A Randomized Patient-and-physician Blinded, Placebo-controlled, 24-week Study to Assess the Safety, Tolerability and Efficacy of LMB763 in Patients With Diabetic Nephropathy
Phase: PHASE2
Conditions: Diabetic Nephropathy
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
LMB763 (nidufexor)
Clinical Trial Protocol CLMB763X2202 / NCT03804879
A randomized patient-and-physician blinded, 
placebo-controlled, 24-week study to assess the safety, 
tolerability and efficacy of LMB763 in patients with diabetic 
nephropathy
Document type:
Amended Protocol Version
EUDRACT number:
2018-002491-40
Version number:
03 (Clean)
Clinical Trial Phase:
II
Release date:
27-Oct-2020
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 procedures. Note: The SOM will not be a part of the Clinical Study Report.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................19
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.1.5
Clinical Data..........................................................................................26
1.1.6
Human Safety and Tolerability Data.....................................................26
1.1.7
Human Pharmacokinetic Data...............................................................26
1.1.8
Human Pharmacodynamic Data............................................................27
1.2
Purpose ..................................................................................................................27
2
Objectives and endpoints...................................................................................................27
3
Study design ......................................................................................................................28
4
Rationale............................................................................................................................30
4.1
Rationale for study design .....................................................................................30
4.1.1
Rationale for choice of background therapy.........................................30
4.2
Rationale for dose/regimen and duration of treatment ..........................................31
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................31
4.4
Purpose and timing of interim analyses/design adaptations..................................31
4.5
Risks and benefits..................................................................................................31
4.5.1
Blood sample volume............................................................................33
5
Population..........................................................................................................................33
5.1
Inclusion criteria ....................................................................................................34
5.2
Exclusion criteria...................................................................................................34
6
Treatment...........................................................................................................................37
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6.1
Study treatment......................................................................................................37
6.1.1
Investigational and control drugs..........................................................38
6.1.2
Additional study treatments ..................................................................38
6.1.3
Treatment arms/group ...........................................................................38
6.2
Other treatment(s)..................................................................................................39
6.2.1
Concomitant therapy.............................................................................39
6.2.2
Prohibited medication ...........................................................................39
6.2.3
Restriction for study patients ................................................................41
6.3
Patient numbering, treatment assignment, randomization.....................................42
6.3.1
Patient numbering .................................................................................42
6.3.2
Treatment assignment, randomization ..................................................42
6.4
Treatment blinding.................................................................................................42
6.4.1
Treatment blinding - study staff............................................................42
6.4.2
Treatment blinding - sponsor staff........................................................43
6.5
Dose escalation and dose modification..................................................................44
6.6
Additional treatment guidance...............................................................................45
6.6.1
Treatment compliance...........................................................................45
6.6.2
Recommended treatment of adverse events..........................................45
6.6.3
Emergency breaking of assigned treatment code..................................46
6.7
Preparation and dispensation.................................................................................46
7
Informed consent procedures ............................................................................................47
8
Visit schedule and assessments .........................................................................................48
8.1
Screening ...............................................................................................................52
8.1.1
Information to be collected on screening failures.................................52
8.2
Patient demographics/other baseline characteristics .............................................52
8.2.1
Hepatitis screen .....................................................................................52
8.2.2
Alcohol test, Drug screen......................................................................52
8.3
Efficacy and Pharmacodynamics...........................................................................52
8.3.1
Renal function assessments, markers of diabetic nephropathy.............52
8.3.2
Type 2 diabetes measures......................................................................53
8.3.3
Appropriateness of efficacy assessments..............................................53
8.4
Safety and Tolerability ..........................................................................................53
8.4.1
Physical examination ............................................................................53
8.4.2
Vital signs..............................................................................................53
8.4.3
Laboratory evaluations..........................................................................54
8.4.4
Electrocardiogram (ECG) .....................................................................55
8.4.5
Pregnancy and assessments of fertility .................................................55

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8.4.6
Appropriateness of safety measurements..............................................55
8.5
Additional assessments..........................................................................................55
8.5.1
Clinical Outcome Assessment - Visual Analog Scale (VAS)...............55
8.5.2
Pharmacokinetics ..................................................................................56
9
Study discontinuation and completion ..............................................................................58
9.1
Discontinuation......................................................................................................58
9.1.1
Discontinuation of study treatment .......................................................58
9.1.2
Withdrawal of informed consent...........................................................60
9.1.3
Lost to follow-up...................................................................................60
9.1.4
Study stopping rules..............................................................................60
9.1.5
Early study termination by the sponsor.................................................61
9.2
Study completion and post-study treatment ..........................................................61
10 Safety monitoring and reporting........................................................................................62
10.1
Definition of adverse events and reporting requirements......................................62
10.1.1
Adverse events ......................................................................................62
10.1.2
Serious adverse events ..........................................................................64
10.1.3
SAE reporting........................................................................................65
10.1.4
Pregnancy reporting ..............................................................................66
10.1.5
Reporting of study treatment errors including misuse/abuse................66
10.2
Additional Safety Monitoring................................................................................67
10.2.1
Liver safety monitoring.........................................................................67
10.2.2
Renal safety monitoring........................................................................68
10.2.3
Fat soluble vitamin deficiency ..............................................................68
11 Data Collection and Database management......................................................................69
11.1
Data collection.......................................................................................................69
11.2
Database management and quality control............................................................69
11.3
Site monitoring ......................................................................................................70
12 Data analysis and statistical methods ................................................................................70
12.1
Analysis sets ..........................................................................................................71
12.2
Patient demographics and other baseline characteristics.......................................71
12.3
Treatments .............................................................................................................71
12.4
Analysis of the primary endpoint(s) ......................................................................71
12.4.1
Definition of primary endpoint(s).........................................................71
12.4.2
Statistical model, hypothesis, and method of analysis..........................71
12.4.3
Handling of missing values/censoring/discontinuations.......................73
12.4.4
Sensitivity and Supportive analyses......................................................73
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12.5
Analysis of secondary endpoints ...........................................................................73
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................73
12.5.2
Pharmacokinetics ..................................................................................73
12.5.5
PK/PD relationships..............................................................................74
12.5.6
Patient reported outcomes.....................................................................74
12.7
Interim analyses.....................................................................................................75
12.8
Sample size calculation..........................................................................................75
12.8.1
Primary endpoint(s)...............................................................................75
13 Ethical considerations and administrative procedures ......................................................76
13.1
Regulatory and ethical compliance........................................................................76
13.2
Responsibilities of the investigator and IRB/IEC..................................................76
13.3
Publication of study protocol and results...............................................................77
13.4
Quality Control and Quality Assurance.................................................................77
14 Protocol adherence ............................................................................................................77
14.1
Protocol Amendments ...........................................................................................78
15 References .........................................................................................................................79
16 Appendices ........................................................................................................................81
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................81
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................82
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......85
List of tables
Table 2-1
Objectives and related endpoints ..........................................................27
Table 6-1
Investigational and control drugs..........................................................38
Table 6-2
Prohibited medication ...........................................................................40
Table 6-3
Permitted medication if dose is stable for at least 1 month prior to 
randomization........................................................................................41
Table 6-4
Blinding and unblinding plan................................................................44
Table 8-1
Assessment Schedule ............................................................................48
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................67
Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................82
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers...83
Table 16-3
Specific Renal Alert Criteria and Actions.............................................85
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List of figures
Figure 3-1
LMB763X2202 study design................................................................30
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List of abbreviations
ACEI
angiotensin converting enzyme inhibitor
ADA/EASD
American Diabetes Association / European Association for the Study of Diabetes
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANIT
alpha-naphthyl-isothiocyanate
aPTT
activated Partial Thromboplastin Time
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase
BCRP
Breast cancer resistance protein, a member of the ATP-binding cassette 
transporters
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulations
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central nervous system
CPK
Creatine phosphokinase
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTCAE
Common terminology criteria for adverse events
CV
coefficient of variation
CYP
Cytochrome P450 enzyme (i.e., CYP2C8, CYP2C9, CYP1A2, CYP2A6, CYP2D6, 
CYP2E1, CYP3A4/5)
ECG
Electrocardiogram
EDC
Electronic Data Capture
EDD
estimated date of delivery
eGFR
Estimated glomerular filtration rate
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good laboratory practice
GLP-1
Glucagon-like peptide-1
h
hour
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HbA1c
Glycated haemoglobin
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDL
high-density lipoprotein
HDL-C
High density lipoprotein cholesterol
HIV
human immunodeficiency virus
i.v.
intravenous
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL-6
Interleukin-6
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
KDIGO
Kidney Disease: Improving Global Outcomes guidelines
LDH
lactate dehydrogenase
LDL
Low density lipoprotein
LDL-C
Low density lipoprotein cholesterol
LFT
Liver function test
LLN
lower limit of normal
LP(a)
lipoprotein (a)
LQT724
acyl glucuronide metabolite of LMB763 (nidufexor)
MCP-1
monocyte chemoattractant protein 1
MDRD
Modification of Diet in Renal Disease (equation for estimating eGFR)
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
mm Hg
millimeters of mercury
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
NCDS
Novartis Clinical Data Standards
NOAEL
No observed adverse effect level
NOVDD
Novartis Data Dictionary
NSAID
Non-steroidal anti-inflammatory drug
p.o.
oral
PBC
Primary biliary cholangitis
PD
pharmacodynamic(s)
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PK
pharmacokinetic(s)
POC
proof of concept
PSC
Primary sclerosing cholangitis
PT
prothrombin time
QMS
quality management system
QTcF
QTc Fridericia correction formula
RAS
renin-angiotensin system
RBC
red blood cell(s)
SAD/MAD
Single-ascending dose/multiple-ascending dose
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGLT-2
Sodium-glucose linked transporter-2
SMAD3
Mothers against decapentaplegic homolog 3 also known as SMAD family member 
3
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TD
Study Treatment Discontinuation
UACR
Urinary albumin to creatinine ratio
UDP
Uridine 5'-diphospho-glucuronosyltransferase (UGT)
UGT1A1
UDP glucuronosyltransferase 1A1
UGT1A3
UDP glucuronosyltransferase 1A3
ULN
upper limit of normal
ULQ
upper limit of quantification
VAS
Visual Analog Scale
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
WTH
Waist-to-hip ratio
γGT or GGT
γ-glutamyl transferase -or- Gamma-glutamyl transferase
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of patients fulfilling certain criteria
Control drug
Any drug(s) (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 patient in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
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.
Enrollment
Point/time of patient entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
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,” "Investigational Medicinal 
Product," or “test substance”
LMB763
Investigational Novartis compound (nidufexor) to be studied in this protocol
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Mobile healthcare 
professional
A qualified healthcare professional, such as a Nurse or Phlebotomist, who 
performs certain protocol procedures for the participant in a remote location 
such as a participant’s home.
Nidufexor
Investigational Novartis compound (LMB763) to be studied in this protocol
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.
Patient
An individual with the condition of interest
Personal Data
Patient information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes patient identifier 
information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment
Remote
A location that is not the investigative site where the investigator will conduct 
the trial and where source data will be maintained, but is for example the 
participant’s home or another appropriate location

