Clinical trial NCT02515331
Conditions: Patients, Resistant Hypertension
Keywords: resistant hypertension
Sponsor: Novartis Pharmaceuticals
Start date: 2015-11-04; Completion date: 2017-08-17
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the present study was to determine whether LHW090 displays the clinical safety and efficacy profile to support further development in patients with resistant hypertension.

Detailed description:

Arms: arm 1: LHW090 100 mg once daily for 28 days arm 2: LHW090 200 mg once daily for 28 days arm 3: Matching placebo to LHW090 oral dose for 28 days
Interventions: intervention 1: LHW090 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsule - oral dose intervention 2: Capsule - oral dose

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LHW090
Clinical Trial Protocol CLHW090X2202
A randomized, sponsor open,site and subject double blind, 
parallel group, placebo-controlled study to evaluate the 
safety and efficacy of LHW090 after 4 weeks treatment in 
patients with resistant hypertension
Authors:
 
 
Document type:
AmendedProtocolVersion
EUDRACT number:
2015-001890-42
Version number:
v05(Clean)
Development phase:
II
Release date:
22-Aug-2016
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of figures......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................10
Protocol synopsis...............................................................................................................13
1 Introduction.......................................................................................................................17
1.1
Background............................................................................................................17
1.1.1
Relevant data summary.........................................................................18
1.2
Study purpose........................................................................................................21
2 Study objectives.................................................................................................................22
2.1
Primary objective(s)...............................................................................................22
2.2
Secondary objective(s)...........................................................................................22
2.3
Exploratory objective(s)........................................................................................22
3 Investigational plan...........................................................................................................23
3.1
Study design...........................................................................................................23
3.2
Rationale of study design.......................................................................................24
3.3
Rationale of dose/regimen, duration of treatment.................................................24
3.4 
Rationale for choice of comparator.......................................................................25
3.5
Purpose and timing of interim analyses/design adaptations..................................25
3.6
Risks and benefits..................................................................................................26
4 Population..........................................................................................................................26
4.1
Inclusion criteria....................................................................................................27
4.2
Exclusion criteria...................................................................................................27
5 Restrictionsfor StudySubjects.........................................................................................29
5.1
Contraception requirements...................................................................................29
5.2 
Allowable Medications..........................................................................................29
5.3
Prohibited treatment...............................................................................................
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5.4
Dietary restrictions and smoking...........................................................................31
5.5
General restrictions................................................................................................31
6 Treatment...........................................................................................................................31
6.1
Study treatment......................................................................................................31
6.1.1
Investigational treatment.......................................................................31
6.2
Treatment arms......................................................................................................31
6.3
Permitted dose adjustments and interruptions of study treatment.........................31
6.4
Treatment assignment............................................................................................32
6.5
Treatment blinding.................................................................................................32
6.6
Emergency breaking of assigned treatment code..................................................33
6.7
Treatment exposure and compliance.....................................................................33
6.8
Recommended treatment of adverse events..........................................................33
6.9 
Rescue medication.................................................................................................33
6.10 Concomitant treatment...........................................................................................33
7 Discontinuation and study completion..............................................................................34
7.1
Discontinuation of study treatment........................................................................34
7.2
Study completion and post-study treatment..........................................................35
7.2.1
Lost to follow-up...................................................................................35
7.3
Withdrawal of consent...........................................................................................35
7.4
Study Stopping rules..............................................................................................36
7.5
Early study termination..........................................................................................36
8 Procedures and assessments..............................................................................................37
8.1
Informed consent procedures.................................................................................38
8.2
Subject demographics/other baseline characteristics.............................................38
8.3
Efficacy / Pharmacodynamics...............................................................................39
8.3.1
Ambulatory blood pressure monitoring................................................39
8.4
Safety.....................................................................................................................39
8.4.1
Physical examination............................................................................39
8.4.2
Vital signs..............................................................................................39
8.4.3
Height and weight.................................................................................40
8.4.4
Laboratory evaluations..........................................................................40
8.4.5
Electrocardiogram (ECG).....................................................................40
8.5
Pharmacokinetics...................................................................................................41
8.6
Other assessments..................................................................................................41
8.6.1
Exploratory Biomarker assessments: cGMP, Aldosterone, 
Neprilysin..............................................................................................41


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9 Safety monitoring..............................................................................................................42
9.1
Adverse events.......................................................................................................42
9.2
Serious adverse event reporting.............................................................................44
9.2.1
Definition of SAE.................................................................................44
9.2.2
SAE reporting........................................................................................45
9.3
Liver safety monitoring.........................................................................................46
9.4
Renal safety monitoring.........................................................................................49
9.5
Pregnancy reporting...............................................................................................50
9.6
Prospective suicidality assessment........................................................................50
9.7
Early phase safety monitoring...............................................................................50
10 Data review and database management.............................................................................51
10.1 Site monitoring......................................................................................................51
10.2 Data collection.......................................................................................................51
10.3 Data Monitoring Committee..................................................................................53
10.4 Adjudication Committee........................................................................................53
11 Data analysis......................................................................................................................53
11.1 Analysis sets..........................................................................................................53
11.2 Subject demographics and other baseline characteristics......................................53
11.3 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................53
11.4 Analysis of the primary variable(s).......................................................................54
11.4.1
Variable(s).............................................................................................54
11.4.2
Statistical model, hypothesis, and method of analysis..........................54
11.4.3
Handling of missing values/censoring/discontinuations.......................54
11.4.4
Supportive analyses...............................................................................55
11.5 Analysis of secondary and exploratory variables..................................................55
11.5.1
Efficacy / Pharmacodynamics...............................................................55
11.5.2
Safety.....................................................................................................55
11.5.3
Pharmacokinetics..................................................................................56
11.5.4
Pharmacokinetic / pharmacodynamics interactions..............................56
11.5.5
Other assessments.................................................................................56
11.6 Sample size calculation..........................................................................................57
11.7 Power for analysis of key secondary variables......................................................57
11.8 Interim analyses.....................................................................................................57
12 Ethical considerations........................................................................................................58
12.1 Regulatory and ethical compliance........................................................................58


