Clinical trial NCT02678000
Conditions: Chronic Kidney Disease (CKD)
Sponsor: Novartis Pharmaceuticals
Start date: 2017-03-10; Completion date: 2018-10-11
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blind, parallel group, placebo-controlled study, in two sequential parts that evaluated the renal safety, tolerability and pharmacokinetics of LHW090 in patients with moderately impaired renal function.

Detailed description:

Arms: arm 1: For Part 1, patients will receive 3 doses of LHW090 once daily with escalating doses every 4 days for a total 12 days of treatment.

For Part 2, patients will receive LHW090 once daily for 4 weeks. arm 2: For Part 1, patients will receive matching placebo once daily for 12 days. For Part 2, patients will receive matching placebo once daily for 4 weeks.
Interventions: intervention 1: LHW090 intervention 2: Placebo
Intervention descriptions: intervention 1: LHW090 is orally administered intervention 2: Matching placebo of LHW090

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
LHW090
Clinical Trial Protocol CLHW090X2102
A two part randomized, double-blind, parallel-group, 
placebo-controlled study to evaluate the renal safety, 
tolerability and pharmacokinetics of LHW090 in patients 
with moderately impaired renal function on angiotensin 
receptor blockers
Document type:
Amended Protocol Version
EUDRACT number:
2015-004570-15
Version number:
v04 (Clean)
Development phase:
II
Release date:
07-Aug-2017
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols...........................................................................9
Protocol synopsis...............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Study purpose ........................................................................................................23
2
Study objectives.................................................................................................................23
2.1
Primary objective(s)...............................................................................................23
2.2
Secondary objective(s)...........................................................................................23
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale of study design.......................................................................................27
3.3
Rationale of dose/regimen, duration of treatment .................................................28
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................29
3.6
Risks and benefits..................................................................................................29
4
Population..........................................................................................................................30
4.1
Population..............................................................................................................30
4.2
Inclusion criteria ....................................................................................................31
4.3
Exclusion criteria...................................................................................................31
5
Restrictions for study subjects...........................................................................................34
5.1
Contraception requirements...................................................................................34
5.2
Prohibited treatment...............................................................................................34
5.3
Dietary restrictions and smoking...........................................................................35
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5.4
General restrictions................................................................................................35
6
Treatment...........................................................................................................................36
6.1
Study treatment......................................................................................................36
6.1.1
Investigational treatment.......................................................................36
6.2
Treatment arms......................................................................................................36
6.3
Permitted dose adjustments and interruptions of study treatment.........................36
6.4
Treatment assignment............................................................................................37
6.5
Treatment blinding.................................................................................................37
6.6
Emergency breaking of assigned treatment code ..................................................38
6.7
Treatment exposure and compliance .....................................................................38
6.8
Recommended treatment of adverse events ..........................................................39
6.9
Rescue medication.................................................................................................39
6.10
Concomitant treatment...........................................................................................39
7
Discontinuation and study completion ..............................................................................39
7.1
Discontinuation of study treatment........................................................................39
7.2
Study completion and post-study treatment ..........................................................40
7.2.1
Lost to follow-up...................................................................................40
7.3
Withdrawal of consent...........................................................................................40
7.4
Study Stopping rules..............................................................................................41
7.5
Early study termination..........................................................................................41
8
Procedures and assessments ..............................................................................................42
8.1
Informed consent procedures.................................................................................52
8.2
Subject demographics/other baseline characteristics.............................................52
8.3
Efficacy / Pharmacodynamics ...............................................................................52
8.4
Safety.....................................................................................................................52
8.4.1
Physical examination ............................................................................52
8.4.2
Vital signs..............................................................................................53
8.4.3
Height and weight .................................................................................53
8.4.4
Laboratory evaluations..........................................................................53
8.4.5
Electrocardiogram (ECG) .....................................................................54
8.4.6
Pregnancy and assessments of fertility .................................................54
8.5
Pharmacokinetics...................................................................................................55
8.6
Other assessments..................................................................................................55
9
Safety monitoring..............................................................................................................56
9.1
Adverse events.......................................................................................................56
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9.2
Serious adverse event reporting.............................................................................57
9.2.1
Definition of SAE .................................................................................57
9.2.2
SAE reporting........................................................................................58
9.3
Liver safety monitoring .........................................................................................59
9.4
Renal safety monitoring.........................................................................................62
9.5
Pregnancy reporting...............................................................................................63
9.6
Prospective suicidality assessment ........................................................................64
9.7
Early phase safety monitoring ...............................................................................64
10 Data review and database management.............................................................................65
10.1
Site monitoring ......................................................................................................65
10.2
Data collection.......................................................................................................65
10.3
Database management and quality control............................................................66
10.4
Data Monitoring Committee..................................................................................66
10.5
Adjudication Committee........................................................................................66
11 Data analysis......................................................................................................................67
11.1
Analysis sets ..........................................................................................................67
11.2
Subject demographics and other baseline characteristics......................................67
11.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................67
11.4
Analysis of the primary variable(s) .......................................................................67
11.4.1
Variable(s).............................................................................................67
11.4.2
Statistical model, hypothesis, and method of analysis..........................67
11.4.3
Handling of missing values/censoring/discontinuations.......................68
11.4.4
Supportive analyses...............................................................................68
11.5
Analysis of secondary and exploratory variables ..................................................69
11.5.1
Efficacy / Pharmacodynamics...............................................................69
11.5.2
Safety.....................................................................................................69
11.5.3
Pharmacokinetics ..................................................................................70
11.5.5
Other assessments .................................................................................70
11.6
Sample size calculation..........................................................................................70
11 7
Power for analysis of key secondary variables
70
12 Ethical considerations........................................................................................................71
12.1
Regulatory and ethical compliance........................................................................71
12.2
Responsibilities of the investigator and IRB/IEC..................................................72
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12.3
Publication of study protocol and results...............................................................72
13 Protocol adherence ............................................................................................................72
13.1
Protocol Amendments ...........................................................................................72
14 References .........................................................................................................................74
15 Appendix 1: (Blinding table).............................................................................................75
16 Appendix 2: (ARB dosing)................................................................................................77
List of tables
Table 8-1
Assessment Schedule, Part 1.................................................................42
Table 8-2
Assessment schedule Part 2, Patients 1-16 ...........................................46
Table 8-3
Assessment Schedule, Part 2 Patients 17 to 72, approximately............50
Table 9-1
Liver Event and Laboratory Trigger Definitions ..................................60
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers...61
Table 9-3
Specific Renal Alert Criteria and Actions.............................................63
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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
ASL-MRI
arterial spin labeling magnetic resonance imaging
AST
aspartate aminotransferase
ANP
atrial natriuretic peptide
b.i.d.
twice a day
BMI
Body Mass Index
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CKD
chronic kidney disease
CRF
Case Report/Record Form (paper or electronic)
CRI
chronic renal insufficiency
CRO
Contract Research Organization
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
ELISA
Enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
FIH
first in human
GCP
Good Clinical Practice
hr
hour
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board


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IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LLN
lower limit of normal
mg
milligram(s)
ml
milliliter(s)
o.d.
once a day
NEP
neprilysin
p.o.
oral
PA
posteroanterior
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RBC
red blood cell(s)
RBF
renal blood flow
REB
Research Ethics Board
RHT
resistant hypertension
SAE
serious adverse event
SD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma concentration-time curve from time zero to time 't' 
where t is a defined time point after administration [ng x hr / mL]
AUClast
The area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration [ng x hr / mL]
AUCtau
The area under the plasma concentration-time curve from time zero to the end 
of the dosing interval tau [ng x hr / mL]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [ng / mL]
Tmax
The time to reach the maximum concentration after drug administration [hr]


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Protocol No. CLHW090X2102
Protocol synopsis
Protocol number
LHW090X2102
Title
A two part randomized, double-blind, parallel-group, placebo-controlled study 
to evaluate the renal safety, tolerability and pharmacokinetics of LHW090 in 
patients with moderately impaired renal function on angiotensin receptor 
blockers
Brief title
Study of the safety, tolerability, and pharmacokinetics of LHW090 in patients 
with moderately impaired renal function
Sponsor and Clinical 
Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
To determine whether LHW090 displays the clinical safety profile to support 
further development in patients with moderately impaired renal function.
Primary Objective(s)
Part 1: To assess the safety and tolerability of doses of LHW090 in patients 
with moderate renal impairment to inform design of Part 2.
Part 2: To assess the renal safety of LHW090 in patients with moderate renal 
impairment.
Secondary 
Objectives
All Parts: To evaluate the pharmacokinetics of LHW090 and its active 
metabolite, LHV527, in patients with moderate renal impairment.
All Parts: To assess the safety and tolerability of LHW090 relative to placebo 
in patients with moderate renal impairment.
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study, 
in two sequential parts to evaluate the renal safety, tolerability and 
pharmacokinetics of LHW090 in patients with moderately impaired renal 
function. 
Population
Patients aged 40 to 85 (inclusive) with an estimated glomerular filtration rate 
(eGFR) between 30 and 59 mL/min/1.73m2 at screening (inclusive) on a 
stable dose of an angiotensin receptor blocker (ARB) will be considered for 
this study.
Inclusion criteria

Written informed consent must be obtained before any assessment is 
performed.

Male and female patients, age 40 to 85 years of age (inclusive) on a 
stable (at least 1 month) dose of an angiotensin receptor blocker (ARB) 
and stable moderately impaired renal function, defined here as an eGFR 
30-59 mL/min/1.73m2 (inclusive) using the 4 variable MDRD Study 
equation for at least 3 months.

At screening, vital signs (systolic and diastolic blood pressure and pulse 
rate) will be assessed in the sitting position after the patient has rested 
for at least five minutes, and again after three minutes in the standing 
position. Sitting vital signs should be within the following ranges:
oral body temperature between 35.0-37.5 °C
systolic blood pressure, 100-170 mm Hg
diastolic blood pressure, 50-100 mm Hg
pulse rate, 50 - 95 bpm


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Patients should be excluded if their standing vital signs (relative to 
sitting) show findings which, in the opinion of the Investigator, are 
associated with clinical manifestation of postural hypotension (i.e. 
absence of any other cause). The Investigator should carefully 
consider enrolling patients with either a > 20 mm Hg decrease in 
systolic or a >10 mm Hg decrease in diastolic blood pressure, 
accompanied by a > 20 bpm increase in heart-rate (comparing 
standing to sitting results).

Patients must weigh at least 50 kg to participate in the study, and must 
have a body mass index (BMI) within the range of 18 - 40 kg/m2. BMI = 
Body weight (kg) / [Height (m)]2.