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Run in Failure
A patient who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to patient’s medications or other 
intervention)
Screen Failure
A patient who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the patient permanently stops taking study treatment prior to the defined 
study treatment completion date
Patient
A trial participant (can be a healthy volunteer or a patient)
Patient number
A unique number assigned to each patient upon signing the informed consent. 
This number is the definitive, unique identifier for the patient and should be 
used to identify the patient throughout the study for all data collected, sample 
labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed patient, 
corresponding to a specific treatment arm 
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 
study consent
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data

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Protocol summary
Protocol number
CLMB763X2202
Full Title
A randomized patient-and-physician blinded, placebo-controlled, 24-week 
study to assess the safety, tolerability and efficacy of nidufexor in patients 
with diabetic nephropathy
Brief title
A study of the safety and efficacy of nidufexor in patients with diabetic 
kidney disease
Sponsor and 
Clinical Phase
Novartis
Phase 2 
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
Nidufexor is a potent partial agonist of the bile acid receptor Farnesoid X 
Receptor. In diabetic nephropathy, hyperglycemia, dyslipidemia and 
oxidative stress induce fibrosis and inflammation, resulting in endothelial 
and podocyte epithelial injury. Nidufexor addresses fibrosis, oxidative 
stress, inflammation and cell death, and therefore has the potential to 
improve the management of diabetic kidney disease when added to the 
standard of care (angiotensin converting enzyme inhibitor or angiotensin 
receptor blocker). This non-confirmatory Phase 2 study is designed to 
determine the safety, tolerability, efficacy, pharmacokinetics and 
pharmacodynamics of nidufexor in combination with dose of angiotensin 
converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)
that is the standard of care as judged by the PI or sub-I in patients with 
type 2 diabetes and nephropathy.
Primary Objective(s) 
To compare the effect of nidufexor to placebo on albuminuria in patients 
with diabetic nephropathy already receiving treatment with an angiotensin 
converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) 
as measured by serial urinary albumin to creatinine ratio and 24 hour 
urinary albumin at baseline and end of study.
To assess the safety and tolerability of nidufexor, as measured by vital 
signs, 
physical 
examination, 
laboratory 
measurements, 
electrocardiograms, and reports of adverse events
Secondary 
Objectives
To assess the pharmacokinetic properties of nidufexor at steady state in 
patients with type 2 diabetes and nephropathy as measured by -plasma 
concentrations of nidufexor
To determine the effect of nidufexor on renal tubular function as measured 
by free water clearance by the kidney
To determine the effect of nidufexor on anthropometric assessments 
(weight, body mass index, and waist-to-hip ratio)
To determine the effect of nidufexor on lipids as measured by a fasting 
lipid profile

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Study design
A non-confirmatory, multicenter, patient and investigator blinded, 
randomized, 
placebo-controlled, 
fixed-dose, 
proof-of-concept 
trial 
assessing nidufexor vs. placebo. The study consists of a 30-day 
(Day -30 to Day-1) Screening period, followed by a 24-week Treatment 
Period (Days 1 through 168), at which point End of Study (EOS) 
assessments will occur on Day 169. PK profiling (up to 6 hours post-dose) 
will be done on Day 1 and Day 14. 
Population
Approximately 116 men and women, between 18 and 75 years of age, 
with type 2 diabetes and diabetic nephropathy will be enrolled.
Key Inclusion 
criteria

Written informed consent must be obtained before any assessment
is performed

Male and female patients ≥ 18 years and ≤ 75 years (at the time of
the screening visit)

Diagnosis of type 2 diabetes mellitus, with diagnosis made at least 6
months prior to screening, as determined by American Diabetes
Association criteria

Diabetic nephropathy as evidenced by Urine albumin-Cr ratio
(UACR) ≥ 300 mg/g Cr while receiving a dose of angiotensin
converting enzyme inhibitor (ACEI) or angiotensin receptor blocker
(ARB) that is the standard of care as judged by the PI or sub-I

Dose of either (ACEI or ARB) that is standard of care as judged
by the PI or sub-I must also be stable, defined as <25% dose
change over at least 4 weeks prior to screening.
Key Exclusion 
criteria

History of Type 1 diabetes mellitus, or uncontrolled type 2 diabetes
mellitus as evidenced by HbA1c > 11%

The presence of kidney disease, other than diabetic nephropathy;
severe renal impairment manifesting as serum creatinine-based
eGFR <30 mL/min/1.73 m2 at screening, as determined by the
CKD-EPI formula; history of renal transplant or planned renal
transplant during the study, history of: primary kidney disease,
including, but not limited to primary glomerulonephritis, focal
segmental glomerulosclerosis, polycystic kidney disease, or
membranous nephropathy; secondary kidney disease other than
diabetic nephropathy, including but not limited to lupus nephritis,
obstructive uropathy, and renovascular disease; or acute renal
dialysis or acute kidney injury stage 2 or 3. as defined in the
Kidney Disease: Improving Global Outcomes [KDIGO] guidelines

Uncontrolled hypertension despite receiving anti-hypertensive
therapy as evidenced by BP >150/90 mm Hg at rest as determined
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by the lowest of 3 measurements obtained over approximately 
15 minutes while sitting

History or presence of liver disease including serum ALT or AST >1.5
x ULN; active Hepatitis B or C virus (HCV, HBV) infection (positive
HBV surface antigen (HBsAg) test excludes a patient); primary biliary
cholangitis (PBC); primary sclerosing cholangitis (PSC); alcoholic
liver disease; cirrhosis; definite autoimmune liver disease or overlap
hepatitis; suspected or confirmed Gilbert's syndrome; known bile duct
obstruction; suspected or proven liver cancer; liver transplantation or
current placement on a liver transplant list (Note: Patients with NASH
or NAFLD are not excluded, if their transaminase levels comply with
exclusion criterion); or clinical evidence of hepatic decompensation or
severe liver impairment as defined by the presence of any of the
following abnormalities: serum albumin <LLN; Total Bilirubin > 120%
of ULN; alkaline phosphatase >300 U/L; history of esophageal
varices, ascites or hepatic encephalopathy; splenomegaly; platelet
count <LLN; or prior or planned (during the study period) bariatric
surgery (e.g., gastroplasty, roux-en-Y gastric bypass).

History or current diagnosis of ECG abnormalities indicating
significant risk of safety for patients participating in the study
Study treatment
25 mg nidufexor capsules 
matching placebo capsules
Efficacy 
assessments

Urine albumin-creatinine ratio (UACR) at serial time points, as
specified in the Assessment Schedule

24-hour urinary albumin at baseline and end of study
Pharmacodynamic 
Assessments

Estimated glomerular filtration rate (eGFR), as determined by the
Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation