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12.2 Responsibilities of the investigator and IRB/IEC..................................................58
12.3 Publication of study protocol and results...............................................................59
13 Protocol adherence............................................................................................................59
13.1 Protocol Amendments...........................................................................................59
14 References.........................................................................................................................60
List of tables
Table 8-1
Assessment schedule.............................................................................37
Table 9-1
Liver Event and Laboratory Trigger Definitions..................................47
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers...47
Table 9-3
Specific Renal Alert Criteria and Actions.............................................49
List of figures
 
Figure 3-1
Study design..........................................................................................
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List of abbreviations
ABPM
Ambulatory blood pressure monitor
ACE
Angiotensin-converting-enzyme 
AE
Adverse event
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
ARB
Angiotensin Receptor Blocker
ASH/ISH
American Society of Hypertension and the International Society of 
Hypertension
ANP
Atrial natriuretic peptide
AST
Aspartate aminotransferase
BMI
Body Mass Index
BNP
B-type natriuretic peptide
BP
Blood pressure
CABG
Coronary artery bypass grafting
CD-ROM
Compact disc –read only memory
CNP
C-type natriuretic peptide
CFR
Code of Federal Regulation
cGMP
Cyclic guanosine monophosphate
CK
Creatine kinase
CRF
Case Report/Record Form (paper or electronic)
CRI
Chronic renal impairment
CRO
Contract Research Organization
C-SSRS 
Columbia Suicide Severity Rating Scale
CV
Coefficient of variation
DDI
Drug-drug interaction
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ESC
European Society for Cardiology
FDA
Food and Drug Administration
FIH
First in human


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GCP
Good Clinical Practice
GFR
Glomerular filtration rate
h
hour
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
LFT
Liver function test
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities 
mg
Milligram(s)
ml
Milliliter(s)
NEP
Natriuretic peptides
NSAIDS
Nonsteroidal anti-inflammatory drugs
PA
Posteroanterior
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
p.o.
Oral(ly)
RBC
Red blood cell(s)
REB
Research Ethics Board
RHT
Resistant hypertension
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SOM
Site operations manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TIA
Transient ischemic attack


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ULN
Upper limit of normal
WBC
White blood cell(s)
WHO
World Health Organization


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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 [ngx hr/ mL]
AUClast
The area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration [ngx hr/ mL]
Cmax
The observed maximum plasma concentration following drug administration 
[ng/ mL]
Tmax
The time to reach the maximum concentration after drug administration [hr]


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Protocol synopsis
Protocol number
LHW090X2202
Title
A randomized, sponsor open, site and subject blind, parallel group, placebo-
controlled study to evaluate the safety and efficacy of LHW090 after 4 weeks 
treatment in patients with resistant hypertension
Brief title
Safetyand efficacy study of LHW090 in resistant hypertension patients
Sponsor and Clinical 
Phase
Novartis 
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
To determine whether LHW090 displays the clinical safety and efficacyprofile 
to support further development in patients with resistant hypertension.
Primary Objective(s)
To assessthe safety and tolerability of LHW090 for 4 weeks on a 
background of conventional anti-hypertensive medications in patients 
with resistant hypertension. 
To evaluate the effect of LHW090 on placebo-adjusted mean daytime 
systolic blood pressure (SBP) after 4 weeks in patients with resistant 
hypertension.
Secondary 
Objectives
To evaluate the pharmacokinetics (PK) of LHW090 and its active 
metabolite LHV527 in patients with resistant hypertension.
Study design
This is a non-confirmatory, randomized, sponsor open, site and subject blind, 
parallel group, placebo-controlled study to evaluate the safety and efficacy of 
4 weeks treatment with LHW090 in patients with resistant hypertension. 
Patients with uncontrolled hypertension as defined as a mean daytime 
systolic blood pressure ≥ 135 mmHg by ambulatory blood pressure 
monitoring (ABPM) on a stable (at least 1 month) regimen of an angiotensin 
receptor blocker (ARB) plus a diuretic plus at leastoneadditional class of
anti-hypertensive medication will be considered for this trial. Patients with 
resistant hypertension will be randomized to either placebo or 1 of 2 dose 
regimens of LHW090, i.e. LHW090 100 mg once dailyorLHW090 200 mg 
once daily, as an add-on to their anti-hypertensive regimen at baseline.
Each subject will participate in an approximately3 week screening period, a 
2-week single blind placebo run-in period, baseline assessments, a 4 week 
treatment period, and an end of study assessment. During the 2 week 
placebo run-in period, patients will receive regular reminders to be compliant 
with their anti-hypertensive medications. At the end of this run-in period, 
patients who demonstrate ≥80% compliance with placebo will be 
randomized. Compliance will be established by pill count and review of 
medication diary. Subjects will be advised that study entry cannot be fully 
determined until the completion of the run-in period. 