Able to communicate well with the investigator, to understand and comply 
with the requirements of the study.
Exclusion criteria

History of angioedema, drug-related or otherwise, as reported by the 
patient.

Use of angiotensin converting enzyme inhibitors (ACE inhibitors), 
mineralocorticoid receptor antagonists (e.g. spironolactone or 
eplerenone), aliskiren, vasopressin receptor antagonists (e.g. tolvaptan), 
or oral alkalinizing agents (e.g. sodium and potassium citrate or Shohl's 
solution).
Note: Patients who discontinue their ACE-inhibitor and substitute with 
an angiotensin receptor blocker (ARB) may be eligible to be re-
screened provided their medication regimen has been stable for at 
least 1 month and their renal function has been stable for at least 3 
months. Any substitutions or changes to a patient's medication 
regimen must be done under the guidance of the patient's treating 
physician.

History of a renal transplant.

Known current significant left ventricular outflow obstruction, such as 
obstructive hypertrophic cardiomyopathy or significant severe valvular 
disease on prior or current echocardiogram.

A serum potassium ≤ 3.5 mmol/l or ≥ 5.5 mmol/l at screening.

A previous history or previously diagnosed kidney disorder which, in the 
opinion of the Investigator, may place the patient at higher risk from 
his/her participation in the study or is likely to confound the interpretation 
of the study results. Such kidney disorders may include renal cystic 
disease such as autosomal dominant polycystic kidney disease (history 
of an incidental asymptomatic acquired renal cyst(s) is excepted); 
obstructive uropathy; renal stone(s) in the past 2 years; chronic interstitial 
nephropathy; drug-induced nephropathy; residual renal insufficiency 
following an episode of acute kidney injury or acute tubular necrosis 
related to renal atheroembolic disease, septic shock or ischemic 
nephropathy; renal tubular acidosis requiring treatment; nephrotic 
syndrome or nephrotic range proteinuria; or renal artery stenosis.

Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant.
Investigational and 
reference therapy

LHW090
Efficacy/PD 
assessments

Not applicable


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Safety assessments
!
Vital signs
!
Hematology
!
Chemistry
!
Urinalysis
!
ECG evaluation
!
Physical exam
!
Columbia-Suicide Severity Rating Scale
!
AE/SAEs
Other assessments
!
Pharmacokinetics
Data analysis
A sample size of 12 patients (2:1 active: placebo) will be considered for Part 
1 to assess the safety and tolerability.
A sample size of 72 patients (3:3:2 high dose:low dose:placebo) will be 
considered for Part 2 to assess the changes in serum creatinine.
All data for vital signs, ECG evaluations, hematology, blood chemistry and 
urinalysis will be listed for each patient and summarized by descriptive 
statistics per part, treatment group, and for visit/ time interval where 
appropriate.
Summary tables with the number, percentage, and severity of adverse events 
will be provided to assess safety and tolerability per part and treatment 
group.
Proportion of patients change from baseline serum creatinine <0.3 mg/dL and 
≥ 0.3 mg/dL will be evaluated and summarized.
For Part 2, a Chi-square test will be performed to compare the proportion of 
patients who develop a renal event (a reproducible increase from baseline 
serum creatinine of ≥ 0.3 mg/dL confirmed on a repeat central laboratory
measurement within 24-48 hours) in the LHW090 and placebo groups. For 
this endpoint, baseline is defined as the average of all available pre-dose 
measurements coming from central laboratory results.
All PK
 data will be listed and summarized by part, treatment, 
and visit/timepoint. 
Key words
Moderate renal impairment
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1
Introduction
1.1
Background
The adequate and timely control of blood pressure in patients diagnosed with hypertension is 
an important public health goal. Hypertension is a major risk factor for heart disease, kidney 
disease and stroke. Despite the available medications that treat high blood pressure, 
hypertension remains uncontrolled in more than 50% of patients (Valderrama et al 2012). 
The phenomenon of resistant hypertension (RHT) was defined by JNC 7 in 2003 as blood 
pressure that was uncontrolled despite treatment with three or more anti-hypertensive agents, 
one of which is a diuretic (Chobanian et al 2003). More recently, the European Society for 
Cardiology (ESC) and the joint American Society of Hypertension and the International 
Society of Hypertension (ASH/ISH) have issued similar definitions (Mancia et al 2013; 
Weber et al 2014). Patients with RHT are more likely to display the sequelae of uncontrolled 
hypertension such as an enlarged heart or kidney damage. Depending on the population 
examined and the level of medical screening, it has been estimated that 5 to 30% of the 
hypertensive population may meet this definition (James et al 2014); however, the prevalence 
is likely to rise with aging of the population and the increasing incidence of diabetes, obesity, 
and chronic kidney disease.
The natriuretic peptide (NP) family mediates a wide-ranging number of potentially salutary 
effects on the heart, vasculature, kidney and other target tissues. The NP family is comprised 
of three structurally related peptide hormones-atrial natriuretic peptide (ANP), B-type 
natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP and BNP are primarily 
expressed in the heart and released by cardiomyocytes in response to mechanical stretch. 
Binding of natriuretic peptides to their receptors, NPR-A and NPR-B, activates a guanylate 
cyclase resulting in increased intracellular levels of cGMP. Physiologically, NPs have been 
shown to stimulate the excretion of sodium and water by the kidneys, induce relaxation of 
vascular smooth muscle cells, and have anti-fibrotic and anti-hypertrophic effects on the heart. 
ANP is largely degraded by a transmembrane endopeptidase called neprilysin (NEP) while a 
smaller fraction is removed from the circulation by binding to a clearance receptor, NPR-C. 
Studies suggest that circulating levels of ANP can be increased by inhibiting NEP. 
Thus, NEP inhibitors are a potential therapeutic target for the treatment of hypertension. 
Clinically, NEP inhibitors given in combination with an angiotensin receptor blocker (ARB) 
have been shown to reduce blood pressure in patients with essential hypertension 
(Bavishi et al 2015). NEP inhibition in combination with an ARB may represent an attractive 
therapeutic option for patients with RHT.
 
 
 
Chronic kidney disease is 
recognized as a risk factor for resistant hypertension and it is estimated that 20-25% of 
patients with RHT have some degree of renal impairment (Calhoun et al 2008). The purpose 
of the current study is to provide data on the clinical safety, tolerability and pharmacokinetics 
of 4 week dosing of LHW090 in patients with moderate renal impairment.
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1.1.1
Relevant data summary
The most relevant data for the present study are summarized in the sections below. 
For detailed information, please refer to the Investigators Brochure.
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1.2
Study purpose
To determine whether LHW090 displays the clinical safety profile to support further 
development in patients with moderately impaired renal function.
2
Study objectives
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)
!
Part 1: To assess the safety and 
tolerability of doses of LHW090 in 
patients with moderate renal impairment 
to inform design of Part 2.
!
Part 2: To assess the renal safety of 
LHW090 in patients with moderate renal 
impairment.
!
Part 1: Safety endpoints (including 
adverse events and serious adverse 
events) up to and including the EOS; 
plasma pharmacokinetic parameters, and 
serum creatinine
!
Part 2: Proportion of patients who 
develop a renal event as defined by a 
≥0.3 mg/dL increase in serum creatinine 
from baseline
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)
!
All Parts: To evaluate the 
pharmacokinetics of LHW090 and its 
active metabolite, LHV527, in patients 
with moderate renal impairment. 
!
Plasma pharmacokinetic parameters 
(Cmax, Tmax, AUC)
!
All Parts: To assess the safety and 
!
Safety endpoints (including adverse 
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tolerability of LHW090 relative to 
placebo in patients with moderate renal 
impairment.
events and serious adverse events) up to 
and including the EOS
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3
Investigational plan
3.1
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study, in two sequential 
parts to evaluate the renal safety, tolerability and pharmacokinetics of LHW090 in patients 
with moderately impaired renal function. Patients aged 40 to 85 (inclusive) with an estimated 
glomerular filtration rate (eGFR) between 30 and 59 mL/min/1.73m2 at screening (inclusive) 
on a stable dose of an angiotensin receptor blocker (ARB) will be considered for this study.
The study will be conducted in two parts. Part 1 will enroll a single cohort of 12 patients who 
will be randomized in a 2:1 ratio of LHW090 to placebo. An intra-patient dose escalation 
scheme will be employed starting at a 
 daily dose for the first four day cycle, and 
then the dose will be escalated 
 once daily for the next four days and then 
 
once daily for four days. If a renal event occurs during the treatment periods of the study or 
any of the individual stopping criteria are met, then dosing will be stopped for that individual 
patient. For the purposes of this study, a renal event will be defined as a reproducible increase 
from baseline serum creatinine of ≥ 0.3 mg/dL confirmed on a repeat measurement within 
24-48 hours (Mehta et al 2007, Khwaja 2012). Throughout the study, any serum creatinine 
assessment that is increased ≥0.3 mg/dL compared to baseline will trigger a repeat assessment 
of serum creatinine after 24 hours to confirm whether criterion for a renal event is met.
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Part 1 is comprised of a screening period, a baseline period, a treatment period and an end of 
study evaluation. Patients who meet the eligibility criteria at screening will be domiciled on 
Day -2 for diet stabilization. Laboratory assessments performed at screening will be used to 
determine patient eligibility for the trial. On Day -1, safety and baseline assessments of renal 
function 
 will be performed 
 
 Starting on Day 1, the patient 
will begin treatment with study drug or placebo, and dose will escalate two times for a total 
dosing period of 12 days. Pharmacokinetic 
 assessments will be 
collected as shown in the assessment schedule. After completing dosing, patients will be 
monitored for an additional 48 hours after which they will be discharged at the discretion of 
the investigator. The patient will be asked to return to the site approximately one week later 
for end of study assessments.
 