Free water clearance

Weight

BMI

Waist-to-hip (WTH) ratio

Fasting lipid profile
Pharmacokinetic 
Assessments

Cmax

Tmax

AUClast
Key Safety 
Assessments

vital signs

physical examination

laboratory markers in blood and urine

ECG

adverse event monitoring

Visual analog scale for itch
CCI
CCI
CCI

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Other Assessments
Data Analysis
The primary objective of this study is to assess the safety and tolerability 
of nidufexor as well as the efficacy of nidufexor on albuminuria in patients 
with diabetic nephropathy during 24 weeks of treatment. For efficacy 
evaluation, log-transformed ratios to baseline UACR and 24-hour urine 
albumin excretion at Week 24 are the primary endpoints. A repeated 
measures Analysis of Covariance (ANCOVA) will be performed for 
log-transformed ratio to baseline UACR measured at each visit. Similarly,
an ANCOVA with treatment as the classification factor and log-
transformed baseline as the covariate will be conducted for 
log-transformed ratio to baseline 24-hour urine albumin excretion.
For 
analytical 
purposes, 
all 
safety 
data, 
including 
laboratory 
measurements, vital signs, adverse events, ECG, are considered primary 
endpoints. Safety and tolerability data will be summarized. Formal 
statistical analysis will not be performed on the safety and tolerability data.
Log-transformed ratio to baseline for eGFR, free water clearance, HbA1c 
and fasting lipid profiles (total cholesterol, HDL, LDL, triglycerides and 
Lp(a)) as well as change from baseline in weight, BMI and WTH ratio will 
be analyzed using the same repeated measures ANCOVA with baseline 
in lieu of log-transformed baseline as a covariate for change from baseline 
analysis.
Key Words
Nidufexor, 
LMB763, 
Farnesoid 
X 
receptor, 
placebo-controlled, 
multicenter, patient and investigator blinded, randomized, placebo-
controlled, fixed-dose, proof-of-concept trial, diabetic nephropathy, type 2 
diabetes, tolerability, safety, 24-hr urinary albumin, urinary albumin to 
creatinine ratio (UACR), free water clearance, HbA1c, estimated 
glomerular filtration rate (eGFR), CKD-EPI, angiotensin receptor blocker 
(ARB), angiotensin converting enzyme inhibitor (ACEI), fasting lipid profile
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1
Introduction
1.1
Background
LMB763 (nidufexor) is a potent partial agonist of the bile acid receptor Farnesoid X Receptor 
(FXR). Proposed indications for nidufexor include non-alcoholic steatohepatitis (NASH), 
cholestatic and other hepatic disorders caused by over production and malabsorption of bile 
acids, and diabetic nephropathy.
In diabetic nephropathy, hyperglycemia, dyslipidemia and oxidative stress induce fibrosis and 
inflammation, resulting in endothelial and podocyte epithelial injury. In the kidney, FXR 
is expressed in the glomeruli and tubules (Marquardt et al 2017, Zhang et al 2014). 
FXR agonism decreases markers of fibrosis, oxidative stress, inflammation and cell death in 
rodent models of kidney disease. Specifically, FXR agonism decreases SMAD3 in a mouse 
renal fibrosis model (Zhao et al 2016), and decreases MCP-1, IL-6, H2O2 and markers of 
apoptosis in a mouse ischemia-reperfusion renal injury model (Gai et al 2016). 
Furthermore, FXR agonism in uninephrectomized obese mice reduces albuminuria and urinary 
H2O2, and improves renal histology, oxidative stress, lipid accumulation and mitochondrial 
function (Gai et al 2016, Gai et al 2017). In this same model, nidufexor in combination with 
angiotensin receptor blockade (ARB) reduced albuminuria better than either nidufexor or ARB 
alone.
Diabetic nephropathy is the single most common cause of chronic kidney disease in the USA, 
affecting approximately 16 million Americans. Diabetic nephropathy is a global health 
problem: a cross sectional study among over 32,000 type 2 diabetic patients from 33 countries 
revealed that the prevalence of micro- and macroalbuminuria is 38.8% and 9.8%, respectively 
(Gheith et al 2016). Other analyses suggest that diabetic nephropathy affects approximately 
18 million people in India (Pradeepa and Mohan 2017), and approximately 44 million people 
in China (Ma et al 2018).
The standard of care, primarily angiotensin converting enzyme inhibitor (ACEI) or angiotensin 
receptor blocker (ARB), is focused on delaying rather than preventing progression to end stage 
renal disease (Umanath and Lewis 2018). Nidufexor addresses fibrosis, oxidative stress, 
inflammation and cell death, and therefore has the potential to improve the management of 
diabetic kidney disease when added to the standard of care ACEI or ARB.
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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1.1.5
Clinical Data
Two clinical studies have been completed for nidufexor: a SAD/MAD safety/tolerability study 
in healthy subjects and a proof-of concept study in patients with biopsy-proven or phenotypic 
NASH. (see Protocol Section 1.1.6, and the Investigator's Brochure for additional information).
1.1.6
Human Safety and Tolerability Data
Study 
CLMB763X2201 was a randomized, patient- and investigator-blinded, placebo-controlled, 
multicenter study to assess the safety, tolerability, pharmacokinetics and efficacy of nidufexor 
in patients with biopsy-proven or phenotypic NASH. A total of 121 patients were randomized 
of which 81 subjects received nidufexor at starting doses of 100 mg (Cohort 1; N=37) or 50 mg 
(Cohort 2; N=44). The most commonly reported AE was itch. Discontinuation due to AE was
most frequently in the 100 mg nidufexor group. Itch was considered a tolerability but not safety 
finding, and overall nidufexor was considered generally well tolerated at 50 mg and 100 mg in 
patients with NASH.
Further details are available in the Investigator’s Brochure.
1.1.7
Human Pharmacokinetic Data
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1.1.8
Human Pharmacodynamic Data
1.2
Purpose
The purpose of this proof-of-concept study is to determine whether LMB763 (nidufexor), an 
FXR agonist, warrants continued clinical development for the treatment of diabetic nephropathy.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
To compare the effect of nidufexor to 
placebo on albuminuria in patients with 
diabetic nephropathy already receiving 
treatment with ACEI or ARB
Urine albumin-creatinine ratio (UACR) at serial time 
points, as specified in the Assessment Schedule
24-hour urinary albumin at baseline and end of study
To assess the safety and tolerability of 
nidufexor
Safety endpoints including:
vital signs
physical examination
laboratory measurements
ECG parameters
adverse events
Secondary objective(s)
Endpoint(s) for secondary objective(s)
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Objective(s)
Endpoint(s)
To determine the effect of nidufexor on 
renal filtration function
Estimated glomerular filtration rate (eGFR), as 
determined by the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation 
(Levey and Stevens 2010)
To assess the pharmacokinetic properties 
of nidufexor on day 1 and at steady state 
in patients with type 2 diabetes and 
nephropathy
Cmax, Tmax and AUC0-6h.
To determine the effect of nidufexor on 
renal tubular function
Free water clearance
To determine the effect of nidufexor on 
anthropometric assessments
Assessments
Weight
BMI
Waist-to-hip (WTH) ratio
To determine the effect of nidufexor on 
lipids 
Fasting lipid profile, including lipoprotein (a) [Lp(a)]
3
Study design
This study is a non-confirmatory, multicenter, patient- and investigator-blinded, randomized, 
placebo-controlled, fixed-dose, proof-of-concept trial assessing nidufexor vs. placebo in 
approximately 100 patients receiving standard of care (optimal tolerated doses of ARB or 
ACEI) for diabetic nephropathy due to type 2 diabetes. The study consists of a 30-day (Day -
30 to Day-1) Screening Period, followed by a 24-week Treatment Period (Days 1 through 168), 
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at which point End of Study (EOS) assessments will occur on Day 169. All study visit 
assessments will occur pre-dose, starting on Day 1 of the therapeutic period. PK profiling (up to 
6 hours post-dose) will be done on Day 1 and 14. Post Study Safety Contact will occur 
approximately 28 days after discontinuing study treatment (Day 197). 
Patients will be provided with a supply of study medication for self-administration during the 
treatment period. Detailed instructions for taking study treatment will be provided in the 
Site Operations Manual (SOM). Patients will continue to take study medication 
 for 
24 weeks (Day 1-168), as instructed by the investigator, and study assessments will be 
performed once monthly until the EOS visit (Day 169).
At the investigator’s direction and based on benefit-risk considerations of the participant’s 
clinical condition, qualifying patients may be offered the option to have certain clinical trial 
procedures according to Table 8-1 performed at a remote location. Procedures will be performed 
remotely under the oversight of the investigator, who retains accountability for oversight and 
all efficacy and safety decisions with delegation of tasks to mobile health professionals (i.e.,
research nurses). The remote procedures will be offered in certain countries and sites as 
determined by Novartis based on national and local regulations. The mobile research nurses 
will be provided by a third-party vendor sourced by Novartis. Where a site wishes to use their 
own mobile health professionals that are not provided by Novartis, this must be agreed with 
Novartis prior to implementation.
The study design scheme appears below. On visit days, study medication will be administered 
by site personnel or delegate. Each visit during the treatment and follow-up periods will have 
an allowable window of +/-5 days.
During the entire study period, patients will be instructed to contact the investigator at any time 
if they experience any adverse events of concern. The investigator may choose to place the 
patient under a period of close observation if adverse events or significant laboratory 
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.
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Figure 3-1
LMB763X2202 study design
Patients will be randomized in a 1:1 ratio to receive nidufexor 
or placebo. Approximately 
116 patients will be enrolled in the study and randomized. Approximately 100 patients are expected to 
complete the study.
Treatment randomization may occur prior to day 1 as soon as patient eligibility is confirmed from 
baseline assessments
4
Rationale
4.1
Rationale for study design
The design of this study addresses the primary objective of determining the effect of nidufexor 
on urinary albumin excretion over a 24-week treatment period, in patients with 
macroalbuminuric diabetic nephropathy on ACEI or ARB therapy. Change in albuminuria 
(UACR and 24-hour urine albumin excretion) and annualized rate of change in eGFR over the 
24-week treatment period are the primary and secondary endpoints, respectively. These two
parameters comprise the current gold standard (Levey et al 2015) for assessing stage and
progression of proteinuric chronic kidney diseases such as diabetic nephropathy secondary to
Type 2 Diabetes.

Patient- and investigator-blinded study: Blinding of patients and investigators allows for
an unbiased assessment of patient readouts such as adverse events.

Randomized: Randomization decreases the chance of an imbalance in patient
characteristics between groups, thereby facilitating an unbiased assessment of safety,
tolerability, and efficacy.

Placebo-controlled: This is critical to establish that any safety, tolerability, or efficacy
outcome can be attributed to the study drug as opposed to an effect of study procedures.

Fixed-dose: This study will not involve dose adjustments unless needed due to tolerability
issues (see Section 6.5). The dose selection rationale is described in the next section.
4.1.1
Rationale for choice of background therapy
Pharmacologic blockade of the renin-angiotensin system (RAS) with ACEI or ARB slows and 
delays progressive decline in kidney function in proteinuric diseases such as diabetic 
nephropathy. RAS blockade benefits proteinuric kidney disease via several mechanisms, 
including reduction in intraglomerular pressure, improved blood pressure control, and possibly 
anti-fibrotic actions. RAS blockade is therefore standard of care for many proteinuric kidney 
diseases, aiming to reduce urine protein excretion as the key pharmacodynamic marker 
(Umanath and Lewis 2018).
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4.2
Rationale for dose/regimen and duration of treatment
The CLMB763X2202 study population is expected to have comparable PK to the 
CLMBX2201 population. 
The duration of the study is based on (a) the high variability typical of urine albumin 
measurements, and (b) the high variability and slow rate of change in eGFR; the 24-week 
treatment period will allow more robust assessment of a potential anti-proteinuric effect 
(primary endpoint) and potential slowing of eGFR decline (secondary endpoint). Since both of 
these parameters demonstrate high intra- and inter-patient variability, repeated measures over 
24 weeks will provide more robust data to detect potential treatment effects.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
ACEI or ARB agents are currently prescribed to patients with type 2 diabetes in an attempt to 
modulate intraglomerular pressures and prevent diabetic nephropathy. All patients will be 
receiving stable doses of an ACEI or an ARB agent at screening, and a placebo will be used as 
a comparator to nidufexor to evaluate the treatment effect of nidufexor added to standard of 
care (ACEI or ARB).
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol.
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Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the patient will not 
reliably comply, they should not be entered or continue in the study.
As well as the risks and potential risks described in the Investigator's Brochure, there may be 
unknown risks of nidufexor, which may be serious and unforeseen. The risk to patients in this 
trial may be minimized by compliance with the eligibility criteria and study procedures, as well 
as close clinical monitoring, stopping rules, and periodic review of safety data.
Refer to the current section of the nidufexor IB for latest information on identified and potential 
adverse effects.
A high level summary of risks are provided below.
In the CLMB763X2201 study (NASH patients), adverse events 
related to increased ALT were reported more commonly in placebo (4/40; 10%) than in groups 
receiving 50 mg nidufexor (2/44; 4.5%) or 100 mg nidufexor (1/37; 2.7%); adverse events 
related to increased AST were reported in 1 (2.5%) patients receiving placebo, and 1 (2.3%) 
and 4 (10.8%) patients receiving 50 mg and 100 mg nidufexor, respectively. However, no new 
significant liver enzyme abnormalities were reported in the study due to the study medication. 
Transaminases will be monitored in this study.
LDL-C elevations and reductions in both HDL-C and triglycerides have been noted in clinical 
trials with a bile acid derived FXR-agonist.
. Serum lipids will be monitored during this study.
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Refer to Section 7 of the latest version of nidufexor Investigator's Brochure for detailed 
information on identified and potential adverse effects.
In addition, investigators will be advised to manage glycemic control for all patients in a manner 
consistent with local treatment guidelines for type 2 diabetes. In the absence of local guidelines, 
investigators are referred to the joint ADA/EASD guidelines for the management of glucose 
control in patients with type 2 diabetes (Inzucchi et al 2015).
The assessment of the Benefit/Risk for the study in the context of COVID-19 pandemic 
concluded the absence of additional risks for the study population and/or related to the 
investigational medicinal product.
4.5.1
Blood sample volume
A total blood volume of approximately 240 mL is planned to be collected over a period of 
approximately 32 weeks from each patient as part of the study. Additional samples may be 
required for safety monitoring, which are not included in the noted estimate. This estimate 
includes approximate planned overdraw amounts required by locally available blood collection 
tubes. 
Timings of blood sample collections are outlined in the Assessment Schedule and a summary 
blood log is provided in the Site Operations Manual (SOM). Instructions for sample collection, 
processing, storage and shipment information may be found in the SOM and the central 
laboratory manual.
See the Section 8.5.3.2 on the use of residual biological samples.
5
Population
The study population will be comprised of male and female patients with diabetic nephropathy 
due to type 2 diabetes.
Approximately 116 patients will be randomized in the study. Approximately 100 patients are 
expected to complete the study.
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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. 
A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source 
documentation.
Deviation from any entry criterion excludes a patient from enrollment into the study. Details on 
re-screening are located in Section 8.1.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients ≥ 18 years and ≤ 75 years (at the time of the screening visit).
3. Diagnosis of type 2 diabetes mellitus, with diagnosis made at least 6 months prior to
screening, as determined by American Diabetes Association criteria
American Diabetes Association 2010
4. Diabetic nephropathy as evidenced by Urine albumin-Cr ratio (UACR) ≥ 300 mg/g Cr at
screening while receiving a dose of ACE-I or ARB that is the standard of care as judged
by the PI or sub-I