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On Day -2, patients will commence 24 hour ABPM monitoring and return the 
next day (Day -1) to have the ABPM device removed and the data collected. 
Patients may have additional attemptsto complete a successful ABPM 
assessment (defined by satisfactory BP data sampling over the 24 hours and 
standards for device quality check) if the first attempt is unsuccessful 
(O
'Brienet al 2013). Upon collection of satisfactory baseline ABPM 
assessment, subjects will then return for baseline pharmacodynamic 
assessments on Day -1 and then begin active treatment on Day 1. Patients 
will be randomized to either:

LHW090 100 mg once daily for 28 days

LHW090 200 mg once daily for 28 days

Matching placebo for 28 days
Subjects have the option to return on Day 3 for vital sign. Subjects will then 
visit the clinic at weekly intervals (Day 7, 14 and 21) for safety, PK, and PD 
assessments. On visit days, subjects will be instructed to take their 
medications at the site. On Day 27, patients will commence a final24 hour 
ABPM assessment and then return the next day to have the device removed 
and then begin collection of Day 28 steady-state PK and PD assessments. 
Patients will be asked to return after approximately 1 week for end of study 
(EOS) assessments.
Population
The study population will be comprised of patients with uncontrolled 
hypertension (here defined as having a mean daytime systolic BP 
≥135mmHgby ABPM) despite treatment with optimaldosesof an ARB plus 
a diureticplus at least one additionalclass of anti-hypertensive medications. 
Approximately 80 patients age 40 to 85 years old (inclusive) will be enrolled 
and randomized in the study.
Inclusion criteria

Written informed consent must be obtained before any assessment is 
performed.
Male and female patients, age 40 to 85 years inclusive.
Demonstrating a ≥ 80% medication compliance rate during the single-
blind run-in period.
Patients with uncontrolled hypertension (here defined as having a mean 
daytime systolic BP ≥ 135mmHgby ABPMat screening) despite 
treatment with a stable (at least 1month) regimen that includes an 
optimal dose of an ARB plus optimal doses ofa diuretic plus at least one
additionalclass of anti-hypertensive medication.
For the purposes of this trial, optimal doses of anti-hypertensive 
medications are defined as:
the highest dose listed in the clinical practice guideline from the 
American Society for Hypertension and the International Society for 
Hypertension (Weber et al 2014)or
the highest allowable prescribed dose per the manufacturer
's label 
or
the highest dose tolerated by an individual patient or
the highest dose appropriate for an individual patient in the judgment 
of the Investigator
Note: documented ABPM values within 3 months of screening are 
acceptable.

Subjects must weigh at least 45 kg to participate in the study and must 
have a body mass index (BMI) within the range of 18-40kg/m2.


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
Able to communicate well with the investigator, to understand and comply 
with the requirements of the study.
Exclusion criteria
Patients with an estimated GFR <60 ml/min/1.73m2.
Use of angiotensin converting enzyme inhibitors (ACE-inhibitors).
Note: Patients who discontinue their ACE-inhibitor and substitute with an 
angiotensin receptor blocker may be eligible to be re-screened provided 
their anti-hypertensive regimen has been stable for at least 1month. Any 
substitutions or changes to a patient
's anti-hypertensive regimen should 
be done under the guidance of the patient
's treating physician.
Severe hypertension as defined by systolic blood pressure ≥180 mmHg 
or diastolic blood pressure ≥110 mmHg at screeningor baseline.
A history of secondary hypertension of any etiology including but not 
limited to unilateral or bilateral renal artery stenosis, polycystic kidney 
disease, coarctation of the aorta, primary hyperaldosteronism, Cushing
's 
disease, pheochromocytoma, and drug-induced hypertension.Ifthe 
patient has not been evaluated for secondary hypertension, investigators 
are responsible to evaluate all potential secondary causes of 
hypertension considering clinical history, physical examination, laboratory 
investigations or other relevant diagnostic measures in accordance with 
current practices and clinical guidelines before entering the patient into 
the study (Chobanianet al 2003; Mancia et al 2013; Weber et al 2014).
Known current significant left ventricular outflow obstruction, such as 
obstructive hypertrophic cardiomyopathy or significant severe valvular 
disease on prior or current echocardiogram).
A history of known moderate or malignant hypertensive retinopathy 
defined as moderate (retinal signs of hemorrhage), microaneurysms, 
cotton-wool spots, hard exudates, or a combination thereof) or malignant 
(signs of moderate retinopathy plus swelling of the optic disk).Patients
with a stable ophthalmologic history in the past 6 months are eligible. 
Anynew or progressive retinal changes, acute glaucoma or other 
ophthalmologic conditions within the past 6 months should be evaluated 
by the treating ophthalmologist during screening.
To facilitate ABPM assessment, an upper arm circumference greater 
than 42 cm or third shift or overnight workers.
History within the previous 6 months of myocardial infarction, coronary 
artery bypass graft (CABG), percutaneous coronary intervention (PCI), 
hypertensive encephalopathy, stroke, or transient ischemic attack (TIA).
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant.
Investigational and 
reference therapy
Subjects will be assigned to one of the following 3 treatment arms in a ratio of 
1:1:2:
Study treatments are defined as:
A:  100 mg LHW090 
B:  200 mg LHW090
C:  matching placebo
Efficacy/PD
assessments
ABPM


