Secondary objectives
6.2.1
Variables
The secondary variables of this study are:

Intrahepatic lipid: Percent (%) Liver fat as measured by Magnetic Resonance Imaging 
(MRI).

Anthropometric assessments: Weight, BMI, waist-to-hip (WTH) ratio

Non-invasive markers of liver fibrosis:

Fibroscan® (in a subset of patients)

Enhanced liver fibrosis panel (ELF) and fibrosis biomarker test (originally 
known as Fibrotest®/FibroSure®).

Fasting lipid profile: total cholesterol, HDL, LDL and triglycerides

Itch scored on 100 mm visual analog scale (VAS) ratings.
Baseline for all secondary parameters is defined as the last measurement prior to the first 
dose.
6.2.2
Descriptive analyses
The secondary variables and the corresponding change from baseline and percent change from 
baseline will be listed by treatment, subject and visit/time and descriptive statistics will be 
provided by treatment and visit/time, as needed. Summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, maximum
as appropriate.  


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Graphical methods will be employed to show group summary plots over time by treatment as 
required.
6.2.3
Statistical model, assumptions and hypotheses
Log-transformed ratio to baseline % liver fat and fasting lipid profiles as well as change from 
baseline % liver fat, weight, BMI, WTH ratio and itch VAS score will be analyzed. Parameters 
with more than one post-treatment measurement will be subjected to the same repeated 
measures ANCOVA described for the primary analysis using log-transformed baseline in lieu 
of untransformed baseline as a covariate for the log-transformed data analysis. For parameters 
with only one post-treatment measurement an ANCOVA with treatment as a classification 
factor and baseline (or log-transformed baseline if applicable) as a covariate will be employed.
Fibroscan® (in a subset of patients), ELF and fibrosis biomarker test data will be analyzed 
similarly and the log-transformation applied prior to the analysis as needed. For % liver fat, if 
historical placebo control data in a similar patient population are identified in the literature or 
become available from in-house studies later on then they may be incorporated into a Bayesian 
analysis as described for ALT.
The subgroup of subjects with baseline liver fat ≥10% may be analyzed separately as needed.
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7
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.
7.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
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7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment and subject and 
summarized by treatment. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment and subject.
Treatment
Use of concomitant medications and data on administration of study drug will be listed by 
treatment, and subject.
The number and percent of subjects with dose adjustments may be tabulated and the summary
statistics for the study day at which the dose adjustment occurred provided by treatment.
Vital signs
All vital signs data will be listed by treatment, subject, 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, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. 
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by system organ 
class and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
Separate tables and listings will be presented indicating event toxicity grade and study drug 
relationship.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.


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8
Statistical methods for 
Pharmacokinetic/Pharmacodynamic/Pharmacogenetic
interactions
The relationship between LMB763 PK parameters (Cmax and AUCtau) and key PD parameters
(including, but not limited to ALT, AST, GGT, ALP, FGF19, C4, % liver fat, Cholesterol (total,
LDL and HDL) and the relationship between UGT1A1 polymorphism (if data available) and 
PK parameters as well as the relationship between PD markers (FGF19, C4) and efficacy 
markers (ALT, GGT, fibrosis markers) may be explored using a graphical approach and 
descriptive statistics may be provided. The effect of LMB763 
levels on QTcF will 
also be explored. Additional statistical analysis such as ANOVA or regression may be 
performed, if necessary. Modelling approach may also be used to explore the PK/PD 
interactions. Results from the exploratory assessment of the relationship between UGT1A1 
polymorphism and PK parameters will be reported in the CSR if the decision to carry-out this 
exploratory gated assessment is taken prior to or at IA2.
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10
Derivations
10.1.1
HOMA-IR
Depending on the units which fasting glucose and fasting insulin are given in, HOMA-IR will 
be calculated as:
HOMA-IR = Fasting glucose (mmol/L) x fasting insulin (mU/L) / 22.5
HOMA-IR = Fasting glucose (mg/dL) x fasting insulin (mU/L) / 405
10.1.2
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®
The score is calculated as:
z = 4.467 × log10(α2-macroglobulin) − 1.357 × log10(Haptoglobin) + 1.017 × log10(GGT ) + 
0.0281 × Age + 1.737 × log10(Bilirubin) − 1.184 × ApoA1 + 0.301 × Sex (0=female, 1=male) 
−5.540.
Where:
α2-macroglobulin is given in g/L,
Haptoglobin is given in g/L,
GGT is given in U/L,
Age is given in years,
Bilirubin is given in μmol/L,
ApoA1 is given in g/L,
Sex is given as 0 for female and 1 for male.
Reference: [http://www.google.com/patents/US6631330]
10.1.3
FIB-4
FIB-4 = (age * AST) / (platelets * sqrt(ALT)),
where age is given in years, AST and ALT in U/L and platelets in 109/L.
10.1.4
APRI
APRI = (AST / ULN (AST)) / platelets,
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where platelets are given in 109/L and ULN is the upper limit of the normal range for AST.
10.1.5
Disease scores and diagnostic algorithms 
10.1.5.1 NAFLD fibrosis score
The NAFLD fibrosis score is calculated as [Angulo et al. (2007)]:
z = -1.675 + 0.037 * age + 0.094 * BMI + 1.13 * diabetes (0=no, 1=yes)  + 0.99 * (AST/ALT) 
– 0.013 * platelets – 0.66 * albumin,
where age is given in years, BMI in kg/m2, platelets in 109/L, albumin in g/dL.
10.1.5.2 Algorithm for diagnosis of NASH
A diagnostic algorithm was developed by [Bazick et al. (2015)]:
Logit(P) = 27.00 + 0.106 * BMI (kg/m2) – 0.035 * waist (cm) + 0.068 * AST (U/L) – 0.016 * 
ALT (U/L) + 0.71 * albumin (g/dL) + 0.24 * HbA1c (%) + 0.0570 *  HOMA-IR (mg/dL * 
µU/mL/405) + 0.0014 * ferritin (ng/dL) + 0.57 * white (0=no, 1=yes).
A subject is classified as having NASH if the calculated probability P is ≥ 0.77.
11
Reference list
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al (2015) Farnesoid X nuclear receptor 
ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet p. 956-65.


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