 
Part 2 will be double-blind and placebo-controlled to assess the safety and tolerability of 2 
dose levels of LHW090, 
 LHW090 once daily for 4 weeks. 
Approximately 72 patients will be enrolled in Part 2 and randomized in a 3:3:2 ratio to 
LHW090
and placebo. Therefore, in Part 2, approximately 27 patients are 
expected to be randomized to each of the active doses, and 18 patients are expected to be 
randomized to placebo. Randomization will be stratified by ARB dose (see Appendix 2) at the 
time of enrollment. Patients who meet the eligibility criteria at screening will have baseline 
assessments of renal function (serum creatinine, urinalysis) collected on Day -1 prior to 
beginning the treatment phase on Day 1. Centrally-analyzed laboratory assessments 
performed at screening will be used to determine patient eligibility for the trial. 
The first 16 patients in Part 2 will be domiciled for the first 7 days of dosing to ensure careful 
monitoring of renal function and pharmacokinetic parameters (see Table 8-3) On Day 7 at the 
investigator’s discretion, the patients will be released to complete the remaining 3 weeks of 
the treatment phase.
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3.2
Rationale of study design
The primary objective(s) of this study is to collect information pertaining to the safety 
(including renal safety) and tolerability of LHW090 in patients with moderate renal 
impairment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chronic kidney 
disease (CKD) is a risk factor for the development of drug-related nephrotoxicity 
(Loghman-Adham et al 2012)
 
 
 
 
 
A two part sequential design was chosen to assess the safety and tolerability of doses lower
than the expected therapeutic doses of LHW090 in renal patients before starting Part 2 which 
will test LHW090 
daily for 4 weeks. For Part 1, an intra-patient dose 
escalation scheme was selected in order to reduce the number of patients and shorten the 
duration 
 Two up-titrations after four days of once daily doses in 
Part 1 were chosen 
 
Patients in Part 1 will be domiciled beginning on Day -2 and for 
at least 48 hours after the last dose so that renal function and PK can be closely monitored as 
the dose is escalated to the target dose. 
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In Part 2, 4 weeks dosing was chosen 
 
 to support future studies. 
Patients will be randomized in a 3:3:2 ratio to LHW090 
 or placebo, 
respectively, in order to have more patients exposed to repeat doses of LHW090 than to 
placebo and thus maximize the information collected with active treatment. The first 16
patients in Part 2 will be domiciled beginning on Day -1 and until Day 7 so that renal function 
and PK can be closely monitored. On Day 7 at the investigator’s discretion, patients will be 
released to complete the remaining 3 weeks of the treatment phase.
An adaptive strategy will be used in Part 2 to efficiently identify whether the LHW090 
 
administered for 4 weeks are safe and well-tolerated in 
this renally impaired population. A sponsor open, investigator-subject double-blind design 
was chosen to enable earlier detection of any potential safety issues in Part 2 and to allow 
opportunities for adaptive changes if safety or tolerability issues arise. 
Since ARB therapy has been associated with increases in serum creatinine levels, which may 
be more pronounced in CKD patients; randomization for Part 2 will be stratified by ARB 
dose--"low" versus "usual" as described in Appendix 2 in order to balance the influence of 
ARB dose on serum creatinine. A cross-over design was not considered in order to minimize 
the potential for carry-over effects. A double-blind study was chosen to reduce bias.
3.3
Rationale of dose/regimen, duration of treatment
In Part 1, patients will receive escalating doses of LHW090 
 
with each dose administered once daily for four days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 The pharmacokinetics of LHW090 
and LHV527 
 is anticipated to be similar between Parts 1 and 2. Likewise, after 
the domiciling period for Part 2, LHW090 
 pharmacokinetics of 
LHW090 and LHV527 are also anticipated to be similar at the end of Part 2 (i.e., day 28). 
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In Part 2, importantly, although the proposed doses of LHW090 are 
 once 
daily, pending evaluation of data from Part 1, a lower dose may be studied 
 
 
 
3.4
Rationale for choice of comparator
In this study, the comparator will be placebo in order to evaluate the effects of LHW090 in 
patients with moderate renal impairment on angiotensin receptor blocker therapy without 
interference by an active comparator.
3.6
Risks and benefits
There is no benefit expected for subjects participating in this study.
In Part 1, patients will receive escalating doses of LHW090 
 over 
four days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 Based on other compounds with a 
similar mode of action, low blood pressure may be a potential risk.
 
 
An allergic-type reaction called angioedema has been reported with a compound with a 
similar mode of action as LHW090. This risk may be increased when LHW090 is taken 
concomitantly with an ACE inhibitor. Subjects who are unable to substitute an ACE inhibitor
with an angiotensin receptor blocker are excluded from this study. Due to the potential for 
pharmacokinetic drug-drug interactions, subjects taking statins should be monitored for 
statin-related myopathy during the duration of the study. For further details, refer to the 
Investigator Brochure and Section 5.2 “Prohibited treatment”.
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, 
individual and study stopping criteria, and close clinical monitoring. Clinical monitoring 
includes regular monitoring of renal function in an in-patient setting in Part 1. 
 
 
 
In Part 1, a maximum of 235 mL of blood is planned to be collected over a period of 7 weeks 
from each subject as part of the study. In Part 2, a maximum of 135 mL of blood is planned to 
be collected over a period of 9 weeks from each subject as part of the study. 
Additional samples for monitoring of any safety findings would be in addition to this. This is 
not considered to be a risk for this population.
There may be unknown risks of LHW090 which may be serious and unforeseen.
4
Population
4.1
Population
The study population will be comprised of patients aged 40 to 85 (inclusive) on a stable dose 
of an ARB with stable (at least 3 months) moderately impaired renal function defined here as 
an eGFR of 30-59 mL/min/1.73m2 (inclusive).
For the purposes of this trial, eGFR will be calculated using the 4 variable MDRD Study 
equation as follows (Levey et al 2006): estimated GFR = 175 × (Scr)-1.154 × (Age)-0.203 × 
(0.742 if female) × (1.212 if African American) where Scr is serum creatinine in mg/dL.
For Part 1, a cohort of 12 patients will be enrolled and randomized. For Part 2, a total of 
approximately 72 patients will be enrolled and randomized.
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Description for population (Part 1, Part 2)
4.2
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed.

If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness.
2. Male patients and female patients without childbearing potential, age 40 to 85 years of age 
(inclusive) on a stable (at least 1 month) dose of an angiotensin receptor blocker (ARB) 
and stable moderately impaired renal function, defined here as an eGFR 30-59 
mL/min/1.73m2 (inclusive) using the 4 variable MDRD Study equation for at least 
3 months.
3. At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be 
assessed in the sitting position after the patient has rested for at least five minutes and 
again after three minutes in the standing position. Sitting vital signs should be within the 
following ranges:
oral body temperature between 35.0-37.5 °C
systolic blood pressure, 100-170 mm Hg
diastolic blood pressure, 50-100 mm Hg
pulse rate, 50 - 95 bpm
Patients should be excluded if their standing vital signs (relative to sitting) show findings 
which, in the opinion of the Investigator, are associated with clinical manifestation of 
postural hypotension (i.e. absence of any other cause). The Investigator should carefully 
consider enrolling patients with either a > 20 mm Hg decrease in systolic or a >10 mm Hg 
decrease in diastolic blood pressure, accompanied by a > 20 bpm increase in heart-rate 
(comparing standing to sitting results).
4. Patients must weigh at least 50 kg to participate in the study, and must have a body mass 
index (BMI) within the range of 18 - 40 kg/m2. BMI = Body weight (kg) / [Height (m)]2.
5. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.3
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
3. History of angioedema, drug-related or otherwise, as reported by the patient.
4. Use of angiotensin converting enzyme inhibitors (ACE inhibitors), mineralocorticoid 
receptor antagonists (e.g. spironolactone or eplerenone), aliskiren, vasopressin receptor 
antagonists (e.g. tolvaptan), or oral alkalinizing agents (e.g. sodium and potassium citrate 
or Shohl's solution).
Note: Patients who discontinue their ACE-inhibitor and substitute with an angiotensin 
receptor blocker (ARB) may be eligible to be re-screened provided their medication 
regimen has been stable for at least 1 month and their renal function has been stable for at 


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least 3 months. Any substitutions or changes to a patient's medication regimen must be 
done under the guidance of the patient's treating physician.
5. History of a renal transplant.
6. Known current significant left ventricular outflow obstruction, such as obstructive 
hypertrophic cardiomyopathy or significant severe valvular disease on prior or current 
echocardiogram.
7. A history of clinically significant ECG abnormalities, as determined by the Investigator, 
or any of the following ECG abnormalities at screening:

QTcF > 480 msec
8. Known history or current clinically significant arrhythmias.
9. History within the previous 6 months of myocardial infarction, coronary artery bypass 
graft (CABG), percutaneous coronary intervention (PCI), stroke, transient ischemic attack 
(TIA) or acute kidney injury.
10. Hemoglobin levels below 9.0 g/dL at screening.
11. A serum potassium ≤ 3.5 mmol/l or ≥ 5.5 mmol/l at screening.
12. A previous history or previously diagnosed kidney disorder which, in the opinion of the 
Investigator, may place the patient at higher risk from his/her participation in the study or 
is likely to confound the interpretation of the study results. Such kidney disorders may 
include renal cystic disease such as autosomal dominant polycystic kidney disease (history 
of an incidental asymptomatic acquired renal cyst(s) is excepted); obstructive uropathy; 
renal stone(s) in the past 2 years; chronic interstitial nephropathy; drug-induced 
nephropathy; residual renal insufficiency following an episode of acute kidney injury or 
acute tubular necrosis related to renal atheroembolic disease, septic shock or ischemic 
nephropathy; renal tubular acidosis requiring treatment; nephrotic syndrome or nephrotic 
range proteinuria; or renal artery stenosis.
13. Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing, or 
longer if required by local regulations.
14. Significant illness which has not resolved within two (2) weeks prior to initial dosing.
15. History of immunodeficiency diseases, including a positive HIV  test result.
16. A positive Hepatitis B surface antigen or Hepatitis C test result.
17. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases.
18. Pregnant or nursing (lactating) women.
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant.
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), total hysterectomy or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential. 


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20. Sexually active males unwilling to use a condom during intercourse while taking drug and 
for 2 weeks after stopping study medication. A condom is required for all sexually active 
male participants to prevent them from fathering a child AND to prevent delivery of the 
investigational drug via seminal fluid to their sexual partner. In addition, male participants 
should not donate sperm for the time period specified above.
21. On the Columbia-Suicide Severity Rating Scale, score “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or 
“yes” on any item of the Suicidal Behavior section, except for the “Non-Suicidal-Self 
Injurious Behavior” (question also included in the Suicidal Behavior section), if this 
behavior occurred in the past 2 years.
Any patient meeting this exclusion criterion should be excluded from the study and 
referred to a mental health care professional.
22. Any surgical or medical condition, which in the opinion of the Investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study.
Subset of patients in MRI substudy (Part 2), inclusion/exclusion criteria:
1. Patients with contraindications to MRI, including:

Brain aneurysm clip

Implanted neural stimulator

Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires

Prosthetic heart valves

Cochlear implant

Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)

Other implanted medical devices (e.g., insulin pumps)

Metal shrapnel or bullets still in the body

Severe claustrophobia

Tattoos (as determined by the Investigator and Imager)

Weight in excess of MRI machine capacity
Note: In the case where a safety laboratory assessment at screening is outside of the range 
specified above, the assessment may be repeated once prior to randomization. If the repeat 
value remains outside of the specified ranges, the subject is excluded from the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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5
Restrictions for study subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the following restrictions:
5.1
Contraception requirements
Not applicable. Only women of non-childbearing potential will be included in this study.
5.2
Prohibited treatment
Use of the following medications is not allowed during the course of the study from screening 
(Visit 1) to the end of the study. Patients who are receiving such medication(s) will be 
excluded, or if ethically and clinically justified, the medication(s) should be gradually 
withdrawn at least seven days before Visit 2:

ACE inhibitors, mineralocorticoid receptor antagonists (e.g. spironolactone or eplerenone), 
aliskiren, vasopressin receptor antagonists (e.g. tolvaptan), or oral alkalinizing agents (e.g. 
sodium and potassium citrate or Shohl's solution)
o
Note: Patients who discontinue their ACE-inhibitor and substitute with an 
angiotensin receptor blocker (ARB) may be eligible to be re-screened provided their 
medication regimen has been stable for at least 1 month and their renal function has 
been stable for at least 3 months. 