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Safety assessments
Vital signs
Hematology
Chemistry
Urinalysis
ECG evaluation
Physical exam
AE/SAEs
Other assessments
Data analysis
The primary efficacy variable will be the change in the 12 hour average of 
systolic blood pressure measured by ambulatory blood pressure monitoring 
(ABPM) 28 days following the start of treatment. Out-of-office ABPM is a 
more reliable measure of a patient
's blood pressure than office-based BP 
readings which may be falsely elevated because of "white-coat" phenomena 
(Bakris et al 2010). The change from baseline in the placebo group will be 
compared to the change from baseline in the pooled LHW090 doses. 
Thecriteria to demonstrate efficacy (success) will be based on statistically 
significant (1-sided p<0.1) greater reduction from baselinein mean daytime 
SBP with active treatment (pooled doses) than with placebo, as well as an 
estimated median reduction on active treatment (pooled active doses) of at 
least 7 mmHg higher than on placebo. The threshold of a 7 mmHg reduction 
in placebo-adjusted systolic BP by ABPM is considered clinically significant 
since similar magnitude changes were observed in a phase 3 trial of an 
endothelin-receptor antagonist, darusentan, for the same indication 
(Weberetal 2009).
Study patients will be randomized into one of 3 groups, placebo, 100 mg 
LHW090 and 200 mg LHW090, as an add-on therapy to conventional 
background anti-hypertensive therapy. 40 patients will be randomized to 
placebo, and 20 to each dose of active treatment. This will give around 32 
completers in the placebo group and 16 on each active dose group. 
Theprimary analysis of change in mean daytime systolic blood pressure will 
be performed using the data collected during the period 0900 to 2100 
consistent with recommendations from the European Society for 
Hypertension (O
'Brienet al 2013). The average of these 12 hours of data will 
be produced using data from the baseline ambulatory blood pressure 
monitoring on Day -2 and Day 27.
The change from baseline in mean daytime SBP will be estimated from a 
longitudinal model using all data collected for every patient until Day 27. 
Themodel will include fixed effects for baseline, treatment (including dose), 
and visit, and a random effect for each subject. This analysis is unbiased 
under the assumption that the data are missing at random (MAR).
Key words
Resistant hypertension
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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 (Valderramaetal2012). 
Thephenomenon 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 issuedsimilar definitions (Manciaetal2013; 
Weber etal2014). 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 potentiallysalutary 
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 toa 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). 
NEPinhibition in combination with an ARB may represent an attractive therapeutic option for 
patients with RHT.
LHW090 is an orally administered prodrug, which upon ester hydrolysis is metabolized to 
LHV527, a highly potent and specific inhibitorof NEP. LHW090 was safe and well-tolerated 
when administered to healthy subjects and subjects with baseline chronic renal insufficiency.
The purpose of the current study is to determine whether LHW090 displays the clinical safety 
and efficacy profile to support further development forRHT.


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1.1.1
Relevant data summary


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1.2
Study purpose
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The purpose of the present study is to determine whether LHW090 displays the clinical safety 
and efficacy profile to support further development in patients with resistant hypertension.


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2
Study objectives
2.1
Primary objective(s)
Objective
Endpoint
To assess the safety and tolerability of 
LHW090 for 4 weeks on a background of 
conventional anti-hypertensive medications 
in patients with resistant hypertension. 
Safety endpoints (adverse events, 
serious adverse events) up to and 
including end of study assessments
To evaluate the effect of LHW090 on 
placebo-adjusted mean daytime systolic 
blood pressure (SBP) after 4 weeks in 
patients with resistant hypertension.
Change from baseline daytime SBP on 
week 4 by Ambulatory blood pressure 
monitoring
2.2
Secondaryobjective(s)
Objective
Endpoint
To evaluate the pharmacokinetics (PK) of 
LHW090 and its active metabolite 
LHV527 in patients with resistant 
hypertension.
PK parameterson Day 28 (Cmax, Tmax, 
AUClast, AUC0-t)
2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is anon-confirmatory, randomized, sponsor open, site and subject blind, parallel group, 
placebo-controlled study to evaluate the safety and efficacy of 4 weeksonce dailytreatment 
with LHW090 in patients with resistant hypertension. Patients with uncontrolled hypertension
defined as a mean daytime systolic blood pressure ≥ 135mmHgby ambulatory blood pressure 
monitoring (ABPM) on a stable (at least 1 month) regimen of optimal doses of an angiotensin 
receptor blocker (ARB) plus a diuretic plus at least oneadditionalclass of anti-hypertensive 
medication will be considered for this trial (Weber et al 2014;Vongpatanasin2014;
Calhounetal2008). Patients with resistant hypertension will be randomized to either placebo 
or 1 of 2 dose regimens of LHW090, i.e. LHW090 100 mg once daily, LHW090 200 mg once 
daily, as an add-on to their anti-hypertensive regimen at baseline.
Each patientwill participate in an approximately 3 week screening period, a 2-week single 
blind placebo run-in period, baseline assessments, a 4 week treatment period, and an end of 
study assessment(Figure 3-1). During the 2 week placebo run-in period, patients will receive 
regular reminders by the site to be compliant with their anti-hypertensive medications. At the 
end of this run-in period, patients who demonstrate ≥ 80% compliance with placebo will be 
randomized.Compliance will be established by pill count and review of medication diary.
Patients will be advised that study entry cannot be fully determined until the completion of the 
run-in period. 
On Day -2, patients will commence 24 hour ABPM monitoring and return the next day 
(Day-1) to have the ABPM device removed and the data collected. Patients may have 
additional attemptsto complete a successful ABPM assessment (defined by satisfactory BP 
data sampling over the24 hours and standards for device quality check) if the previous 
attemptsare unsuccessful (O
'Brien et al 2013). Upon collection of satisfactory baseline 
ABPM assessment, patients will then return for baseline pharmacodynamic assessments on 
Day -1 and then begin active treatment on Day 1. Patients will be randomized in a 1:1:2 
fashion to either:
LHW090 100 mg once dailyfor 28 days
LHW090 200 mg once dailyfor 28 days
Matching placebo for 28 days
Patientshave the option toreturn on Day 3 for vital signs. Patientswill then visit the clinic at 
weekly intervals (Day 7, 14 and 21) for safety, PK, and PD assessments. On visit days, 
patientswill be instructed to take their medications at the site. On Day 27, patients will 
commence a final 24 hour ABPM assessment and then return the next day to have the device 
removed and then begin collection of Day28 steady-state PK and PD assessments.As stated 
above, patients may have additionalattemptsto complete a successful ABPM assessment 
(defined by satisfactory BP data sampling over the 24 hours and standards for device quality 
check) at the Sponsor’s discretion if previousattemptsareunsuccessful (O
'Brienetal2013). 
Patients will be asked to return after approximately 1 week for end of study (EOS) 
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Figure 3-1
Study design
3.2
Rationale of study design
The study design addresses the primary objectives of evaluating the clinical safety and 
efficacy of LHW090 in patients with resistant hypertension as an add-on therapy to 
conventionally prescribed anti-hypertensive medications. The parallel design was chosen to 
allow comparison of LHW090 to placebo in a reasonable timeframe. The 2-week single-blind, 
placebo run-in period allows for an assessment of the patient
's compliance with anti-
hypertensive medications prior to entering the sponsor open, site and subject blindtreatment 
period. The randomization ratio of 1:1:2 will provide equal sample sizes (1:1) in the 
comparison of the LHW090 patients versus the placebo patients.  This ratio allows for the 
most powerful comparison.  ABPM is the method of choice for measuring blood pressure 
changes with new anti-hypertensive drugs as it allows an assessment of the effect of the drug 
over a 24 hour period. Moreover, out-of-office BP measurements such as ABPM are 
considered a more reliable means of diagnosing and monitoring resistant hypertension since 
office-based BP may be confounded by 
'white-coat
' effects. Though both systolic and diastolic 
blood pressure readings will be collected over a 24 hour period, changes in the patient
's 
daytime systolic blood pressure will beassessed as the primary objective in order to minimize 
differences in individual subject variation in daytime versus nighttime blood pressures.
3.3
Rationale of dose/regimen, duration of treatment
The doses of LHW090 were selected based on the safety and tolerability observed in the FIH
study. The administration of multiple doses of LHW090 in healthy subjects up to 400mg 
once daily for 14 days was safe and well tolerated with no deaths or severe adverse events 
reported. Most adverse events were mild and none of the adverse events led to the 
discontinuation of the subjects from the study. The relationship between exposure(AUC24hr) 