Dose of ACE-I or ARB that is the standard of care as judged by the PI or sub-I must
also be stable, defined as <25% dose change that occurred at least 4 weeks prior to
screening.
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
3. History of Type 1 diabetes mellitus
4. Uncontrolled type 2 diabetes mellitus as evidenced by HbA1c >11% at screening
5. The presence of kidney disease, other than diabetic nephropathy, at screening including:

Primary kidney disease, including, but not limited to primary glomerulonephritis,
focal segmental glomerulosclerosis, polycystic kidney disease, or membranous
nephropathy;

Secondary kidney disease, other than diabetic nephropathy, including but not limited
to lupus nephritis, obstructive uropathy, and renovascular disease;

History of acute renal dialysis or acute kidney injury stage 2 or 3 as defined in the
Kidney Disease: Improving Global Outcomes [KDIGO] guidelines
(Okusa and Davenport 2014)
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6. Severe renal impairment manifesting as serum creatinine-based eGFR
<30 mL/min/1.73 m2 at screening, as determined by the CKD-EPI formula
(Levey and Stevens 2010)
7. History of renal transplant or planned renal transplant during the study
8. Diagnostic or interventional procedure requiring any potentially nephrotoxic contrast
agent within 4 weeks of the first screening visit, or planned during the study
9. Uncontrolled hypertension (Whelton et al 2018), despite receiving anti-hypertensive
therapy, as evidenced by BP >150/90 mm Hg at rest at screening as determined by the
lowest of 3 measurements obtained over approximately 15 minutes while sitting
10. History or presence of liver disease at screening including:

Active Hepatitis B or C virus (HCV, HBV) infection

Note: A positive HBV surface antigen (HBsAg) test excludes a patient

Primary biliary cholangitis (PBC)

Primary sclerosing cholangitis (PSC)

Alcoholic liver disease

Cirrhosis

Definite autoimmune liver disease or overlap hepatitis

Suspected or confirmed Gilbert's syndrome

Known bile duct obstruction

Liver transplantation or current placement on a liver transplant list

Suspected or proven liver cancer

Note: Patients with NASH or NAFLD are not excluded, if their transaminase
levels comply with exclusion criterion 11
11. Serum ALT or AST >1.5 x ULN at screening.
12. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the
presence of any of the following abnormalities at screening:

Serum albumin <LLN

Total Bilirubin >120% X ULN or Gilbert's syndrome

Alkaline phosphatase >300U/L

History of esophageal varices, ascites or hepatic encephalopathy

Splenomegaly

Platelet count <LLN
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18. Receiving any of the prohibited medications listed in Table 6-2, (e.g. UGT1A1 inhibitors,
herbal remedies that inhibit UGT1A1, non-selective UGT inhibitors, ACEI and ARB in
combination, direct renin inhibitors, SGLT2 inhibitors, GLP1-receptor agonists) and
unable to switch to suitable alternatives at least 5 days prior to first study dose and for the
duration of the study
19. 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.
20. 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 of screening, regardless of whether there is evidence of local recurrence or
metastases
21. History or current diagnosis of ECG abnormalities prior to first study dose indicating
significant risk of safety for patients participating in the study
22. 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
23. Known positivity for Human Immunodeficiency Virus (HIV) infection
24. Women of childbearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during dosing
of study treatment.
Basic 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

Note: 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)

Note: For female patients on the study the vasectomized male partner should be
the sole partner for that patient

Barrier methods of contraception: condom or occlusive cap (e.g., diaphragm or
cervical/vault caps).

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

Note: 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
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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 before taking study treatment. 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 childbearing potential.
25. 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
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
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 SOM and on the medication label.
Instructions for administering study treatment
On visit days, study medication will be administered after an overnight fast of at least 6 h by 
site personnel or delegate. Medication will be administered with a half a glass (approximately 
120 mL) of water in the morning. Each patient’s mouth must be checked to ensure that the 
medication was swallowed. Patients must be instructed not to chew the medication, but to 
swallow it whole.
Patients are encouraged to follow a similar routine for taking study treatment on non-visit days.
However it is not essential for medication to be taken under fasted conditions.
Visit days - All doses administered to the patient on visit days will be recorded on the Dosage 
Form CRF.
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Non-visit days - Patients will be provided with individual diaries to record each administration 
of study treatment on non-visit days. If a patient misses a dose at scheduled time +/- 5 h then 
this should be recorded as a missed dose and next dose should be taken at the scheduled time 
the following day.
Novartis will provide the site with an emergency study card to hand over to all study participants 
who receive a dose of study medication (nidufexor or placebo), which will state that the subject 
is participating in a clinical study and may have received an investigational drug.
This emergency study card will also include the contact information of the Study 
Doctor/Investigative Site. Designated study staff will instruct study participants to present this 
card to a medical care provider if they have any medical issues during the course of the study.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drugs
Investigational/Control Drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Packaging
Sponsor 
(global or 
local)
LMB763 25 mg
Capsule
Oral
Double blind 
patient specific 
kits
Novartis
Placebo LMB763
Capsule
Oral
Double blind 
patient specific 
kits
Novartis
The investigational drug, nidufexor, and matching placebo will be prepared by Novartis and 
supplied to the investigator site as double blind patient specific kits to be dispensed by study 
pharmacist or other approved trained personnel. Study treatments are defined as:

25 mg LMB763 capsules

matching placebo capsules
6.1.1.1
Decentralized Clinical Trial Model (select US sites only)
The study medication and all required clinical study supplies will be distributed via direct-to-
participant shipment utilizing an extension of the IND for compliance purposes.
6.1.2
Additional study treatments
Background therapy must include either an angiotensin converting enzyme inhibitor (ACEI) or 
an angiotensin receptor blocker (ARB), as per the inclusion criteria. Use of dual 
renin-angiotensin system inhibitors (ACEI + ARB) is prohibited.
6.1.3
Treatment arms/group
Patients will be assigned at Visit 101 to one of the following treatment arms in a ratio of 1:1.
Study treatments are defined as:
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
LMB763
 (
 LMB763 25 mg capsules)

Placebo (
 placebo capsules)
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Treatment other than study treatment is permitted through the entire study duration, if such 
treatment is not prohibited as defined in Section 6.2.2.
Hormonal contraception is allowed during this study (see Section 5.2).
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the patient was enrolled into the study must be recorded 
in the concomitant medications / significant non-drug therapies or procedures pages.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication.
If in doubt the investigator should contact the Novartis translational medical expert, or designee, 
before randomizing a patient or allowing a new medication to be started. If the patient is already 
enrolled, the investigator should contact the Novartis translational medical expert, or designee, 
to determine if the patient should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Persistent Hyperglycemia: Investigators are advised to manage glycemic control for all patients 
in a manner consistent with local treatment guidelines for type 2 diabetes. In the absence of 
local guidelines, investigators are referred to the joint ADA/EASD guidelines for the 
management of glucose control in patients with type 2 diabetes (Inzucchi et al 2015).
Dose Adjustments: Nidufexor may moderately reduce the clearance of medications that are 
substrates of CYP2C8. Administration of nidufexor with pioglitazone, rosiglitazone, or 
glyburide (glibenclamide) could result in higher serum concentrations of these medications, 
thereby increasing the potential for hypoglycemia. Frequent, regular fingerstick blood glucose 
monitoring is advisable during the treatment phase of this study, with subsequent dose 
adjustments of these medications as needed.
NSAIDs, COX-2s: Modest doses of non-steroidal anti-inflammatory drugs (NSAIDs) or 
selective cyclooxygenase-2 (COX-2) inhibitors may be used for a period not longer than 7 days.
6.2.2
Prohibited medication
Use of the treatments displayed in Table 6-3 are NOT allowed after the start of study treatment 
until the patient's final dose of oral study medication (nidufexor or placebo).
Nidufexor is metabolized primarily by UGT1A1. There is a potential for inhibitors of UGT1A1 
to affect the clearance of nidufexor. There is also a potential that nidufexor will affect the 
disposition of medications that are substrates of CYP2C8.
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Patients with known Gilbert’s syndrome and those taking concomitant medications and 
herbal remedies that inhibit UGT1A1 or are a profound CYP2C8 substrate should be 
EXCLUDED from clinical trials of nidufexor until formal clinical drug-drug interaction 
studies have been performed.
Restricted Antihyperglycemic Medications: The SGLT-2 inhibitors (e.g. canagliflozin, 
dapagliflozin, empagliflozin) and GLP-1 receptor agonists (e.g. exenatide, liraglutide, 
albiglutide, dulaglutide, semaglutide, lixisenatide) are prohibited medications in this study. 
A list of generic and trade names is provided in the SOM.
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Specific UGT1A1 inhibitors: e.g 
atazanavir, gemfibrozil, indinavir, 
itraconazole, ketoconazole, 
manidipine, and zafirlukast
Any use from first 
drug intake to end-
of-study visit
Discontinue UGT1A1 inhibitor, if 
possible. Stop nidufexor. Check a 
random nidufexor level, noting time 
elapsed since last dose.
Herbal remedies inhibiting 
UGT1A1:e.g Silybum marianum 
(sylamarin, milk thistle) and 
Valeriana officinalis (valerian)
Any use from first 
drug intake to end-
of-study visit
Discontinue herbal remedy. Stop 
nidufexor and check a random nidufexor 
level, noting time elapsed since last 
dose.
Non-selective UGT inhibitors: e.g 
diclofenac, probenecid, valproic 
acid
Any use from first 
drug intake to end-
of-study visit
Discontinue non-selective UGT 
inhibitors, if possible. Stop nidufexor 
and check a random nidufexor level, 
noting time elapsed since last dose.
Aliskiren, direct renin inhibitors
Any use from first 
drug intake to end-
of-study visit
Discontinue direct renin inhibitor, if 
possible. If not possible, stop nidufexor 
and check a random nidufexor level, 
noting time elapsed since last dose.
ACEI + ARB in combination
Any use from first 
drug intake to end-
of-study visit
Discontinue either ARB or ACE inhibitor, 
if possible. If not possible, stop 
nidufexor and check a random nidufexor 
level, noting time elapsed since last 
dose
Sodium-glucose co-transporter 2 
(SGLT2) inhibitors
Any use from first 
drug intake to end-
of-study visit
Discontinue SGLT2 inhibitors, if 
possible. If not possible, stop nidufexor 
and check a random nidufexor level, 
noting time elapsed since last dose.
GLP-1 receptor agonists
Any use from first 
drug intake to end-
of-study visit
Discontinue GLP-1 receptor agonists, if 
possible. If not possible, stop nidufexor 
and check a random nidufexor level, 
noting time elapsed since last dose.
Patients on medications specified in Table 6-3 can be included if the investigator determines 
the following criteria have been met:

Usage is considered medically necessary, and

Dose has been stable for at least 1 month prior to screening, and

Dose is expected to remain stable for the duration of the study

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No new use of these medications is allowed after entering the study, with the exception of drugs 
to control medically significant elevations in LDL-C, which has 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 from the dose at 
randomization, per local treatment guidelines. For all other medications listed in Table 6-3, the 
definition of stable will be left to investigator discretion.
Table 6-3
Permitted medication 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)1

Insulin (within 25% of the dose at randomization)2

Beta-blockers and thiazide diuretics. Thiazide diuretic use should also be maintained constant
throughout the trial, if possible.