Chronic administration (defined as >3 days per week) of NSAIDs or COX-2 inhibitors. 
The long-term chronic use of aspirin for cardiovascular prophylaxis is allowed provided 
the total daily dose does not exceed 325 mg. Intermittent doses of NSAIDs or COX-2 
inhibitors are allowed but must not be within 48 hours prior to any scheduled visit or 
assessment or serum creatinine.

Use of other investigational drugs at screening or within 30 days or 5 half-lives of the drug 
at screening, whichever is longer, unless local health authority guidelines mandate a 
longer period.

Treatment with any medication that is contraindicated in renally impaired patients

IV contrast dyes such as that used for a radiologic procedure

Recombinant human erythropoietin
The following medications are prohibited due to potential for pharmacokinetic drug-drug 
interactions: bupropion, efavirenz, ifosfamide (sensitive CYP2B6 substrates); amodiaquine, 
paclitaxel, pioglitazone, repaglinide (sensitive CYP2C8 substrates); celecoxib, glimepiride, 
phenytoin, warfarin (sensitive or narrow index CYP2C9 substrates); glyburide (CYP2C9 and 
OATP1B1 substrate); irinotecan (OATP1B1 & BCRP substrate); topotecan (BCRP substrate);
methotrexate (OAT1/3, BCRP substrate), bosentan (OATP1B1 substrate), atazanavir, 
cyclosporine, eltrombopag, gemfibrozil, lopinavir, rifampin, ritonavir, saquinavir, tipranavir 
(OATP1B1/1B3 inhibitors); cimetidine, diclofenac, probenecid (OAT1/3 inhibitor).


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All other prior non-study medications (not specifically contraindicated in the exclusion 
criteria) will be allowed, provided the patient has been on a standard treatment regimen 
(at least 4 weeks of the same dose) and the treatment is not planned to be changed during the 
course of the study.
5.3
Dietary restrictions and smoking

In Part 1, no alcohol is permitted from the domiciling period until after Study Completion 
evaluation. In Part 2, no alcohol will be permitted during the domiciling period and 
starting 24 hours prior to and during study visits.

Intake of xanthine (e.g. caffeine) containing food or beverages (i.e., coffee, tea, soda, 
chocolate) will be restricted to no more than 2 cups/day.

Subjects can drink water ad libitum. To ensure adequate hydration for urine collections in 
Part 1, subjects are recommended to have a fluid intake of at least 240 mL every 4 hours 
during waking hours in addition to fluid taken with meals and medication.

Subjects should be counseled to avoid consuming large portions of cooked meat in the 
24 hours prior to laboratory assessments. This restriction will reduce the variability in 
serum creatinine assessments which can be falsely elevated by dietary meat intake. 
During the domiciling period in Part 1 and Part 2, meals will be outlined by the study 
center’s dietician in accordance with nutritional guidelines for patients with chronic 
kidney disease and nutritional counseling from the subject’s physician.
Subjects will follow a standard weight maintaining diet while domiciled. No food other than 
that specified in the protocol will be consumed at any time during confinement. 
Subjects should be advised to consume the entire contents of the meal provided.
Meals should be provided only after all study procedures including blood and urine 
collections scheduled for that time have been completed.
A copy of the diet with content and nutritional information (amount of protein, carbohydrates, 
fat and calories for each meal) will be provided to the Sponsor prior to study start upon 
request.
5.4
General restrictions

In Part 1, no strenuous physical exercise (e.g. weight training, aerobics, football) for 
7 days prior to dosing until after Study Completion evaluation.

In Part 2, no strenuous physical exercise (e.g. weight training, aerobics, football) for 
7 days prior to dosing until after Study Completion evaluation, particularly for the 
48 hours prior to study visits.


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6
Treatment
6.1
Study treatment
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatment are outlined in Section 3 of the Site Operations 
Manual.
6.1.1
Investigational treatment
The Investigational drug LHW090 
 matching placebos will be 
prepared by Novartis and supplied to the investigator site as open labelled bulk supply for 
Part 1.
For Part 2, LHW090 and its matching placebo will be supplied as double blind patient packs.
6.2
Treatment arms
Part 1: Subjects will be assigned to one of the following 2 treatment arms in a ratio of 2:1:
!
A: LHW090 
 daily for 4 days, followed by 
 4 days followed by 
 4 days
!
B: Matching placebo
Part 2: Subjects will be assigned to one of the following LHW090 treatment arms or placebo 
in a ratio of 3:3:2:
!
A: LHW090 
 once daily
!
B: LHW090 
 once daily
!
C: Matching placebo
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments are not permitted. Subjects should be reminded of the 
importance of study drug compliance and compliance should be monitored and recorded.
In Part 2, patients should be instructed to bring their study medications with them on visit 
days for pill counts. If a short treatment interruption becomes necessary for an important 
reason, the subject may resume the study treatment. However, drug interruption should end, if 
possible, at least 3 days prior to the next study visit. A drug interruption occurring for 
≥4 consecutive days or ≥5 total treatment days during the outpatient phase of the study will be 
considered a protocol deviation.
In the event that a subject will be transitioned to an ACE inhibitor at the end of the study or 
after premature discontinuation of study medication, a minimum of 72 hours must transpire 
between the last dose of LHW090 and the first dose of ACE inhibitor. Consideration should 
also be given to the existing ARB treatment of subjects in the study; concomitant treatment 
with an ACE inhibitor and an ARB should be avoided according to current guidelines and in 
compliance with the applicable local prescribing information of renin angiotensin aldosterone 
system (RAAS) agents.
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6.4
Treatment assignment
Randomization numbers will be assigned in ascending, sequential order to eligible subjects 
(see Site Operations Manual for details). The investigator will enter the randomization 
number on the CRF.
In Part 1, randomization numbers will be generated using the following procedure to ensure 
that treatment assignment is unbiased and concealed from subjects and investigator staff. 
A randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management, using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio. The randomization scheme for subjects 
will be reviewed and approved by a member of the Novartis Randomization Group.
In Part 2, at Visit 2, all eligible subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the subject fulfills all inclusion/exclusion criteria. 
The IRT will assign a randomization number to the subject, which will be used to link the 
subject to a treatment arm and will specify a unique medication number for the first package 
of investigational treatment to be dispensed to the subject.
A subject randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of treatment arms to randomization numbers. Once a 
patient is deemed eligible for enrollment into the study and ready for dosing, the next lowest 
available randomization number will be assigned. These randomization numbers are linked to 
the different treatment arms, which in turn are linked to medication numbers. A separate 
medication list will be produced by or under the responsibility of Novartis Drug Supply.
Management using a validated system that automates the random assignment of medication 
numbers to packs containing the investigational drug(s).
6.5
Treatment blinding
This is a sponsor-open, investigator and subject double-blind study: subjects, investigator staff, 
and persons performing the assessments will remain blind to the identity of study treatments 
according to the specifications provided in Appendix 1.
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.
Randomization data are kept strictly confidential, and are accessible only to authorized 
personnel (e.g. unblinded site staff (pharmacist or authorized designee at the site), unblinded 
sponsor staff (e.g. for drug resupply, unblinded monitor), and sample analysts), until 
unblinding of the trial as described in the table in the blinding table in Appendix 1.
The study statistician, the study programmer and other personnel involved in data analysis 
(e.g. biomarker expert) will have access to the randomization list for planned and unplanned 
interim analyses, and are allowed to share unblinded information with the rest of the clinical 
team as appropriate for internal decision purposes, as outlined in the blinding table in 
Appendix 1.


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Unblinding will occur in the case of patient emergencies (see Section 6.6), at the time of the 
interim analysis and at the conclusion of the study.
6.6
Emergency breaking of assigned treatment code
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
investigator site(s) and a complete set will be available at Novartis for Part 1 of the study. 
All code break cards must be retained until the end of the study and returned to Novartis. 
They must be stored in a secure place but be accessible in case of emergency. The investigator 
will receive a blinded code break card for each subject, with the details of drug treatment 
covered by a removable, scratch-off cover. In an emergency, the scratch-off cover can be 
removed to determine the treatment. The scratch-off covers are not to be removed for any 
reason other than an emergency. When the investigator removes the scratch-off cover he/she 
must note the date, time, and reason for removing it and retain this information with the case 
report form documentation. The unblinded treatment code should not be recorded on the 
CRF. The investigator must also immediately inform the Novartis local monitor that the code 
has been broken.
For Part 2, emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Clinical Trial Head that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT/code break cards in case of emergency. If appropriate, the investigator will inform 
the subject how to contact his/her backup in cases of emergency when he/she is unavailable.
An assessment will be done by the appropriate site personnel and the sponsor after an 
emergency unblinding to assess whether or not study drug should be discontinued for a given 
subject and, if applicable, whether the subject can continue into the next trial phase (e.g., an 
unblinded extension).
6.7
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with LHW090, as detailed in Section 8.5.
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6.8
Recommended treatment of adverse events
Adverse events should be treated at the discretion of the Investigator based on his/her 
judgment and best medical practices. Medication used to treat AEs must be recorded on the 
Concomitant medications/Significant non-drug therapies CRF.
6.9
Rescue medication
Rescue medication to treat severe or serious conditions as per standard of care, at the 
discretion of the Investigator, is allowed. Use of rescue medication must be recorded on the 
Concomitant medications/Significant non-drug therapies CRF after start of study drug.
6.10
Concomitant treatment
All prescription medications, over-the-counter drugs, herbal medications and significant 
non-drug therapies (including physical therapy and blood transfusions) taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant Medications/Non-drug therapies page of the eCRF.
Certain prescription, over-the-counter or herbal medications will not be allowed during the 
course of the study unless the patient has been on a standard treatment regimen for at least 
30 days prior to first dosing and will continue their regular regimen without changes 
throughout the study (unless required to treat adverse events). Some of these medications may 
have to be discontinued, as per discussion with the sponsor. Please refer to Section 5.2 for 
prohibited treatments.
Due to the potential for pharmacokinetic drug-drug interactions, subjects taking statins should 
be monitored for statin-related myositis (e.g. muscle pain or elevations in creatinine kinase) 
during the duration of the study. Under the guidance of their treating physician, subjects on 
rosuvastatin may consider halving their dose or switching to another statin for the duration of 
the study.
The investigator should instruct the patient to notify the study site about any new medications 
(prescription or over-the-counter) he/she takes after the start of the study drug. Medication 
entries should be specific to trade name, the single dose and unit, the frequency and route of 
administration, the start and discontinuation date and the reason for therapy.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Study treatment must be discontinued and the patient withdrawn from the study if the patient 
withdraws consent. Patients may voluntarily withdraw from the study for any reason at any 
time. They may be considered withdrawn if they state an intention to withdraw, fail to return 
for visits, or become lost to follow-up for any other reason. If a patient withdrawal occurs for 
any reason, the Investigator must make every effort to determine the primary reason for a 
patient's withdrawal from the study and record this information on the CRF.