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and urine cGMP excreted over 24 hours was analyzed in healthy subjects. Based on Emax 
modeling, LHW090 100 mg once daily was estimated to be the ED90. Experience with the 
combined angiotensin receptor-neprilysin inhibitor compound, LCZ696, across multiple 
studies of patients with essential hypertension, suggests that the pharmacodynamic effects on 
urine cGMP peak at lower doses than the peak BP lowering effects; this is the rationale for 
studying the 200 mg dose level.Moreover, in the LCZ696 studies, most of the 
antihypertensive effect of LCZ696 had occurred by the fourth week of treatment 
(Ruilopeetal 2010). Therefore, a fourweek duration of treatment was selected because a 
shorter duration of treatment may underestimate the full antihypertensive effect of LHW090. 
With regard to PK, the exposure of the active metabolite LHV527 at 100 mg and 200mg 
doses are expected to remain at ≥ IC90 levels (in vitro plasma inhibitory concentrations for 
NEP inhibition) across the 24 hour duration at steady-state.
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
Corporate Confidential Information
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.6
Risks and benefits
This study will be conducted in patients with resistant hypertension. There is no benefit 
expected for subjects participating in this study. All patients will receive study medication on 
top of their usual antihypertensive medications.
 
 
 
 
 
 
 
 
 
 
 
 
There may beunknown risks of LHW090which may be serious and unforeseen.
4
Population
The study population will be comprised of patients with uncontrolled hypertension 
(heredefined as having a daytime systolic BP ≥ 135 mmHg by ABPM) despite treatment with 
optimaldosesof an ARB plus adiureticplus at least one additional class of anti-hypertensive 
medication.
Approximately 80 patients,aged40 to 85 years old (inclusive),will be enrolled and 
randomized in the study.
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibilitycriteria at screening 
and baseline(day -2).A relevant record (e.g. checklist) of the eligibility criteria must be 
stored with the source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
Replacement subjects will be enrolled to replace subjects who discontinuethe study for 
reasons other than safety or lack of efficacy
Corporate Confidential Information
.
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4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients, age 40 to 85 years inclusive.
3. Demonstrating a ≥ 80% medication compliancerate during the single-blind run-in period.
4. Patients with uncontrolled hypertension (here defined as having a mean daytime systolic 
BP ≥135mmHg by ABPMat screening) despite treatment with a stable (at least 1month) 
regimen that includesoptimal dosesof an ARB plus a diuretic (thiazide or loop) plusat 
leastone additionalclass of anti-hypertensive medication.
For the purposes of this trial, optimal doses of anti-hypertensive medications are defined 
as:
thehighest dose listed in the clinical practice guideline from the American Society for 
Hypertension and the International Society for Hypertension (Weber et al 2014)or
the highest allowable prescribed dose per the manufacturer
's label or
the highest dose tolerated by an individual patient or
the highest dose appropriate for an individual patient in the judgment of the 
Investigator
Note: documented ABPM values within 3 months of screening are acceptable.
5. Subjects mustweigh at least 45 kg to participate in the study and must have a body mass 
index (BMI) within the range of 18-40kg/m2.
6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
Noadditional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Use of otherinvestigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer; or longer if required by local regulations, and for 
any other limitation of participation in an investigational trial based on local regulations.
2. History of hy
persensitivity to any of the study
 drugs or to drugs of similar chemical classes.
3. Patients with an estimated GFR <60 ml/min/1.73m2 at screening using the MDRD 
equation.
4. Use of angiotensin converting enzyme inhibitors (ACE-inhibitors).
Note: Patients who discontinue their ACE-inhibitor and substitute with an angiotensin 
receptor blocker may be eligible to be re-screened provided their anti-hypertensive 
regimen has been stable for at least 1 month. Any substitutions or changes to a patient
's 
anti-hypertensive regimen should be done under the guidance of the patient
's treating 
physician.
5. History of angioedema, drug-related or otherwise, as reported by the patient.