Fibrates, statins1 niacin, ezetimibe3

Vitamin E

Thyroid hormone

Psychotropic medications (phenothiazines or second generation antipsychotics)

Hormonal (estrogen, progesterone, or estrogen/progesterone containing) birth control
1There is a potential for nidufexor 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 MUST be paid 
to the drug interaction sections of the prescribing information for these compounds 
2Unless adjustment is required due to intercurrent illness; 
3Unless adjustment is required to treat medically significant increases in LDL-C that have been 
confirmed upon repeat testing.
6.2.3
Restriction for study patients
For the duration of the study, the patients should be informed and reminded of the restrictions 
outlined in this section. See also male and female contraception requirements in Section 5.2
In the event a patient presents with symptoms of COVID-19, the Investigator should ask the 
patient to quarantine per local guidelines.
6.2.3.1
Dietary restrictions and smoking
No special restrictions for the study. Appropriate diet for type 2 diabetes should be followed.
6.2.3.2
Other restrictions
None.

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6.3
Patient numbering, treatment assignment, randomization
6.3.1
Patient numbering
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.
6.3.2
Treatment assignment, randomization
Randomized treatment will be assigned by the IRT 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). However, randomization numbers 
will not be shared with the study staff, and will remain on the back-end of the IRT system. 
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.
The randomization numbers will be generated using the following procedure to ensure that the 
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.

Note: These randomization numbers are linked to the different treatment arms.

The randomization scheme for patients will be reviewed and approved by a member of the
Randomization Office. If a patient is deemed eligible for enrollment into the study, they
will be randomized and treatment will be assigned via the IRT system.

Patients will be assigned randomization numbers 5101-5340.

Note: Follow the details outlined in the Site Operations Manual regarding the
process and timing of treatment assignment and randomization of patients.
6.4
Treatment blinding
This is a patient- and investigator-blinded study. Patients, investigators, and sponsor staff 
(see Table 6-4) 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.
6.4.1
Treatment blinding - study staff
All study staff (including study investigator, study nurses/coordinators) will be blinded to study 
treatment throughout the study. Unblinding a single patient for safety reasons (i.e. necessary for 
patient safety management) will occur via an emergency system (see SOM and IRT manual for 
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6.4.2
Treatment blinding - sponsor staff
The following are unblinded sponsor roles:

Sponsor randomization office

Drug supply (global clinical supplies)

Study statistician

The study statistician will be able to access the randomization list and is allowed to
share unblinded information with the rest of the clinical team as appropriate for
internal decision purposes. For example, unblinded summaries and unblinded
individual data can be shared with the team for interim analyses.
The following are additional unblinded sponsor roles:

Medical lead (study safety physician / TME) and sponsor pharmacovigilance staff

Note: The TME and pharmacovigilance staff may have access to individual,
group/cohort, or the entire study treatment allocations as needed to oversee safety on
the trial.

Other sponsor roles:

The sample analysts will receive a copy of the randomization schedule (via request to
the Randomization Office), to facilitate analysis of the PK samples. The sample
analysts will provide the sample data to the study team under blinded conditions
unless otherwise allowed.

Study programmers and other personnel involved in study data analysis (e.g. PK
expert, 
) are allowed to access treatment assignment information for 
the purpose of conducting interim analyses of the data.

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 at the time of interim analyses while the study is ongoing.

All unblinded personnel will otherwise keep randomization lists and data or
information that could unblind other study team members confidential and secure
except as described above.
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Following final database lock ALL roles are considered unblinded.
Table 6-4
Blinding and unblinding plan
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis 
Patient
B
B
UI*
B
Site staff, including PI, SC, study nurses
and mobile health professionals
B
B
UI*
B
Unblinded Pharmacovigilance sponsor 
staff
B
UI
UI
UI
All other sponsor staff, including:

TME

Study Leader

Bio-analysts, including PK and
BMD

Bio-experts, including PK and
BMD

Statistical programmers

Data analysts

Clinical trial team members

Sponsor management and
decision boards

Supportive functions
B
UI
UI
UI
Drug Supply (Global Clinical Supplies)
UI
UI
UI
UI
Sponsor Randomization Office
UI
UI
UI
UI
Study Statistician
UI
UI
UI
UI
Key:
*Unblinding allowed at the single patient level ONLY
UI: Allowed to be unblinded on individual patient level (includes single patient, group/cohort 
of patients, or entire study/all patients)
B: Remains blinded
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions should be kept as 
short as possible and dates recorded in the eCRF. If these are for reasons of significant 
noncompliance or extended dosing interruptions related to AEs, the investigator should use 
discretion to discontinue the patient from study treatment. The investigator may consult with 
the Sponsor medical lead if necessary. 
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If this modification is not tolerated, the medication should be discontinued. Please refer to
Section 9.1.1.
If the reduced dose is tolerated, an attempt to increase the dose after two weeks of reduced 
dosing could be considered or the reduced dose can continue for the remainder of the study.
Use of bile acid binding resins for treatment of pruritus is not recommended.
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 nidufexor.
In the event a patient develops flu-like symptoms during the treatment period and the 
investigator is concerned the patient may have a COVID-19 infection, treatment interruption 
may be considered. If an investigator decides to interrupt study treatment for this reason, the 
investigator must ensure that the patient has a SARS-Cov-2 PCR test to confirm the infection
within approximately 5 days.

If the test is positive, the investigator may decide to extend the treatment interruption and 
monitor the patient’s condition to determine if discontinuation is warranted. Treatment 
interruption should not exceed 14 days.

If the test is negative, the investigator may decide to resume study treatment.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
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 (or delegate) 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. Patients who are not >80% compliant with study 
drug administration will be counseled by the investigator and reminded by site personnel or 
delegate regarding the importance of taking all doses. Dose reductions due to tolerability issues 
should not be factored into the compliance calculation. 
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events.
Medication used to treat AEs must be recorded on the Concomitant Medications/Significant 
non-drug therapies CRF.

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6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required in order to treat the patient 
safely. Blinding codes may also be broken after a participant discontinues treatment due to 
disease progression if deemed essential to allow the investigator to select the participant’s next 
treatment regimen, and after discussion and agreement with the sponsor. 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 Novartis 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 provide:

protocol number

protocol title

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
Patients should be discontinued from the study after emergency unblinding but should not be 
considered withdrawn from the study. Where possible, they should return for end-of-study 
assessments as described in Section 9.1.1.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the patient by contacting 
the IRT and obtaining the medication number(s). 
Nidufexor will be administered to the patient via the oral route. On study visit days, 
administration will occur in the presence of the study nurse or delegate. At home, the patient 
will self-administer study medication. See the Site Operations Manual for further details.