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The Investigator should discontinue study treatment for a given patient or withdraw the 
patient from study if on balance they believe that continuation would be detrimental to the 
patient's well-being. Under the following circumstances, individual study treatment must be 
discontinued and the patient monitored until resolution of the reason for discontinuation 
according to the Investigator's discretion:

A reproducible and persistent (confirmed on repeat assessment within 24 – 48 hr) increase 
in serum creatinine ≥0.3 mg/dL from baseline. Any increases in serum creatinine 
≥0.3 mg/dL based on local laboratory assessments should trigger repeat assessments of 
serum creatinine until event resolution (e.g. serum creatinine within 10% of baseline) or 
event stabilization. Baseline is defined as the average of all available pre-dose 
measurements. 

Systolic blood pressure <90 mm Hg (must be confirmed on repeat measurement after 
30 minutes) or symptomatic hypotension

Any protocol deviation (e.g. use of an ACE inhibitor) that results in a significant risk to 
the patient's safety
7.2
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. Study completion is defined as when the last 
subject completes their End of Study visit, and any repeat assessments associated with this 
visit have been documented and followed-up appropriately by the Investigator, or in the event 
of an early study termination decision, the date of that decision.
At a minimum, subjects will be contacted for safety evaluations during the 30 days following 
the Study Completion visit, including a final post-study safety contact at the 30-day point
after last visit. Documentation of attempts to contact the subject should be recorded in the 
source documentation.
7.2.1
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contact and does not allow analysis of already obtained biologic material.


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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
7.4
Study Stopping rules
The study will be put on hold if any of the following criteria are met and no further dosing
will occur pending a full safety review:

1 or more study-drug related SUSAR is reported

2 patients experience a systolic blood pressure <90 mm Hg that is persistent (>8 hours) 
and symptomatic and suspected to be related to the study drug

3 patients experience a doubling of their baseline serum creatinine (based on local 
laboratory assessments) that is suspected to be related to the study drug. Baseline is 
defined as the average of all available pre-dose measurements.

3 patients experience a similar AE which is assessed as moderate in intensity and is 
potentially related to the study drug
This study can continue if, after the review, the Investigator and Sponsor agree that it can 
safely continue.
The study may also be stopped at any time by the sponsor.
7.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
subjects should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests.
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
8
Procedures and assessments
Table 8-1
Assessment Schedule, Part 1
Epoch
Screening
Treatment
Study Phase
Screening
Baseline
Treatment
Visit numbers (internal use only)
1
2
3
101
102
103
104
105
106
107
108
Visit name (internal use only)
Screening
Day 
-2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Study Day(s)
-28 to -2
-2
-1
1
2
3
4
5
6
7
8
Time (post-dose)
-
-
0h 4h 8h 12h
-
-
-
0h 1h 2h 3h 4h 8h 12h
-
-
-
0h 1h 2h 3h 4h 8h 12h
Informed consent
X
Inclusion / Exclusion criteria
X
X
Study drug administration
X
X
X
X
X
X
X
X
Subjects domiciled
X
Medical history/current medical conditions
X
Demography
X
Body height
X
Body weight
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Hepatitis and HIV Screen
X
Alcohol Test, Drug Screen, and Cotinine 
Test
X
ECG evaluation
X
X
Hematology
X
X
X


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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Epoch
Screening
Treatment
Study Phase
Screening
Baseline
Treatment
Visit numbers (internal use only)
1
2
3
101
102
103
104
105
106
107
108
Visit name (internal use only)
Screening
Day 
-2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Study Day(s)
-28 to -2
-2
-1
1
2
3
4
5
6
7
8
Time (post-dose)
-
-
0h 4h 8h 12h
-
-
-
0h 1h 2h 3h 4h 8h 12h
-
-
-
0h 1h 2h 3h 4h 8h 12h
Blood chemistry2
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X 
Urine albumin:creatinine ratio3
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Columbia-Suicide Severity Rating Scale
X
X
Adverse events
X
Concomitant therapies
X
Phase/Study completion information
X 
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Epoch
Treatment
Study Phase
Treatment
Study Completion /Early termination
30 day Safety Follow up call
Visit numbers (internal use only) 109
110
111
112
113
114
199
n/a
Visit name (internal use only) Day 
9
Day 
10
Day 
11
Day 12
Day 
13
Day 
14
End of study
Study Day(s)
9
10
11
12
13
14
21
-1 +2
51
Time (post-dose)
-
-
-
0h
1h
2h
3h
4h
8h
12h
-
-
-
Informed consent
Inclusion / Exclusion criteria
Study drug administration
X
X
X
X
Subjects domiciled
X
Medical history/current medical 
conditions
Demography
Body height
Body weight
Vital Signs
X
X
X
X
X
X
X
Physical examination
X
X
Hepatitis and HIV Screen
Alcohol Test, Drug Screen, and 
Cotinine Test
ECG evaluation
X 
Hematology
X
X
X
Blood chemistry2
X
X
X
X
X
X
X
Urinalysis
X 
X 
X
X 
X 
X
X 
X 
X 
X 
X
X
X
X
X
X
X
X
X
X
X
X
PK blood collection6
X
X
X
X
X
X
X
X
X
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Epoch
Treatment
Study Phase
Treatment
Study Completion /Early termination
30 day Safety Follow up call
Visit numbers (internal use only) 109
110
111
112
113
114
199
n/a
Visit name (internal use only) Day 
9
Day 
10
Day 
11
Day 12
Day 
13
Day 
14
End of study
Study Day(s)
9
10
11
12
13
14
21
-1 +2
51
Time (post-dose)
-
-
-
0h
1h
2h
3h
4h
8h
12h
-
-
-
X
Columbia-Suicide Severity Rating 
Scale
X 
X
Adverse events
X
X
Concomitant therapies
X
Phase/Study completion 
information
X 
X
1 Visit structure given for internal programming purpose only
2 including Cystatin C
3 First morning void
6 PK blood samples obtained at 0h will be pre-dose samples on Days 4, 8 and 12
7 Pre-dose
9 Assessments on Study Days 1-3, 5-7, and 9-11 should be done pre-dose.
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Table 8-2
Assessment schedule Part 2, Patients 1-16 
Epoch
Screening
Treatment
Study Phase Screening Baseline
Treatment
Study Completion
30 
Day 
safety 
follow 
up 
call
Visit Numbers1
V1
V22
V3
V3.1
V3.2
V3.3
V3.4
V3.5
V43
V5
V6
V7
V777
n/a
Visit numbers 
(internal use 
only) 
1
4
201
201.1 201.2
201.3
201.4 201.5
202
203
204
205
299
Visit name 
(internal use 
only)
Screening
Day -1
Day 1
Day 
2
Day 
3
Day  4
Day 
5
Day 
6
Day 7
Day 
14
Day 
21
Day 28
End of study
Study Day(s)
-28 to -4
-1
1
2
3
4
5
6
7
-1 +1
14
-1 +1
21
-1 +1
28
-1 +0
35
-1 +2
65
Time (post-dose)
-
0h
-
0h 1h 2h 3h 4h 8h 12h
-
-
-
0h
1h
2h
3h
4h
8h
-
Informed consent
X
Inclusion / 
Exclusion criteria
X
X
Dose 
administration4
X
Domicile
X
Medical 
history/current 
medical 
conditions
X
Demography
X
Body height
X
Body weight
X
Hepatitis and HIV 
Screen
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
X
X
X
X