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6. Clinically significant ECG abnormalitiesat screeningas determined by the Investigator.
7. Severe hypertension as defined by an office systolic blood pressure ≥180 mmHg or 
diastolic blood pressure ≥110 mmHg at screeningor baseline.
8. A history of secondary hypertension of any etiology including but not limited to unilateral 
or bilateral renal artery stenosis, polycystic kidney disease, coarctation of the aorta, 
primary hyperaldosteronism, Cushing
's disease, pheochromocytoma, and drug-induced 
hypertension. If the patient has not been evaluated for secondary hypertension, 
investigators are responsible toevaluate all potential secondary causes of hypertension 
considering clinical history, physical examination, laboratory investigationsor other 
relevant diagnostic measuresin accordance with current practices and clinical guidelines
before entering the patient into the study(Chobanian et al 2003; Mancia et al 2013; 
Weber etal2014).
9. Known current significant left ventricular outflow obstruction, such as obstructive 
hypertrophic cardiomyopathy or significant severe valvular disease on prior or current 
echocardiogram).
10.A history of known moderate or malignant hypertensive retinopathy defined as moderate 
(retinal signs of hemorrhage), microaneurysms, cotton-wool spots, hard exudates, or a 
combination thereof) or malignant (signs of moderate retinopathy plus swelling of the 
optic disk).Patients with astable ophthalmologic history in the past 6 months are eligible. 
Any new or progressive retinal changes, acute glaucoma or other ophthalmologic 
conditions within the past 6 months should be evaluated by the treating ophthalmologist 
during screening.
11.To facilitate ABPM assessmentof daytime readings, anupper arm circumference greater 
than 42 cmor third shift or overnight workers.
12.History within the previous 6 months of myocardial infarction, coronary artery bypass 
graft (CABG), percutaneous coronary intervention (PCI), hypertensive encephalopathy, 
stroke, or transient ischemic attack (TIA).
13.Hemoglobin levels below 9.0 g/dL at screening.
14.History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situcervical cancer), treated or untreated, within the past 1 year, regardless 
of whether there is evidence of local recurrence or metastases.
15.Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing, or 
longer if required by local regulation.
16.Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
17.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 12months 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 


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the woman has been confirmedby follow up hormone level assessment is she considered 
not of child bearing potential. 
18.Sexually active males must use a condom during intercourse while taking drug and for 
1week after stopping study medication and should not father a child in this period. 
Acondom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.
19.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.
20.On the Columbia-Suicide Severity Rating Scale,score “yes” on item 4 or item 5 ofthe 
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 inthe past2 years.Any patient meeting this exclusion criterion should 
be referred to a mental health care professional.
21.Vulnerable subjects, e.g. subjects kept in detention, soldiers andemployees of the sponsor 
or a clinical research organization, involved in this study.
Note: In the case where a safetylaboratory assessmentat screening andinitial baselineis 
outside of the range specified above, the assessment may be repeated once prior to 
randomization. If the repeat value remains outside ofthespecified ranges, the subjectis 
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.
5 
Restrictionsfor StudySubjects
Patientsmustbe informed and reminded of the following restrictionsfrom screening until the 
end of the study visit:
5.1
Contraception requirements
Not applicable. Only women of non-childbearing potential will be included in this study.
5.2
Allowable Medications
Allowableanti-hypertensives(besides an ARB and a diuretic) include
Calcium channel blockers
Beta-blockers
Potassium-sparing diuretics such as spironolactone, eplerenone, or amiloride
Direct vasodilators
Alpha-blockers
Patients must be on a stable regimen throughout the trial, and for at least one month prior to 
the study.


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5.3
Prohibited treatment
Use of the following medications isnot allowed during the course of the study from screening 
(Visit 1) to the end of the study. Subjects who are receiving such medication(s) will be 
excluded, or if ethically and clinically justified, the medication(s) should be gradually 
withdrawn before Visit 2: 
1. Any drug that, in the discretion of the investigator, may affect the assessment of blood 
pressure in this study or contribute to drug-induced hypertensionsuch as:
Any anti-depressant drugs in the MAO inhibitor class, tricyclics, and venlafaxine, 
duloxetine, and buproprion. Other psychotropic drugs such as benzodiazepines and 
selective serotonin reuptake inhibitors (SSRIs)are permittedif the patient has been on 
a stable dose for the previous 3 months.
Chronic administration (defined as > 3 days per week) of sympathomimetic drugs such 
as those found in nasal decongestants, oral decongestants, diet aids and 
bronchodilators. Doses of sympathomimetic drugs usedoccasionally are prohibited 
24hours prior to the study visit.
Thyroid medication, estrogen-based and/or androgen-based hormone replacement 
therapiesunless on a stable regimen for at least 3 months prior to Visit 1and is not 
expected to change during the course of the study.
Ergot and serotonin (5-hydroxytryptamine) receptor agonist preparations.
Drugs for the treatment of attention deficit hyperactivity disorder (ADHD), including 
methylphenidate, amphetamine, and atomoxetine.
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.
Oral nitrates. Intermittent use ofsublingual nitrates are allowed but must not be used 
within 12 hours prior to any scheduled visit.
Chronic administration (defined as >3 days per week) of PDE5 inhibitors (e.g. 
sildenafil, vardenafil, tadalafil). Intermittent use of PDE5 inhibitors are allowed but 
must not be used within 48 hours prior to any scheduled visit.
Chronic (defined as >3 days per week) treatment with oral or parenteral corticosteroid 
treatment.The use of inhalational corticosteroids is permitted.
2. The following medications are prohibited due to potential for pharmacokinetic drug-drug
interactions: amodiaquine,atazanavir,bosentan,bupropion, celecoxib,cimetidine,
cyclosporine,diclofenac,efavirenz, eltrombopag,gemfibrozil,glyburide,glimepiride,
imatinib, irinotecan, ifosfamide, lapatinib, lopinavir,methotrexate, mitoxantrone, 
paclitaxel,phenytoin, pioglitazone, probenecid,  repaglinide,rifampin, ritonavir,
saquinavir,tipranavir, topotecan,and warfarin.
3. All other prior non-study medications (notspecifically contraindicated in the exclusion 
criteria will beallowed, provided the patienthas been on astandard treatment regimen 
(atleast 4 weeks of thesame dose) and the treatment is not planned to be changed during 
the course of the study.