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7
Informed consent procedures
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed 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.
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 agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male patients must 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.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.
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8
Visit schedule and assessments
The assessment schedule lists all of the assessments and indicates with an “X”, the visits when they are performed. All data obtained from 
these assessments must be supported in the patient’s source documentation. Some assessments in the schedule are marked with an "S" 
indicating that these data are to be evaluated and stored as source data at the site.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as close to the designated day/time as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. This also applies in the event a patient needs to be quarantined for 
an amount of time consistent with local policy due to exposure to or suspected or confirmed COVID-19 infection.  
For patients who withdraw from the study (i.e. withdrawal of consent), no further assessments will be conducted. Further attempts to contact 
the patient are not allowed, unless safety findings require communicating or follow up.
All study assessments described in Table 8-1 may potentially be performed remotely. Implementation of decentralized trial models is 
dependent on local regulations and Sponsor approval. 
Table 8-1
Assessment Schedule
Visit Name/Epoch Screening
Treatment
EOS
Post Study 
Safety 
Contact
Visit Numbers1
1
101
102
1032
1042
1052
1062 1072
199
Days
-30 to -1
1
14
±5
29
±5
57
±5
85
±5
113
±5
141
±5
169
±5
197
±5
Time (post-dose)
-
0h2 1h 2h 4h
6h
0h2 1h 2h 4h
6h
-
-
-
-
-
-
-
Informed consent
X
Inclusion / exclusion criteria
X
Medical history/current medical conditions
X
Demography
X
Body height
X
Body weight
X
X
X
X
X
X
X
X
X4
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Visit Name/Epoch Screening
Treatment
EOS
Post Study 
Safety 
Contact
Visit Numbers1
1
101
102
1032
1042
1052
1062 1072
199
Days
-30 to -1
1
14
±5
29
±5
57
±5
85
±5
113
±5
141
±5
169
±5
197
±5
Time (post-dose)
-
0h2 1h 2h 4h
6h
0h2 1h 2h 4h
6h
-
-
-
-
-
-
-
Waist and hip circumferences5
X
X
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
X
X
X
X4
Blood pressure
X
X
X
X
X
X
X
X
X4
Pulse rate
X
X
X
X
X
X
X
X
X4
Physical examination
S
S
S
S
S
S
S
S
S4
Electrocardiogram (ECG)6
X
X
X
X
X
X
X
X
X4
Hepatitis screen
S
COVID-19 (SARS- Cov2) testing21
S
Alcohol test and drug screen 
S
Pregnancy and assessments of fertility7
X
X4
Clinical Chemistry
X
X
X
X
X
X
X
X
X4
Hematology
X
X
X
X
X
X
X
X
X4
PT/INR8
X
Anticoagulant Panel 
(PT/INR; aPTT; fibrinogen)
X
X
X
Plasma osmolality
X
X4
HbA1c
X
X
X4
Fasting lipid panel
X
X
X
Lipoprotein (a) [Lp(a)]
X
X
X
PK blood collection10
X2
X
X
X
X
X2
X
X
X
X
X2
X2,4
Urinalysis12
X
X
X
X
X
X
X
X
X4
Urine albumin and creatinine13
X
X
X
X
X
X
X
X
X4
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Visit Name/Epoch Screening
Treatment
EOS
Post Study 
Safety 
Contact
Visit Numbers1
1
101
102
1032
1042
1052
1062 1072
199
Days
-30 to -1
1
14
±5
29
±5
57
±5
85
±5
113
±5
141
±5
169
±5
197
±5
Time (post-dose)
-
0h2 1h 2h 4h
6h
0h2 1h 2h 4h
6h
-
-
-
-
-
-
-
Urine protein13
X
X
X
X
X
X
X
X4
24-hr urine collection16
X
X4
Visual analog scale (VAS) - Itch17
X
X
X
X
X
X
X
X
Randomization
X
Study drug administration18
X
X
X
X
X
X
X
Collect study drug/drug accountability19
X
X
X
X
X
X
X4
Dispense study medication
X
X
X
X
X
X
X
Concomitant medications20
X
X
X
X
X
X
X
X
X4
Serious adverse events
As required4
Comments
As required
Study completion information
X4
Safety follow up call
X
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X Assessment to be recorded in the clinical database
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Assessments must be performed pre-dose
3
4 Priority in the event of early discontinuation or withdrawal
5 Waist and hip circumferences (measured in cm); see the SOM for detailed explanation
6 ECG as triplicate measures
7 A serum pregnancy test will be performed at screening; a urine pregnancy test will be used at end of study.
8 Prothrombin Time/International Normalized Ratio
9 Intentionally deleted in Protocol Amendment V03
10 PK samples will be collected after patients have been fasting for at least 6 hours
11
12 Dipstick measurements/macroanalysis for specific gravity,  protein, glucose and blood will be performed. 
Microscopy, WBC, RBC and sediments will also be assessed in case of an abnormal dipstick test.
13 Urine creatinine is collected in parallel with urine albumin and urine protein for the calculation of urine albumin-
to-creatinine ratio (UACR). Note: The sample should be obtained from the 24-hour urine sample at time points 
when 24-hour collection is required.  For visits that are not preceded by a 24-hour collection or due to a 
premature discontinuation, a separate spot urine sample will be collected and processed during the visit. A 
second morning void is preferred. If sample quantify is sufficient, then the same 2nd morning void may be used 
for other urine related assessments.
14 Intentionally deleted in Protocol Amendment V03
15 At time points when 24-hour collection is done prior to a visit, a separate spot urine sample will be collected  
and processed promptly. A second (2nd) morning void is preferred. If sample quantify is sufficient, then the same 
2nd morning void may be used for other urine related assessments. 
16 24-hour urine collection should be performed as an outpatient, within 1-2 days prior to the study visit, and 
brought to the study visit, using supplied collection kit + instructions, as applicable. Quantify the urine volume 
and measure sodium, creatinine, protein, osmolality, and albumin (assays).
17 PRO: VAS assessment for itching of the skin
18 On study visit days, study drug should not be taken until after study visit assessments are completed
19 Collect unused study drug, perform drug accountability (pill count) and document compliance with protocol 
instructions
20 A thorough review of any concomitant medications (including medication name, dose, unit, frequency, and 
route) should be performed at every visit.
21It is highly recommended that PCR testing for COVID-19 be completed within 1 week prior to first dosing.
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8.1
Screening
In general, it is permissible to re-screen a patient if he/she fails the initial screening, if deemed 
feasible or necessary by the study site investigator. If a subsequent re-screen is required after 
the first permissible re-screening (i.e. an additional re-screening attempt), the case should be 
discussed with the Sponsor. Additional re-screenings may be approved on a case-by-case basis. 
Further information on re-screening is outlined in the Site Operations Manual.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason are 
considered a screen failure. Information on data collected for screening failures is available in 
the SOM.
8.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all enrolled patients. 
Details on additional data collected 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.
8.2.1
Hepatitis screen 
All patients will be screened for Hepatitis B and C. See the Site Operations Manual for details.
8.2.2
Alcohol test, Drug screen
All patients will be screened for alcohol and substances of abuse. See the Site Operations 
Manual for details.
8.3
Efficacy and Pharmacodynamics
Efficacy and Pharmacodynamics (PD) of nidufexor will be assessed based on measures 
including renal function and type 2 diabetes status.
Pharmacodynamic samples will be collected at the time points
defined in the 
Assessment Schedule. Follow the instructions outlined in the Site Operations 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. Results will remain 
blinded to the patient, investigative personnel, and blinded sponsor personnel regarding the 
associated treatment assignment throughout the study, as applicable. The number of 
samples/blood draws and total blood volume collected will not exceed those stated in the 
protocol. The PD samples will be obtained and evaluated in all patients.
8.3.1
Renal function assessments, markers of diabetic nephropathy
The following assessment will profile renal function, which are markers of diabetic 
nephropathy:

Urine albumin-creatinine ratio (UACR) at serial time points, as specified in the
Assessment Schedule

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
24-hour urinary collection at baseline and end of study, measured for albumin

Estimated glomerular filtration rate (eGFR), as determined by the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation. (Levey and Stevens 2010)

Free water clearance
8.3.2
Type 2 diabetes measures
The following assessments will be used to measure Type 2 diabetes status:

HbA1c

Weight, BMI, waist-to-hip ratio

Fasting lipid profile to include total cholesterol, HDL cholesterol, LDL cholesterol,
triglycerides and Lp(a)
8.3.3
Appropriateness of efficacy assessments
Change in albuminuria (UACR and 24-hour urine albumin excretion) and annualized rate of 
change in eGFR over the 24-week treatment period are the primary and secondary endpoints, 
respectively. These two parameters comprise the current gold standard (Levey et al 2015) for 
assessing stage and progression of proteinuric chronic kidney diseases such as diabetic 
nephropathy secondary to Type 2 Diabetes. The efficacy measures for renal function 
demonstrate the sensitivity and specificity required to serve as the gold standard diagnostic 
measures in clinical practice. (UACR sensitivity = .85 and specificity =.88; eGFR sensitivity 
=.91 and specificity =.87). The efficacy measures for type 2 diabetes are recognized by medical 
professionals, diabetes organizations, and payers as the essential surrogate and diagnostic 
measures used for patient monitoring to help patients manage the disease, reduce diabetes 
symptoms and, if well controlled, minimize or ameliorate diabetes related end organ damage.
8.4
Safety and Tolerability
Safety assessments are specified within the section below. The methods for recording the 
assessments are specified in the Site Operations Manual. The Assessment Schedule 
(Table 8-1) details the timing of when each assessment is to be performed.
For details on AE collection and reporting, refer to AE section (Section 10.1.1).
8.4.1
Physical examination
Information for all physical examinations must be included in the source documentation. 
Clinically relevant findings that are present prior to signing informed consent must be recorded 
on the appropriate CRF that captures medical history. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event must be recorded as an adverse 
event. See the SOM for details.
8.4.2
Vital signs
Vital signs include BP and pulse measurements. See the SOM for details.

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8.4.3
Laboratory evaluations
A central laboratory will be used for analysis of all safety specimens collected, and will also be 
used for a repository for select bio samples.
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators is in the laboratory manual. Repository samples may be shipped 
to a Novartis analysis laboratory or contracted analysis laboratory at any time during the study 
for processing and analysis.
Clinically notable laboratory findings are defined in Appendix 1 and the Laboratory Manual.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF/ e(CRF) page as appropriate. 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.
8.4.3.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured. A coagulation panel including PT/INR, aPTT, and fibrinogen 
will be measured.
8.4.3.2
Clinical chemistry
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, phosphate, 
bicarbonate/HCO3, LDH, amylase, lipase, creatine kinase (CK), glucose
8.4.3.3
Liver function tests
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL), 
serum albumin (Alb), prothrombin time (PT)/ international normalized ratio (INR), alkaline 
phosphatase (ALP), gamma-glutamyl transferase (γGT)
8.4.3.4
Urinalysis and renal function
Dipstick/macroanalysis measurements for specific gravity, protein, glucose and blood will be 
performed. Microscopy, WBC, RBC and sediments will also be assessed in case of an abnormal 
dipstick test.
The following assessments for renal function will also be completed:

Urine albumin-creatinine ratio (UACR) at serial time points, as specified in the 
Assessment Schedule

24-hour urinary collection at baseline and end of study, measured for albumin

Estimated glomerular filtration rate (eGFR), as determined by the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Levey and Stevens 2010).

Free water clearance

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8.4.3.5
Type 2 diabetes and glycemic control

HbA1c

Fasting lipid profile (total cholesterol, HDL-C, LDL-C, triglycerides and Lp(a))
8.4.4
Electrocardiogram (ECG)
Triplicate twelve-lead ECGs will be collected at the time-points specified in the 
Schedule of Assessments. At each time point, three serial 12-lead ECGs, at 5 minute intervals, 
will be recorded. Full details of all procedures relating to the triplicate ECG collection and 
reporting are contained in the ECG technical manual and SOM.

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

If clinically significant abnormalities are identified that were present prior to the informed 
consent signature, then it should be recorded on the relevant medical history CRF page.

After informed consent signature, any clinically significant abnormalities are recorded on 
the Adverse Events page thereafter. 

Clinically significant findings MUST be recorded on the AE CRF and should be 
discussed with the sponsor in a timely fashion.
8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing 
performed at selected time points during the study. See the Assessment Schedule, Table 8-1, 
for timing of the protocol required pregnancy testing.
Additional pregnancy testing may be performed to meet local requirements. A positive 
pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative. 
If positive, the patient will enter the post-treatment follow up period (see Section 10.1.4).
If additional pregnancy testing is needed per local requirements, those additional results will be 
kept as source documentation only.
8.4.6
Appropriateness of safety measurements
Planned safety assessments are based upon expected organ toxicity as discussed in the rationale 
of study design (Section 4.1) and risk-benefit sections (Section 4.5).
8.5
Additional assessments
8.5.1
Clinical Outcome Assessment - Visual Analog Scale (VAS)
The participant must be given the PRO measure(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Participant’s refusal to complete all or any part of a 
PRO measure should be documented in the study data capture system and should not be 
captured as a protocol deviation. Handling of protocol deviations can be modified if needed.
Participant questionnaires should be completed in the language most familiar to the participant.

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The participant should be given sufficient space and time to complete the PRO measure(s).
The site personnel or delegate should check PRO measure(s) for completeness and ask the 
participant to complete any missing responses. The responses stored electronically in the 
database will be considered the source file.
Completed measure(s) (including when using paper PRO measures and any unsolicited 
comments written by the participant) must be reviewed and assessed by the investigator for 
responses which may indicate potential AEs or SAEs before any clinical study examinations
are performed. This assessment should be documented in study source records. If AE or SAE 
are confirmed, the study investigator should not encourage the participant to change responses 
reported in the completed questionnaires. Study investigators must follow reporting instructions 
outlined in Section 10.1.1 of the study protocol.
A 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 itch imaginable itch). The score (distance from left) on 
the VAS will be recorded by the patient by marking with a line and used to test for an effect of 
nidufexor over placebo. The scale will be completed by patients as indicated in Table 8-1
(Assessment schedule).
8.5.2
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule, Table 8-1. 
Follow instructions outlined in the central laboratory manual and SOM regarding sample 
collection, numbering, processing and shipment. See Section 8.5.3.2 regarding the potential use 
of residual samples.
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the patient or the investigator.
The investigator must discontinue study treatment for a given patient if he/she believes that 
continuation would negatively impact the patient's well-being.
Study treatment MUST be discontinued under the following circumstances:

Hypersensitivity (CTCAE grade 2 or higher, CTCAE Version 5.0) reaction to nidufexor.

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 CTCAE Version 5.0 and believed to be related
to the study drug (apart from liver and renal events - see below).