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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Epoch
Screening
Treatment
Study Phase Screening Baseline
Treatment
Study Completion
30 
Day 
safety 
follow 
up 
call
Visit Numbers1
V1
V22
V3
V3.1
V3.2
V3.3
V3.4
V3.5
V43
V5
V6
V7
V777
n/a
Visit numbers 
(internal use 
only) 
1
4
201
201.1 201.2
201.3
201.4 201.5
202
203
204
205
299
Visit name 
(internal use 
only)
Screening
Day -1
Day 1
Day 
2
Day 
3
Day  4
Day 
5
Day 
6
Day 7
Day 
14
Day 
21
Day 28
End of study
Study Day(s)
-28 to -4
-1
1
2
3
4
5
6
7
-1 +1
14
-1 +1
21
-1 +1
28
-1 +0
35
-1 +2
65
Time (post-dose)
-
0h
-
0h 1h 2h 3h 4h 8h 12h
-
-
-
0h
1h
2h
3h
4h
8h
-
examination
Alcohol Test, 
Drug Screen, and 
Cotinine Test
X
ECG evaluation
X
X 
Hematology
X
X
X
X
X
Blood chemistry5
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Epoch
Screening
Treatment
Study Phase Screening Baseline
Treatment
Study Completion
30 
Day 
safety 
follow 
up 
call
Visit Numbers1
V1
V22
V3
V3.1
V3.2
V3.3
V3.4
V3.5
V43
V5
V6
V7
V777
n/a
Visit numbers 
(internal use 
only) 
1
4
201
201.1 201.2
201.3
201.4 201.5
202
203
204
205
299
Visit name 
(internal use 
only)
Screening
Day -1
Day 1
Day 
2
Day 
3
Day  4
Day 
5
Day 
6
Day 7
Day 
14
Day 
21
Day 28
End of study
Study Day(s)
-28 to -4
-1
1
2
3
4
5
6
7
-1 +1
14
-1 +1
21
-1 +1
28
-1 +0
35
-1 +2
65
Time (post-dose)
-
0h
-
0h 1h 2h 3h 4h 8h 12h
-
-
-
0h
1h
2h
3h
4h
8h
-
PK blood 
collection9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
Columbia-Suicide 
Severity Rating 
Scale
X
X
X
X
X
Concomitant 
Medication 
X
Arterial spin 
labeling MRI10
X
X
Phase/Study 
completion 
information
X 
X
1 Visit structure given for internal programming purpose only
2 MRI can be done within 2 days prior to the baseline visit
3 MRI can be conducted within a day +/- of the Day 7 visit
4 Patient is expected to take the drug every day for 4 weeks. 
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Table 8-3
Assessment Schedule, Part 2 Patients 17 to 72, approximately 
Epoch
Screening
Treatment
Study Phase
Screening
Baseline
Treatment
Study Completion
30 Day safety 
follow up call
Visit Numbers1
V1
V22
V3
V43
V5
V6
V7
V777
n/a
Visit numbers (internal use only) 
1
4
201
202
203
204
205
299
Visit name (internal use only)
Screening
Day -1
Day 1
Day 7
Day 14
Day 21
Day 28
End of study
Study Day(s)
-28 to -4
-1
1
7
-1 +1
14
-1 +1
21
-1 +1
28
-1 +0
35
-1 +2
65
Time (post-dose)
-
0h
-
-
-
-
0h
1h
2h
3h
4h
8h
-
Informed consent
X
Inclusion / Exclusion criteria
X
X
Dose administration4
X
Medical history/current medical conditions
X
Demography
X
Body height
X
Body weight
X
Hepatitis and HIV Screen
X
Vital Signs
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
Alcohol Test, Drug Screen, and Cotinine Test
X
ECG evaluation
X
X 
Hematology
X
X
X
X
X
Blood chemistry5
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood collection9
X
X
X
X
X
X
X
X
X
Adverse events
X
X
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Epoch
Screening
Treatment
Study Phase
Screening
Baseline
Treatment
Study Completion
30 Day safety 
follow up call
Visit Numbers1
V1
V22
V3
V43
V5
V6
V7
V777
n/a
Visit numbers (internal use only) 
1
4
201
202
203
204
205
299
Visit name (internal use only)
Screening
Day -1
Day 1
Day 7
Day 14
Day 21
Day 28
End of study
Study Day(s)
-28 to -4
-1
1
7
-1 +1
14
-1 +1
21
-1 +1
28
-1 +0
35
-1 +2
65
Time (post-dose)
-
0h
-
-
-
-
0h
1h
2h
3h
4h
8h
-
Columbia-Suicide Severity Rating Scale
X
X
X
X
X
Concomitant therapies
X
Arterial spin labeling MRI10
X
X
Phase/Study completion information
X 
X
1 Visit structure given for internal programming purpose only
2 MRI can be done within 2 days prior to the baseline visit
3 MRI can be conducted within a day +/- of the Day 7 visit
4 Patient is expected to take the drug every day for 4 weeks  
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
8.1
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy / Pharmacodynamics
Efficacy is not measured in this clinical study.
8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule detailing when each assessment is 
to be performed.
8.4.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, 
external 
genitalia, 
breast, 
and/or 
pelvic 
exams 
may 
be 
performed.


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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
Information for all physical examinations should be included in the source documents and 
will not be transferred to the sponsor as part of the study analysis. Significant findings that are 
present prior to informed consent are included in the Relevant Medical History section of the 
source documents. Significant findings observed after informed consent signature which meet 
the definition of an Adverse Event must be appropriately recorded on the Adverse Event 
eCRF section.
8.4.2
Vital signs

Body temperature

Blood pressure (BP) 

Pulse 
8.4.3
Height and weight

Height

Body weight

Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
8.4.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
A central laboratory will be used for analysis of all specimens collected. For the purposes of 
monitoring, a separate sample will be obtained for serum creatinine and dipstick urine testing 
at a local laboratory and those results will be entered into the eCRF. Details on the collection, 
shipment of samples and reporting of results by the central laboratory will be provided to 
investigators in the laboratory manual.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured.
Clinical chemistry
Blood samples for clinical chemistry should be collected early morning after an overnight fast 
of at least 8 hours.
Sodium, potassium, creatinine, estimated GFR using the 4 variable MDRD study equation, 
cystatin C, urea, uric acid, chloride, albumin, calcium, phosphate, alkaline phosphatase, total 
bilirubin, GGT, AST, ALT, aPTT (activated partial thromboplastin time), PT/INR, CK, 
glucose, total cholesterol, triglycerides. If the total bilirubin concentration is increased above 
1.5 times the upper limit of normal, direct and indirect reacting bilirubin should be 
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
In Part 1, LFTs (total bilirubin, AST, ALT, GGT, alkaline phosphatase) and coagulation tests 
(aPTT, PT/INR) will be included as part of the chemistry panel on screening, Days -1, 4, 8, 12, 
14, and end of study visits.
Urinalysis
Urine samples for urinalysis, 
 
 
 
 
will be requested while they are at the clinic.
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts. If casts are noted, the type is to be 
specified on the relevant CRF page.
8.4.5
Electrocardiogram (ECG)
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, be appropriately signed and dated to confirm review and filed in the study site 
source documents. For any ECGs with subject safety concerns, two additional ECGs should 
be performed to confirm the safety finding. Clinically significant ECG findings prior to 
dosing with investigational treatment must be discussed with the sponsor. 
Additional details of procedures relating to the ECG collection and reporting will be 
contained in the site operations manual.
For all studies:
PR interval, QRS duration, heart rate, RR, QT, QTc
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
8.4.6
Pregnancy and assessments of fertility
Not applicable. Only women of non-childbearing potential will be included in this study.
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
8.5
Pharmacokinetics
PK samples will be collected at the time-points defined in the Assessment schedule.
Further details on sample collection, numbering, processing and shipment can be found in the
Site Operations Manual. LHW090 and its active metabolite LHV527 will be determined in 
plasma using a validated LC-MS/MS method with the Lower Limit of Quantification (LLOQ) 
of 5.00 ng/mL. Untreated samples (placebo) will not be analyzed unless deemed necessary. 
Concentrations will be expressed in ng per mL units. Concentrations below the LLOQ will be 
reported as “zero” and missing data will be labeled as such in the Bioanalytical Data 
Report.
 
 
 
For standard pharmacokinetic abbreviations and definitions see the list provided at the
beginning of this protocol. The following pharmacokinetic parameters will be determined 
using the actual recorded sampling times and non-compartmental method(s) with Phoenix 
WinNonlin (Version 6.2 or higher): Cmax, Tmax, AUClast, AUC0-t, AUCtau from the 
plasma concentration-time data. Other pharmacokinetic parameters may be determined, if 
relevant. 
 
8.6
Other assessments
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Amended Protocol Version v04 (Clean)
Protocol No. CLHW090X2102
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
!
they induce clinical signs or symptoms,
!
they are considered clinically significant,
!
they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in 
Section 9.3.
Adverse events must be recorded on the Adverse Events CRF for subjects that pass screening 
and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. the severity grade
!
mild: usually transient in nature and generally not interfering with normal activities
!
moderate: sufficiently discomforting to interfere with normal activities
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
severe: prevents normal activities
2. its relationship to the study treatment (no/yes),
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. whether it constitutes a serious adverse event (SAE) See Section 9.2 for definition of SAE
5. action taken regarding [study/investigational] treatment(select as appropriate).
All adverse events should be treated appropriately. Treatment may include one or more of the 
following:

no action taken (i.e. further observation only)

study treatment dosage adjusted/temporarily interrupted

study treatment permanently discontinued due to this adverse event

concomitant medication given

non-drug therapy given

subject hospitalized/subject’s hospitalization prolonged
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or Core Data Sheet (for marketed drugs) or will be 
communicated between IB updates in the form of Investigator Notifications. This information 
will be included in the subject informed consent and should be discussed with the subject 
during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

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requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study  and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs
experienced after this should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
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Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 9-1 and Table 9-2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed in in Table 9-2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.


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For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug (refer to Section 7.1, if appropriate

Hospitalization of the subject if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution.
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF, including the liver 
event overview CRF pages.
Table 9-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
Liver laboratory 
triggers

3 x ULN < ALT / AST £ 5 x ULN

1.5 x ULN < TBL £ 2 x ULN
Liver events

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × 
ULN [mainly conjugated fraction] without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal 
pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity *


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Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more 
than 2 weeks, discontinue the 
study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN accompanied 
by symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and 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 drug 
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 drug 
interruption or discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.
9.4
Renal safety monitoring
Renal events are defined as one of the following:

confirmed (on repeat measurement within 24 – 48 hr timeframe) increase in serum 
creatinine of ≥ 0.3 mg/dL compared to baseline 
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study:

Serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter

Urine dipstick triggers that will require follow up and repeat assessments of the
abnormal laboratory parameter.


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Please refer to Table 9-3 for specific renal alert criteria and actions.
Table 9-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
≥0.3 mg/dL compared to baseline
Confirm ≥0.3 mg/dL increase in 24-48 hr timeframe
Follow serum creatinine until event resolution or 
event stabilization
Serum creatinine increase  ³ 50 % compared 
to baseline*
Follow up within 24-48h if possible
Consider patient hospitalization /specialized 
treatment
Albumin- or Protein-creatinine ratio increase ≥ 
2-fold
Albumin-creatinine ratio (ACR) ≥ 30 mg/g;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR )≥ 150 mg/g 
or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New dipstick hematuria not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until one of the following:
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline)
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.
*Baseline is defined as the average of all pre-dose measurements from central laboratory 
assessments.
9.5
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. 
In addition, pregnancy outcomes must be collected for the female partners of any males who 
took study treatment in this study. 
Consent to report information regarding all pregnancy outcomes should be obtained from the 
mother. 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.


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9.6
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior.
The C-SSRS, which uses a semi-structured interview to probe subject responses, will be 
administered by an individual who has received training and certification in its administration. 
At the first study visit, the “baseline/screening” version of the C-SSRS, will be administered. 
This version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime 
and during a predefined period. At subsequent visits, the “since last visit” version will be 
administered.
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the C-SSRS or “yes” on any item of the Suicidal Behavior section, 
the subject must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the investigator in consultation with the mental health professional to whom the subject is 
referred.
In addition, all life-threatening events should be reported as SAEs. For example, if a subject 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be 
reported if the event was life-threatening. All events of “Non-Suicidal Self-Injurious 
Behavior” (question also included in the Suicidal Behavior section) should be reported as AEs 
and assigned the appropriate severity grade.
All SAEs relating to suicidal behavior should be reviewed by the Safety Management Team 
or Early Project Teams.
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the
Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.