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5.4
Dietaryrestrictions and smoking
Patients should maintain their usual diet prior to, and during the study. Alterations in diet can 
lead to changes in sodium and potassium intake which could influence the results of this study.
No alcohol will be allowed starting24 hours prior to and during study visits and ABPM 
assessments.
Intake of xanthine (e.g.caffeine) containing food or beverages will be allowed during the 
study. Patients should be instructed to maintain their normal daily routine. However, the 
morning ofclinic visits, patients should avoid coffee(and other caffeine containing food 
or beverages), smoking and exercise for at least 30minutes prior to office BP 
measurements.  
In order to avoid wide variations in urine volumesoncollection days, subjects should be 
encouraged to have a fluid intake of approximately 240 mL every 4 hours during their 
waking hours, in addition to the fluid taken with meals and medication.
5.5
General restrictions
While wearing the ABPM, patients should avoid strenuous exercise or activity and 
bathing during the 24 hour period.
6
Treatment
6.1
Study treatment
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatmentare outlined in the Site Operations Manual.
6.1.1
Investigational treatment
The investigational drug, LHW090 100 mg and matching placebowill be prepared by 
Novartis and supplied to the Investigatorsite as single blinded patient packs.
6.2
Treatment arms
Patients will be assigned to one of the following 3treatment arms in a ratio of 1:1:2:
Study treatments are defined as:
A:  100 mg LHW090 
B:  200 mg LHW090 
C:  matching placebo 
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted.If a short treatment 
interruption becomes necessary for an important reason, the subject may resume the study 
treatment. However, drug interruption should end at least 3 days prior to the next study visit. 
In any case, the compliance of the subjects will be monitored and recorded.


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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 48hours must transpire 
between the last dose of LHW090 and the first dose of an 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 
hypertension guidelines(James et al 2014; Mancia et al 2013; Weber etal2014) and in 
compliance with applicable local prescribing informationfor renin angiotensin aldosterone 
(RAAS) agents.
6.4
Treatment assignment
Randomization numberswill be assigned in ascending, sequential order to eligible patients 
(see Site Operations Manual for details).The investigator will enter the randomization 
numberon the CRF.
The randomization numbers will be generated using the following procedure to ensure that
treatment assignment is unbiased and concealed from patients and investigator staff. A patient
randomization list will be produced by the Interactive Response Technology (IRT) provider
using a validated system that automates the random assignment of patient numbers to
randomization numbers. These randomization numbers are linked to the different treatment 
arms.The randomization scheme for patients will be reviewed and approved by a member of 
the Novartis IIS Randomization Group.
Prior to dosing, patients who fulfill all inclusion/exclusion criteria will be randomized viaIRT 
to one of the treatment arms. The investigator or his/her delegate will call or logon to theIRT 
and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will then
assign a randomization number to the patient, which will be used to link the patient to a
treatment arm.  
6.5
Treatment blinding
This is a sponsor open, site and subject double blind study: subjects, investigator staffand
persons performing the assessmentswill remain blind to the identity of study treatments 
according to the specifications provided in the Site Operations Manual.During the placebo 
run-in period (V2), placebo treatment will be administered to all patients and will be known 
by investigator staff and persons performing the assessments.
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, until unblinding of the trial as described in the table in the Blinding levels table in
the Site Operations Manual.
The results of the interim analyses may becommunicated(e.g.dose escalation decision, 
evaluation of PoC criteria or information needed for planning/modifying another study) to 
relevant Novartis teams for information, consulting and/or decision purposes.


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Unblinding will only occur in the case of patient emergencies (seeSection 6.6) and at the 
conclusion of the study.
6.6
Emergency breaking of assigned treatmentcode
Emergency unblinding should only be undertaken when it is essential to treat the patient
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the
possible treatment assignments are sufficient to treat a study patient who presents with an
emergency condition. Emergency code breaks are performed using the IRT system. When the
investigator contacts the system 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 or email
confirming this information. The system will automatically inform the Novartis monitor for
the site, the Clinical Trial Leader andTranslational Medical Expertthat 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 IRTin case of emergency. If appropriate, the investigator will inform the 
patienthow 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 
patientand, if applicable, whether the patientcan continueinto 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 withLHW090 as detailed in Section 8.5.
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 and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteriaprior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the 
CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.


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Due to the potential for pharmacokinetic drug-drug interactions, patients taking statins should 
be monitored for statin-related myositis (e.g. muscle pain or elevations in creatinekinase) 
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.  
7
Discontinuationand study completion
7.1
Discontinuation of study treatment
Subjectsmay voluntarily discontinuestudy treatment 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 subject withdrawal occurs for any reason, the 
investigator must make every effort to determine the primary reason for a subject’s 
withdrawal from the study and record this information on the CRF.
The investigator must discontinue studytreatment for a given patientif, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Study treatment mustbe discontinued under the following circumstances: 
Subject withdraws consent  
Pregnancy
Discontinuation of investigationaltreatment will be at the discretion of the Investigator, under 
the following circumstances:
Emergence of the following adverse events:
Symptomatic hypotension or orthostatic hypotension (hypotensive or orthostatic 
blood pressure readings must be confirmed on repeat measurement within 
30minutes) that requires medical intervention.
Systolic blood pressure <80 mmHg (must be confirmed on repeat measurement 
after 30 minutes)
Symptomatic severe hypertension(e.g., a systolic blood pressure >180 mmHg or a 
diastolic blood pressure >120 mmHg) that requires medical intervention
Any of the following laboratory abnormalities:
A reproducible and persistent (> 24 hours) increase in serum creatinine from 
baseline of >0.3 mg/dL unless the benefit/risk assessment supports continuing 
study treatment. Arenal event leading to patient discontinuation should be 
followed up until event resolution (Serum Cr within 10% of baseline), or event 
stabilization (Serum Cr level with ±10% variability over last 6months).
Use of prohibited treatment as per Section 5.3
Any other protocol deviation that results in a significant risk to the subject’s safety
The appropriate personnel from the site and Novartis will assess whether investigational 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.