A liver safety event with ALT, AST, total bilirubin and/or alkaline phosphatase elevations
mandating study treatment discontinuation. Please refer to Section 10.2.1 (Liver safety
monitoring), Table 16-1 and Table 16-2 for further instructions and monitoring.
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
A renal safety event with serum creatinine elevations mandating study treatment 
discontinuation. Please refer to Section 16.3 and Table 16-3 for further instructions and 
monitoring.

Pregnancy (see Section 10.1.4)

Any protocol deviation that results in a significant risk to the patient’s safety, in the 
opinion of the investigator.

Following emergency unblinding
If a patient presents with COVID-19 symptoms, this does not require the patient to be 
discontinued.  Please refer to Section 6.5 for further instructions.
If discontinuation of study treatment occurs, the investigator must determine the primary reason 
for the patient’s premature discontinuation of study treatment and record this information on 
the applicable CRF.
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 (Section 9.1.2). Where possible, they should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit should be performed, with 
top priority for assessments as noted in the Assessment Schedule for the EOS visit. At this final 
visit, all dispensed investigational product must be collected, and reconciled.
If they fail to complete these assessments for unknown reasons, every effort (e.g. telephone, e-
mail, letter) should be made to contact the patient/pre-designated contact as 
in Section 9.1.3 (Lost to follow-up). This contact preferably should be done according to the 
study visit schedule.
After study treatment discontinuation, the following data (at a minimum) should be collected at 
abbreviated study visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to emergency 
breaking of treatment code, Section 6.6.3.
All patients that complete the study should have a post study safety follow-up phone call 
conducted approximately 28 days after last dose. In the event of premature discontinuation from 
the study, the study staff should attempt a post study safety follow-up phone call approximately 
28 days after the patient’s last visit. In the event of withdrawal of consent, the study staff should 
follow the guidance in Section 9.1.2. The information collected is kept as source documentation. 
All SAEs reported during this time must be reported as described in Section 10.1.3.
9.1.1.1
Replacement policy
Patients will not be replaced.

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9.1.2
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs ONLY when a patient satisfies the following:

Does not want to participate in the study anymore
AND

Does not allow further collection of personal data

Note: In this situation, the investigator should make a reasonable effort (e.g.
telephone, e-mail, letter) to understand the primary reason for the patient’s decision to
withdraw his/her consent and record this information.
If withdrawal of consent occurs, then the study treatment must be discontinued, 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.
All efforts should be made to complete the allowable, necessary assessments prior to study 
withdrawal, if possible. A final evaluation at the time of the patient’s study withdrawal should 
be made as detailed in the Assessment table.
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a patient’s samples until their time of withdrawal) according to applicable law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form.
For EU and the Rest of World: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
9.1.3
Lost to follow-up
For patients whose status is unclear because they fail to complete study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient (e.g. dates of telephone 
calls, registered letters, etc.). A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Study stopping rules
Enrollment in the study will be placed on hold and safety review undertaken if any of the 
following occurs cumulatively across all of the cohorts:

Two or more study treatment-related SAEs

Two or more patients experience study treatment-related hypersensitivity reactions of
CTCAE (Version 5) Grade 3 or higher in intensity;

Three or more patients experience a similar AE as assessed by the Sponsor which was assessed
as CTCAE (Version 5) Grade 3 or higher in intensity, and study treatment-related;

The Sponsor considers that the number and/or severity of AEs, abnormal safety
monitoring tests or abnormal laboratory findings justify putting the study on hold.

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The study may resume following the safety review, if the Sponsor judges it safe to proceed. 
The study will be stopped, and no further dosing will be taken pending a full safety review, 
if the investigator and the Sponsor agree that it is unsafe to continue dosing.
9.1.5
Early study termination by the sponsor
Novartis can terminate the study 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. In making the decision to terminate, Novartis 
will always consider patient welfare and safety. Should early termination be necessary, patients 
must be seen as soon as possible (provide instruction for contacting the patient, when the patient 
should stop taking drug, when the patient should come for a final EOS visit) 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 or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. The last day of study treatment is Day 168, the day 
before the End of Study visit. Study treatment should not be taken on Day 169 – End of Study.
Study completion is defined as when the last patient completes their End of Study visit, and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
All randomized and/or treated patients should have a post-study safety follow-up contact 
conducted approximately 28 days after last administration of study treatment. The information 
collected is kept as source documentation. All SAEs reported during this time must be reported 
as described in Section 10.1.3 and the SOM. Documentation of attempts to contact the patient 
should be recorded in the source documentation.
Continuing care should be provided by the investigator and/or referring physician based on 
patient availability for follow-up. This care may include follow-up and treatment of all 
documented medical conditions according to local or global standards of care. Novartis will not 
provide nidufexor for continuing care beyond the last visit for any patient.

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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, including abnormal laboratory findings, symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual patient and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
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 findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as 
possible) (if the event is serious refer to Section 10.1.2).
1. Severity grading
Common Toxicity Criteria (CTC) AE grade (version 5.0) will be used in this study. Grade refers 
to the severity of the AE. The CTC-AE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline: 
Grade 1: Mild

Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2: Moderate

Minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL*
Grade 3: Severe

Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**
Grade 4: Life-threatening 

Life-threatening consequences; urgent intervention indicated
Grade 5: Death 

Death related to AE

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Notes: 
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 on the AE case report form but is collected as a seriousness 
criteria and is also collected in other CRFs (e.g study completion, death/survival) in the clinical 
database.
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden
2. Its relationship to the study treatment
Yes or No

If the event is due to lack of efficacy or progression of underlying illness (i.e. 
progression of the study indication) the assessment of causality will usually be ‘Not 
suspected’

The rationale for this guidance is that the symptoms of a lack of efficacy or 
progression of underlying illness are not caused by the trial drug, they happen in spite 
of its administration and/or both lack of efficacy and progression of underlying 
disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient
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 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Drug temporarily interrupted with continued follow up

Drug permanently withdrawn
6. Its outcome

not recovered/not resolved;

recovered/resolved;

recovering/resolving,

recovered/resolved with sequelae;

fatal;

unknown.

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Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 28 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
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 must 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 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Appendix 1.
Follow the instructions found in the Site Operations Manual and eCRF completion guidelines 
for data capture methodology regarding AE collection for patients.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical condition(s) which meets any one of the following 
criteria:

fatal

life-threatening
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 (please refer to the ICH-E15D Guidelines 2003).

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 of diabetic nephropathy.

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
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

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

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above
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. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse event.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective of whether a clinical event has occurred.
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 28 days after the last study visit must be reported to 
Novartis/ safety immediately, without undue delay, and under no circumstances later than 
24 hours of learning of its occurrence. Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site.
IMPORTANT: To comply with regulations, all suspected, unexpected, serious adverse 
reactions (SUSARs) occurring in a clinical trial must be reported in an expedited 
timeframe (7 or 15 days) to competent authorities.
1. Screen Failures (e.g. A patient who is screened but is not treated or randomized): SAEs 
occurring after the patient has provided informed consent until the time the patient is 
deemed a Screen Failure must be reported to Novartis
2. Randomized OR Treated patients: SAEs collected until post-study call (contact).
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.
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be 
related to the study treatment, a Chief Medical Officer & Patient Safety (CMO & PS) 

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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.
Any SAEs experienced after the 28 day period after the last study visit and/or following the last 
administration of study treatment (in the event of early discontinuation) should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign the pregnancy consent form to allow the Study 
Doctor to ask about her pregnancy. 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 should be recorded and reported by the investigator to the Novartis Chief Medical 
Office & Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the investigational/study 
treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
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.
The newborn will followed up for at least one year after birth/EDD.
10.1.5
Reporting of study treatment 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.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an AE/SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.

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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration (DAR) eCRF 
(Yes/No)
Document in AE 
eCRF
Complete SAE 
form
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 the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
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.
Please refer to Section 16.2 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Once a participant has been exposed to study treatment, every liver event defined in
Section 16.2 should be followed up by the investigator or designated personnel, as summarized 
below. Additional details on actions required in case of liver events are outlined in Section 16.2
Repeat liver chemistry tests (ALT, AST, TBL, Direct Bilirubin, PT/INR, ALP and γ-GT) to 
confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be promptly available from the central laboratory, then the repeats can also be 
performed at a local laboratory to monitor the safety of the patient. If a liver event is 
subsequently reported, any local liver chemistry tests previously conducted that are 
associated with this event should have results recorded on the appropriate CRF 

If the initial elevation is confirmed, close observation of the patient will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the discontinuation of study treatment 
information located in Section 9), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event 

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy 

Obtaining a more detailed history of symptoms and prior or concurrent diseases. 

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
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.

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 liver event CRF.
Refer to the Site Operations Manual for additional details.
10.2.2
Renal safety monitoring
Once a participant has been exposed to study treatment, the following two categories of 
abnormal renal laboratory alert values should be assessed during the study period:
Serum creatinine increase ≥25% compared to baseline during normal hydration status. Baseline 
serum creatinine is determined as the mean of two serum creatinine measurements (e.g. at 
screening and pretreatment).

Albumin-creatinine ratio (UACR) increase ≥ 2X baseline
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment.
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff as summarized 
in Table 16-3 .
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the investigator or designated personnel as summarized in Section 16.3.
10.2.3
Fat soluble vitamin deficiency 
Although no histological or laboratory findings of fat soluble vitamin (A, D and E) deficiencies 
were observed in the chronic toxicology studies, this has not been assessed in humans and is a 
theoretical risk due to sustained partial suppression of bile acid synthesis in response to 
nidufexor.  The following treatment emergent AEs and laboratory findings should prompt 
consideration of the corresponding vitamin deficiency:

Worsening night vision, xerophthalmia and new ichthyosis: Vitamin A deficiency

Hypocalcemia and symptoms of secondary hyperparathyroidism: Vitamin D deficiency

Vertical gaze palsy, ataxia and hyporeflexia: Vitamin E deficiency
A vitamin deficiency identified during an AE evaluation should be reported in the Adverse 
Events CRF and managed according to the local standard of care.  Deficiency of one fat soluble 
vitamin should prompt an assessment of the other two indicated above.