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10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Novartis. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive a CD-ROM or paper copies of the subject data for archiving at the investigational 
site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
assessment schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.


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10.3
Database management and quality control
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Novartis staff review the data entered into the eCRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff 
who will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed locally and/or centrally as defined in the site operations 
manual and the results will be sent electronically to Novartis (or a designated CRO).
In Part 2 of the study, randomization codes and data in reference to dispensing of study drug(s) 
to the subject and all IRT recorded dosage changes will be tracked using Interactive Response 
Technology (IRT). The system will be supplied by a vendor, who will also manage the 
database. The database will be sent electronically to Novartis (or a designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis (Part 1 
only).
Each occurrence of a code break via IRT (Part 2 only) 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.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.


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11
Data analysis
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol 
deviations with relevant impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by Part, treatment group and 
subject. Summary statistics will be provided by Part, treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by Part, treatment group and subject.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by Part, treatment group and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary safety variable will be the proportion of patients who develop a renal event. 
The two parts of the study will be analyzed separately. A renal event is defined as a 
reproducible increase in serum creatinine of ≥0.3 mg/dL from baseline confirmed on a repeat 
measurement within 24 to 48 hours. This threshold in serum creatinine was selected based on 
the published definitions of acute kidney injury
(Mehta et al 2007, Khwaja 2012). 
Change from baseline will be evaluated and categorized as <0.3 mg/dL and ≥0.3 mg/dL. 
The analysis will be based on central laboratory results. Baseline will be defined as the 
average of all available pre-dose measurements.
11.4.2
Statistical model, hypothesis, and method of analysis
Part 1:
The purpose of the dose escalation in Part 1 is to assess the renal safety and tolerability of 
multiple doses of LHW090 in patients with moderately impaired renal function starting with 
the highest single dose tested in renal patients in the first-in-human study before the start of 
Part 2. Descriptive summary statistics will be provided by treatment group and visit/sampling 
time point, for change from baseline serum creatinine including the frequency (n, %) of renal 
events <0.3 mg/dL and ≥ 0.3 mg/dL.


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Concentration response modeling may be carried out in Part 1 to assess the correlation of 
change in serum creatinine with concentration. In the absence of a significant concentration 
effect on serum creatinine, Part 2 will be initiated 
 If there 
is evidence of significant concentration effect, Part 2 of the study may not be initiated or a 
lower dose may be investigated.
Part 2:
For Part 2, a Chi-square test will be performed to compare the proportion of patients who 
develop a renal event in the LHW090 pooled active doses, LHW090 individual doses and 
placebo groups. This analysis will be stratified by ARB dose (see Appendix 2). A logistic 
model with the baseline ARB dose and the baseline creatinine level as covariates may also be 
used. P-value and 95% CI of the difference in proportions will be presented. Descriptive
summary statistics will be provided by treatment and visit/sampling time point, for change 
from baseline serum creatinine including the frequency (n, %) of renal events <0.3 mg/dL and 
≥ 0.3 mg/dL will be provided.
Historical data from internal Novartis studies in a similar patient population may be used to 
supplement the information from patients on placebo in the current study.
Analyses stratified by degree of proteinuria (microalbuminuria or macroalbuminuria) and/or 
history of diabetes may also be conducted.
11.4.3
Handling of missing values/censoring/discontinuations
For the analysis of the proportion of patients with a renal events described in Section 11.4.3, 
patients who complete at least 2 weeks of treatment will be included in the denominator. 
For the analysis of change from baseline in serum creatinine described in Section 11.4.4, all 
available data will be included and missing data will not be imputed (it will be estimated from 
the likelihood of the repeated measures model). Patients discontinued by the investigator due 
to a doubling of serum creatinine from baseline (based on local measurements) will be 
counted as having a renal event in the primary analysis regardless of the availability of a 
central serum creatinine value. In case more than 10% of patients drop out before 2 weeks, a 
sensitivity analysis using multiple imputation techniques may be considered.
11.4.4
Supportive analyses
Change from baseline for serum creatinine data will be analyzed using a linear mixed effects 
model for repeated measurements. The model will include treatment as a fixed effect, visit as 
a repeated effect, treatment by visit interaction and baseline as a continuous covariate. 
An unstructured covariance model will be used. Point estimates and the associated 95% 
confidence intervals for the difference between treatment and placebo at each visit will be 
provided.
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11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy / Pharmacodynamics
The peak and mean AUC (AUC0-24h) of plasma cGMP, Amount excreted (Ae) of Urine 
cGMP will be calculated and summarized by part and treatment. Change from baseline and 
percent change from baseline of these variables will also be calculated and summarized.
11.5.2
Safety
11.5.2.1 Vital signs
All vital signs data will be listed by Part, treatment group, subject, and visit/time and if ranges 
are available abnormalities (and
relevant orthostatic changes) will be flagged. 
Summary statistics will be provided by Part, treatment group and visit/time.
11.5.2.2 ECG evaluations
All ECG data will be listed by Part, treatment group, subject and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by Part, treatment group and visit/time.
11.5.2.3 Clinical laboratory evaluations
All laboratory data will be listed by Part, treatment group, subject, and visit/time and if 
normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by Part, treatment group and visit/time.
Change from baseline data will also be listed and summarized.
11.5.2.4 Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by Part and treatment. A subject with multiple adverse 
events within a body system is only counted once towards the total of this body system.
11.5.2.5 Other safety evaluations
Urine albumin creatinine ratio and Fractional excretion of phosphate in urine data will be 
listed by Part, treatment group, subject and visit/time. Summary statistics will be provided by 
Part, treatment group and visit/time. Change from baseline data will also be listed and 
summarized.
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11.5.3
Pharmacokinetics
All drug concentrations below the lower limit of quantification (LLOQ) will be reported as 
“zero” and will be treated as zero for calculation of PK parameters.
LHW090/LHV527 plasma concentration data will be listed by Part, treatment, subject, and
visit/sampling time point. Descriptive summary statistics will be provided by treatment and
visit/sampling time point. Summary statistics will include mean (arithmetic and geometric), 
SD, CV (arithmetic and geometric), median, minimum and maximum. An exception to this is 
Tmax where median, minimum and maximum will be presented. Concentrations below 
LLOQ will be treated as zero in summary statistics and for PK parameter calculations. 
A geometric mean will not be reported if the dataset includes zero values.
Pharmacokinetic parameters will be calculated as described in Section 8.5 and will be listed
and summarized by part, treatment and subject.
Unbound PK concentration and PK parameter data will be listed and summarized for Part 1 as 
feasible.
Individual PK profiles and Arithmetic (SD) profile will be provide by part and treatment.
11.5.5
Other assessments
11.6
Sample size calculation
For Part 1, the sample size is driven by feasibility considerations.
For Part 2, with 54 patients in the pooled LHW090 dose groups and 18 patients in the placebo 
group, we can detect a difference of 25% (increase from 3% on placebo to 28% on active) 
between the renal event rates on active (pooled doses) and placebo with 82% power and 10% 
type I error (1-sided test). 
11.7
Power for analysis of key secondary variables
Not applicable.
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
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12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
12.3
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators must apply due diligence to avoid protocol deviations. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.
13.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment.


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Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL 
should be informed and (serious) adverse event reporting requirements (Section 9) followed 
as appropriate.


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14
References
Bavishi C, Messerli FH, Kadosh B, et al (2015) Role of neprilysin inhibitor combinations in 
hypertension: insights from hypertension and heart failure trials. Eur Heart J pii: ehv142 
(Epub ahead of print).
Calhoun DA, Jones D, Textor S, et al (2008) Resistant hypertension: diagnosis, evaluation, 
and treatment. A scientific statement from the American Heart Association Professional 
Education Committee of the Council for High Blood Pressure Research. Hypertension p. 
1403-19.
Chobanian AV, Bakris GL, Black HR, et al (2003) National Heart, Lung, and Blood Institute 
Joint National Committee on Prevention, detection, evaluation, and treatment of high blood 
pressure; National High Blood Pressure Education Program Coordinating Committee. The 
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560-72.
Gu J, Noe A, Chandra P, et al (2010) Pharmacokinetics and pharmacodynamics of LCZ696, a 
novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol;
50:401-14.
James PA, Oparil S, Carter BL, et al (2014) 2014 evidence-based guideline for the 
management of high blood pressure in adults: report from the panel members appointed to the 
Eighth Joint National Committee (JNC 8). JAMA 311:507-20.
Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin 
Pract; c179-84.
Levey AS, Coresh J, Greene T, et al (2006) Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med; 247-54.
Loghman-Adham M, Kiu Weber CI, Ciorciaro C, et al (2012) Detection and management of 
nephrotoxicity during drug development. Expert Opin Drug Saf; 581-96.
Mancia G, Fagard R, Narkiewicz K, et al (2013) ESH/ESC Guidelines for the management of 
arterial hypertension. J Hypertens; 31:1281-1357.
Mehta RL, Kellum JA, Shah SV, et al (2007) Acute Kidney Injury Network: report of an 
initiative to improve outcomes in acute kidney injury. Crit Care; R31.
Valderrama AL, Gillespie C, King SC, et al (2012) Vital Signs: Awareness and treatment of 
uncontrolled hypertension among adults - United States, 2003-2010 Morbidity and Mortality 
Weekly Report. 61(35):703-709.
Weber MA, Schiffirn EL, White WB, et al (2014) Clinical practice guidelines for the 
management of hypertension in the community. A Statement by the American Society of 
Hypertension and the International Society of Hypertension. The Journal of Clinical 
Hypertension Vol 16 (1):14-26.