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11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator study staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies by generating appropriate error messages on the eCRFs, 
which allow modification and/or verification of the entered data by the investigator staff.
The investigator is responsible for assuring that the data entered into the eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
After final 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 (Table 8-1) 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.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator study staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior 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.
Randomization codes and data about all study treatment(s) dispensed to the patient will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis (or a 
designated CRO) at specific timelines.
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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11.3
Site monitoring
Before study initiation, at a site initiation visit, virtual training event, or at an investigator’s 
meeting, a Novartis delegated CRO representative will review the protocol and data capture 
requirements (i.e. eCRFs) 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 field monitor will check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis delegated CRO/CRA organization. Additionally, a central 
analytics organization may analyze data to identify risks and trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
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. Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs. The investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
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12.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment received.
The safety analysis set will include all patients who 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 PK data.
The PD analysis set will include all patients with available PD data and no protocol deviations 
with relevant impact on PD data.
Protocol deviation impact will be documented appropriately and assessed by the Sponsor study 
team, including the Medical and Study Leads with input from of the trial team. 
12.2
Patient demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the Safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles may also be presented.
Relevant medical histories and current medical conditions at baseline will be listed by treatment 
group, system organ class and preferred term.
12.3
Treatments
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by treatment group according to the WHO Drug Reference List, 
which employs the Anatomical Therapeutic Chemical classification system. 
12.4
Analysis of the primary endpoint(s)
The primary objective of this study is to assess the safety and tolerability of nidufexor as well 
as the efficacy of nidufexor on albuminuria in patients with diabetic nephropathy during
24 weeks of treatment.
12.4.1
Definition of primary endpoint(s)
For analytical purposes, all safety data, including laboratory measurements, vital signs, adverse 
events, ECG, are considered primary endpoints.
For efficacy evaluation, log-transformed ratios to baseline UACR and 24-hour urine albumin 
excretion at Week 24 are the primary endpoints.
12.4.2
Statistical model, hypothesis, and method of analysis
12.4.2.1 Safety endpoints
For all safety analyses, the safety set will be used. Safety and tolerability data will be 
summarized. Formal statistical analysis will not be performed on the safety and tolerability data.

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Adverse events
All information obtained on AEs will be displayed by treatment group and patient.
The number (and percentage) of patients with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of treatment but increased 
in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum CTCAE grade
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs and AEs leading to discontinuation.
A patient with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class.
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.
12-lead ECG
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 abnormalities 
will be flagged. Summary statistics will be provided by treatment and visit/time.
12.4.2.2 Efficacy and/or Pharmacodynamic Endpoints
For all efficacy PD analyses, the PD set will be used.
A repeated measures Analysis of Covariance (ANCOVA) will be performed for log-
transformed ratio to baseline UACR measured at each visit. The model will include effects for 
log-transformed baseline, treatment, visit, treatment by visit interaction and visit by 
log-transformed baseline interaction. An unstructured variance-covariance matrix will be used 
to account for correlation among multiple measurements from the same patient and variance 
heterogeneity.
Similarly an ANCOVA with treatment as the classification factor and log-transformed baseline 
as the covariate will be conducted for log-transformed ratio to baseline 24-hour urine albumin 
excretion.
Point estimates, the associated confidence intervals as well as the p-values for treatment 
difference at each visit will be provided within the ANCOVA framework. The null hypothesis 
of no treatment difference in UACR or 24-hour urine albumin excretion will be tested at the 
one-sided 0.1 significance level. A treatment difference of at least 25% in favor of nidufexor 
will be considered clinically significant.

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12.4.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed.
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.
12.4.4
Sensitivity and Supportive analyses
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Log-transformed ratio to baseline for eGFR, free water clearance, HbA1c and fasting lipid 
profiles (total cholesterol, HDL, LDL, triglycerides and Lp(a)) as well as change from baseline 
in weight, BMI and WTH ratio will be analyzed using the same repeated measures ANCOVA 
described in Section 12.4.2 with baseline in lieu of log-transformed baseline as a covariate for 
change from baseline 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.
12.5.2
Pharmacokinetics
Nidufexor 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 8.5.2 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, and AUClast from the plasma concentration-time data. The linear 
trapezoidal rule will be used for AUC calculation.
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12.5.5
PK/PD relationships
The relationship between key efficacy/PD parameters (including, but not limited to UACR, 
24-hour urine albumin excretion and eGFR and nidufexor PK parameters (Cmax and AUC0-6)
may be explored using a graphical approach and descriptive statistics may be provided.
Additional statistical analysis such as regression may be performed, if necessary. Modeling
approach may also be used to explore the PK/PD interactions.
12.5.6
Patient reported outcomes
Change from baseline itch VAS measurements will be analyzed using the same repeated 
measures ANCOVA described in Section 12.4.2.
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12.7
Interim analyses
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Data from 50 patients per arm will provide 72% power to detect the combination of a drug 
effect on UACR at Week 24 that is both clinically significant (defined as an estimated relative 
reduction of at least 25% compared to placebo) and statistically significant (defined as ≥90% 
probability of a > 0% reduction relative to placebo) if the true placebo adjusted reduction is 
30%. The figure below shows the probability of decision making for various true drug effects 
at a sample size of 50 patients per arm. A “Go” decision will be made if both the clinical 
significance and the statistical significance criteria are met while a “No Go” decision will be 
made if neither the clinical significance nor the statistical significance criterion is met. 
Otherwise it will be an indeterminate situation requiring further information to be obtained 
before a decision can be made.
The power calculations were performed using simulations based on log-transformed ratio to 
baseline analysis. The standard deviation was assumed to be 0.6, estimated from published 
studies in the literature (Hanes et al 2018). Treatment comparison was based on a one-sided two 
sample t-test.
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13
Ethical considerations and administrative procedures
13.1
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 CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
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. 
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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.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible databases such as clinicaltrials.gov and 
as required in EudraCT and/or as required by local country registries. In addition, after study 
completion (defined as last patient last visit) and finalization of the study report the results of 
this trial will be submitted for publication and posted in a publicly accessible database of clinical 
trial results, such as the Novartis clinical trial results website and all required Health Authority 
websites (e.g. Clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
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 including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the 
protocol, other than the purpose of the study. If despite this interdiction prohibition, data, 
information, observation would be incidentally collected, the investigator shall immediately 
disclose it to Novartis and not use it for any purpose other than the study, except for the 
appropriate monitoring on study participants.
Investigators 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.

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14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for patient safety 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, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request.
Bakris GL, Agarwal R, Chan JC, et al (2015) Effect of finerenone on albuminuria in patients 
with diabetic nephropathy: a randomized clinical trial. JAMA; 314(9):884-94.
Chalasani N, Regev A (2016) Drug-induced liver injury in patients with preexisting chronic 
liver disease in drug development: how to identify and manage? Gastroenterology; 
151(6):1046-51.
de Zeeuw D, Coll B, Andress D, et al (2014) The endothelin antagonist atrasentan lowers 
residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol; 
25(5):1083-93.
American Diabetes Association (2010), Diabetes Care; 33 (1 Suppl):62-69.
Gai Z, Chu L, Xu Z, et al (2017) Farnesoid X receptor activation protects the kidney from 
ischemia-reperfusion damage. Sci Rep; 7:9815.
Gai Z, Gui T, Hiller C, et al (2016) Farnesoid X receptor protects against kidney injury in 
uninephrectomized obese mice. J Biol Chem; 291(5):2397-411.
Gheith O, Farouk N, Nampoory N, et al (2016) Diabetic kidney disease: world wide 
difference of prevalence and risk factors. J Nephropharmacol; 5(1):49-56.
Hanes R, Judge PK, Staplin N, et al (2018) Effects of Sacubitril/Valsartan versus Irbesartan in 
patients with chronic kidney disease. Circulation; 138(15):1505-1514
International Conference on Harmonization (2003) Post-approval safety data management: 
definitions and standards for expedited reporting ED2 (Internet) Available from: 
<http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Ste
p4/E2D_Guideline.pdf> (Accessed 02 July 2018).
Inzucchi SE, Bergenstal RM, Buse JB, et al (2015) Management of hyperglycemia in type 2 
diabetes, 2015: a patient-centered approach: update to a position statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care; 
38(1):140-9.
Levey AS, Becker C, Inker LA (2015) Glomerular filtration rate and albuminuria for 
detection and staging of acute and chronic kidney disease in adults: a systematic review. 
JAMA; 313(8):837-46.
Levey AS, Stevens LA (2010) Estimating GFR using the CKD Epidemiology Collaboration 
(CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence 
estimates, and better risk predictions. Am J Kidney Dis; 55(4):622-7.
Ma L, Yan M, Kong X, et al (2018) Association of EPHX2 R287Q polymorphism with 
diabetic nephropathy in chinese type 2 diabetic patients. J Diabetes Res; 2786470.
Marquardt A, Al-Dabet MM, Ghosh S, et al (2017) Farnesoid X receptor agonism protects 
against diabetic tubulopathy: potential add-on therapy for diabetic nephropathy. J Am Soc 
Nephrol; 28(11):3182-9.
Okusa MD, Davenport A (2014) Reading between the (guide)lines--the KDIGO practice 
guideline on acute kidney injury in the individual patient. Kidney Int; 85(1):39-48.

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Pradeepa R, Mohan V (2017) Prevalence of type 2 diabetes and its complications in India and 
economic costs to the nation. Eur J Clin Nutr; 71(7):816-24.
Umanath K, Lewis JB (2018) Update on diabetic nephropathy: core curriculum 2018. Am J 
Kidney Dis; 71(6):884-95. 
Whelton PK, Carey RM, Aronow WS, et al (2018) 2017 ACC/AHA/AAPA/ABC/ACPM/ 
AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, 
and Management of High Blood Pressure in Adults: Executive Summary. Hypertension;
71:e13-e115.
Zhang X, Huang S, Gao M, et al (2014) Farnesoid X receptor (FXR) gene deficiency impairs 
urine concentration in mice. Proc Natl Acad Sci USA; 111(6):2277-82.
Zhao K, He J, Zhang Y, et al (2016) Activation of FXR protects against renal fibrosis via 
suppressing Smad3 expression. Sci Rep;(6):37234.

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Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Please refer to the Central Laboratory Manual for a list of clinically significant laboratory values.

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16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS

3 x ULN < ALT / AST ≤ 5 x ULN

1.5 x ULN < TBL ≤ 2 ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

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
Chalasani and Regev 2016

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Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γ-GT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
for patients with normal 
baseline: > 8 × ULN
For patients with elevated 
baseline> 8 X ULN or > 500 U/L 
whichever comes first

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
For patients with normal 
baseline: > 5 to ≤ 8 × ULN
For patients with elevated 
baseline: >5 to ≤ 8 x ULN or
>5X ULN to ≤ 500 U/L 
whichever comes first

Repeat LFT within 48 
hours

If elevation persists, 
continue follow-up 
monitoring

If elevation persists for 
more than 2 weeks, 
discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied by 
symptomsb

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation 
of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)

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Criteria
Actions required
Follow-up monitoring
> 2 × ULN (in the absence of
known Gilbert syndrome)

Repeat LFT within 48
hours

If elevation persists,
discontinue the study drug
immediately

Hospitalize if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN (patient is
asymptomatic)

Repeat LFT within the next
week

If elevation is confirmed,
initiate close observation
of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study
treatment immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment
interruption or
discontinuation

Hospitalization if clinically
appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
Chalasani and Regev 2016

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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase 25 – 49% compared to 
baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 50% 
compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption
Consider patient hospitalization /specialized 
treatment
Urine Event
Albumin-creatinine ratio increase ≥2 fold from 
baseline value
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation
Blood glucose (fasting)
Perform serum creatinine, UACR
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, UACR
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed
Monitor patient regularly (frequency at investigator’s discretion) until either:
Event resolution: sCr within 10% of baseline or albumin-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or albumin-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.
Bakris et al 2015, de Zeeuw et al 2014