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15
Appendix 1: (Blinding table)
Time or Event
Role
Randomization 
list generated
Trt allocation 
& dosing
Safety event 
(single subject 
unblinded)
IA & dose 
escalation
Subjects
B
B
UI
B
Site staff e.g. investigator and study 
nurse
B
B
UI
B
Unblinded site staff e.g. pharmacy staff
B
UI
UI
UI
Drug Supply and Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff e.g. for drug 
re-supply, unblinded monitor, sample 
analytics
B
UI
UI
UI
Statistician/statistical 
programmer/biomarker expert
B
B
UI
UI
Independent committees (e.g. DMC, 
internal stats analysis team) used for 
assessing interim results
NA
NA
NA
NA
All other sponsor staff not identified 
above (trial team, project team, 
management & decision boards, 
support functions)
B
B
UI
UI
IA Interim analyses
UI Allowed to be unblinded on individual patient level
B
Remains blinded
At Database lock all roles can be unblinded
Subjects and investigator will remain blinded to study treatment throughout the study 
(except in the case of a safety event necessitating unblinding). 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.
With the exception of unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment during treatment allocation 
and at the point of subject dosing but may be unblinded to the treatment assignment of an 
individual subject in case of a safety event necessitating unblinding.
Unblinding a single subject for safety reasons (necessary for subject management) will occur 
via an emergency system in place at the site.
Unblinded site staff: Drug product will be supplied in bulk, so an unblinded pharmacist who is 
independent of the study team will be required in order to maintain the blind. This unblinded 
pharmacist will receive a randomization list or treatment allocation cards from Drug Supply 
Management with the appropriate treatment allocation numbers. Appropriate measures must 
be taken by the unblinded pharmacist to ensure that the treatment assignments are concealed 
from the rest of the site staff.


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Unblinded sponsor staff: The following unblinded sponsor roles are required for this study:

Unblinded monitor

Unblinded sample analyst (PK blood and urine)

Unblinded sample analyst (biomarker XXX)
The unblinded monitor is required to review drug accountability and allocation at site. 
The unblinded monitor is not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual subjects. The unblinded monitor will also be able to review 
the treatment allocation cards/randomization list provided to the unblinded pharmacist. 
The names of the unblinded monitor(s) are detailed in the Monitoring Plan.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office) to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the team under blinded conditions. Both the pharmacist and bioanalyst will 
keep this information confidential until clinical database lock.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in the blinding table above. For example, unblinded 
summaries and unblinded individual data can be shared with the team for planned and 
unplanned interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting planned 
and unplanned interim analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project 
while the study is ongoing.


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SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LHW090X
CLHW090X2102
A two part randomized, double-blind, parallel-group, 
placebo-controlled study to evaluate the renal safety,
tolerability and pharmacokinetics of LHW090 in patients 
with moderately impaired renal function on angiotensin 
receptor blockers
Statistical Analysis Plan (SAP)
Amendment 3
Document type:
SAP Documentation – NIBR 
Document status:
Final
Release date:
21-Dec-2018
Number of pages:
14
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
C
Personal Data


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
Primary objective(s) ............................................................................................................5
Secondary objective(s) ........................................................................................................5
1.4
Study design and treatment......................................................................................6
2
First interpretable results (FIR) ...........................................................................................8
4
Statistical methods: Analysis sets........................................................................................8
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
5.3
Statistical model, assumptions and hypotheses .....................................................10
5.3.1
Model checking procedures ..................................................................10
5.4
Graphical presentation of results ...........................................................................10
7
Statistical methods for safety and tolerability data............................................................11
7.1
Variables................................................................................................................11
7.2
Statistical model, assumptions and hypotheses .....................................................12
7.2.1
Model checking procedures ..................................................................12
7.3
Pharmacokinetic / Safety interactions ...................................................................12
7.4
Descriptive analyses ..............................................................................................13
7.5
Graphical presentation...........................................................................................14
9
Reference list.....................................................................................................................14
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List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................9


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1
Introduction 
1.1
Scope of document
The SAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLHW090X2102”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Protocol Version v04 is referred for the current SAP.
1.3
Study objectives
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

Part 1: To assess the safety and 
tolerability of doses of LHW090 in 
patients with moderate renal impairment 
to inform design of Part 2.

Part 2: To assess the renal safety of 
LHW090 in patients with moderate renal 
impairment.

Part 1: Safety endpoints (including 
adverse events and serious adverse 
events) up to and including the EOS; 
plasma pharmacokinetic parameters, and 
serum creatinine

Part 2: Proportion of patients who 
develop a renal event as defined by a 
≥0.3 mg/dL increase in serum creatinine 
from baseline
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

All Parts: To evaluate the 
pharmacokinetics of LHW090 and its 
active metabolite, LHV527, in patients 
with moderate renal impairment. 

Plasma pharmacokinetic parameters 
(Cmax, Tmax, AUC)

All Parts: To assess the safety and 
tolerability of LHW090 relative to 
placebo in patients with moderate renal 
impairment.

Safety endpoints (including adverse 
events and serious adverse events) up to 
and including the EOS


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1.4
Study design and treatment
The study purpose is to determine whether LHW090 displays the clinical safety profile to 
support further development in patients with moderately impaired renal function.
This is a randomized, double-blind, parallel group, placebo-controlled study, in two sequential 
parts to evaluate the renal safety, tolerability and pharmacokinetics of LHW090 in patients 
with moderately impaired renal function. Patients aged 40 to 85 (inclusive) with an estimated 
glomerular filtration rate (eGFR) between 30 and 59 mL/min/1.73m2 at screening (inclusive) 
on a stable dose of an angiotensin receptor blocker (ARB) will be considered for this study.
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The study will be conducted in two parts. Part 1 will enroll a single cohort of 12 patients who 
will be randomized in a 2:1 ratio of LHW090 to placebo. An intra-patient dose escalation 
scheme will be employed starting at a 
 once daily dose for the first four day cycle, and 
then the dose will be escalated 
 once daily for the next four days and then 
 
once daily for four days. If a renal event occurs during the treatment periods of the study or 
any of the individual stopping criteria are met, then dosing will be stopped for that individual 
patient. For the purposes of this study, a renal event will be defined as a reproducible increase 
from baseline serum creatinine of ≥ 0.3 mg/dL confirmed on a repeat measurement within 
24-48 hours (Mehta et al 2007, Khwaja 2012). Throughout the study, any serum creatinine 
assessment that is increased ≥0.3 mg/dL compared to baseline will trigger a repeat assessment 
of serum creatinine after 24 hours to confirm whether criterion for a renal event is met.
Part 2 will be double-blind and placebo-controlled to assess the safety and tolerability of 2
dose levels of LHW090, 
once daily for 4 weeks. Approximately 72 
patients will be enrolled in Part 2 and randomized in a 3:3:2 ratio to LHW090 
 
 and placebo. Therefore, in Part 2, approximately 27 patients are expected to be 
randomized to each of the active doses, and 18 patients are expected to be randomized to 
placebo. Randomization will be stratified by ARB dose (see Protocol) at the time of 
enrollment. Patients who meet the eligibility criteria at screening will have baseline
assessments of renal function
 collected on Day -1 prior to 
beginning the treatment phase on Day 1. Centrally-analyzed laboratory assessments 
performed at screening will be used to determine patient eligibility for the trial.
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The first 16 patients in Part 2 will be domiciled for the first 7 days of dosing to ensure careful
monitoring of renal function and pharmacokinetic parameters. On Day 7 at the investigator’s 
discretion, the patients will be released to complete the remaining 3 weeks of the treatment 
phase
2
First interpretable results (FIR)
FIR contains the key outputs 
4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
All subjects that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set.
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The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety, PK, PD) analysis in case of 
these PDs: 
INC01
Written informed consent was not obtained prior 
to performing study assessment.
Excluded from safety, PK, 
PD analysis set
TRT03
Subject did not receive any dose of study 
treatment.
Excluded from Safety, PK
and PD analysis set
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
PK parameters Cmax, Tmax, AUClast, AUC0-t, AUCtau and other relevant PK parameters 
will be considered.
5.2
Descriptive analyses
LHW090/LHV527 plasma concentration data will be listed by Part, treatment, subject, and
visit/sampling time point. Descriptive summary statistics will be provided by treatment and
visit/sampling time point. Summary statistics will include mean (arithmetic and geometric), 
SD, CV (arithmetic and geometric), median, minimum and maximum. 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. The 
day 28, 24 h concentrations will not be included in these analyses since they were not 
actually collected in this study.
Pharmacokinetic parameters will be listed and summarized by part, treatment and subject. In 
order to calculate AUCtau, day 28, 24 h concentrations are to be set equal to the day 28, 0 h 
(predose) concentrations based on the assumption that steady-state had been achieved. Day 28, 
24 h PK samples were not actually collected in this study.
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Unbound PK concentration and PK parameter data will be listed and summarized for Part 1 as 
feasible.
5.3
Statistical model, assumptions and hypotheses
No formal statistical analyses will be performed for PK data.
5.3.1
Model checking procedures
Not applicable.
5.4
Graphical presentation of results
Individual PK profiles and Arithmetic (SD) profile will be provided by part and treatment.
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7
Statistical methods for safety and tolerability data
7.1
Variables
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The primary safety variable will be the proportion of patients who develop a renal event.
The two parts of the study will be analyzed separately. A renal event is defined as a 
reproducible increase in serum creatinine of ≥0.3 mg/dL from baseline confirmed on a repeat 
measurement within 24 to 48 hours.
Change from baseline for serum creatinine will be evaluated and categorized as <0.3 mg/dL 
and ≥0.3 mg/dL. The analysis will be based on central laboratory results. Baseline will be 
defined as the average of all available pre-dose measurements (excluding screening values).
7.2
Statistical model, assumptions and hypotheses
For Part 2, no inferential analysis of renal events will be conducted due to only having 1 
subject that fulfilled the criteria. A frequency table will be produced instead. 
Historical data from internal Novartis studies in a similar patient population may be used to
supplement the information from patients on placebo in the current study.
For each part, change from baseline for serum creatinine data will be analyzed using a linear 
mixed effects model for repeated measurements. The model will include treatment as a fixed 
effect, visit as a repeated effect, treatment by visit interaction and baseline as a continuous 
covariate. An unstructured covariance model will be used. Point estimates and the associated 
95% confidence intervals for the difference between treatment and placebo at each visit will 
be provided.
7.2.1
Model checking procedures
For the frequency table of the proportion of patients with a renal events, patients who 
complete at least 2 weeks of treatment will be included in the denominator.
7.3
Pharmacokinetic / Safety interactions
The relationship between PK and safety 
 may be explored using a graphical approach. 
Scatter plot between PK concentration and safety 
 at respective time points along with 
regression may be provided. 
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7.4
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by part, treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by part, treatment group and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by part, treatment group and subject.
Vital signs
All vital signs data will be listed by part, treatment group, subject, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by part, treatment group and visit/time.
ECG evaluations
All ECG data will be listed by part, treatment group, subject and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by part, treatment group, and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by part, treatment group, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by part, 
treatment group, and visit/time. Change from baseline data will also be listed and summarized.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
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7.5
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
Mean (SD) for Serum creatinine and change from baseline profiles will be provided.
9
Reference list
ARB dose (refer protocol).
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