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Subjects who discontinue study treatment or who decide they do not wishto participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3). Where possible, they should return for the assessments 
outlined at V777 in the assessment table. If they fail to return for these assessments for 
unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact them 
as specified inSection 7.2.1
7.2
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
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 
ofan 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. 
Documentation of attempts to contact the subjectshould be recorded in the source 
documentation.
7.2.1
Lostto 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
Patients may voluntarily
 withdraw consent to participate in the study for any
 reason at any
 time.
Withdrawal of consent occurs only when a patientdoes not want to participate inthe study 
anymoreanddoes not want any further visits or assessmentsanddoes not want any further 
study related contactanddoes not allow analysis of already obtained biologic material.
If a patientwithdraws 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. Allbiological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the patient
are not allowed unless safety findings require communicating or follow-up.


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7.4
Study Stopping rules
The studywill be stopped ifany of the following criteria are met and no furtherdosingwill be 
takenpending a full safety review:
2severeAEs arereported
3 subjects experience a persistent (> 24 hours) and reproducible increase in serum 
creatinine >0.3 mg/dL from baseline 
3 or more subjectsexperience a similar AE which is assessed as either moderate or severe
in intensity
7.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
subjectsshould 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.
Theinvestigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.




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8.1
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, iflater withdrawn) should be 
documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
 
 
 
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Subject demographics/other baseline characteristics
Corporate Confidential Information
Subject demographic and baseline characteristic data willbe 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.


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8.3
Efficacy/ Pharmacodynamics
Pharmacodynamic assessments are specifiedbelow, with the methods for assessment and 
recording specified in the Study Operations Manual.Assessments will be performed/samples 
collected at the timepoint(s) defined in the Assessment schedule.
In order to better define the PD profile, the timing of the sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceedthose stated in the protocol.  The results need to remain blinded 
during the study.
8.3.1
Ambulatory blood pressure monitoring
Continuous blood pressure monitoring will be performed over 24 hour periods to assess blood 
pressure, heart rate, mean arterial pressure, and pulse pressure. 
The ABPM device vendor will provide a reference/user manual giving more specific details 
on patientconsiderations for inclusion. Procedures for set-up, validation, quality control, use 
of software and transfer of data, and guidance for performing the measurements will also be 
provided in the vendor manual. Investigator site staff that will be performing the ABPM 
measurements will be trained appropriately by the device vendor to ensure the devices are 
used in the correct manner. Training will occur prior to initial use of the devices.
8.4
Safety
Safetyassessments are specifiedbelow;methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment scheduledetailing 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.
Information for all physical examinations should be included in thesource 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 


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8.4.3
Height and weight
Height
Body weight
Body massindex (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
8.4.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt,Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, LDH, GGT, AST, ALT, glucose, total cholesterol, creatine kinase 
(CK), and triglycerides.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
Urinalysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin
Ifthe dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
8.4.5
Electrocardiogram (ECG)
Corporate Confidential Information
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 confirmthe safety finding. Clinically significant ECG findings prior to 
dosing with investigational treatment must be discussed with the sponsor. 
Full details of all procedures relating to the ECG collection and reporting will be contained in 
the technical manual which is provided to the site by the core laboratory.


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For all studies:
PR interval, QRS duration, heart rate, RR, QT, QTc
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
8.5
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.
 
 
 
 
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 from the plasma concentration-time data.
Otherpharmacokinetic parameters may be determined, if relevant.
8.6
Other assessments
Corporate Confidential Information
 
 
 
 
 
 
 
Corporate Confidential Information


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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patientor 
clinical investigation subject after providing written informed consent
Corporate Confidential Information
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.


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The occurrence ofadverse 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 patientswith 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subjectand identifying adverse events. Alert ranges for liver related eventsare included in
Section9.3.
Adverse events must be recorded on the Adverse Events CRF for subjects thatpass screening 
and enterinto the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associatedwith 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
severe:
prevents normal activities
2. its relationship to theinvestigational treatment (no/yes), or other study treatment(non-
investigational) (no/yes), orboth or indistinguishable,
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 9.2for 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 treatmentdosage adjusted/temporarily interrupted 
study treatmentpermanently discontinued due to this adverse event 
concomitant medication given 
non-drug therapy given 
subjecthospitalized/subject’shospitalization prolonged 
6. its outcome (continuing at final exam; resolved)


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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 totreat 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 subjectinformed consent and should be discussed with the subject
during the study as needed.
The investigator should also instruct each subjectto report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’spersonal 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 criteriaof 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 anyone of the 
following criteria:
is fatal or life-threatening 
results in persistent or significant disability/incapacity
constitutes a congenital anomaly/birth defect
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has notworsened 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 subjector may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the subjectwas 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 
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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 subjectsafety, every SAE, regardless of causality, occurring after the subjecthas 
provided informed consent anduntil 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrenceas described below. Any SAEs 
experienced after thisshould only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
SAEs (initial and follow-up) that are recorded electronicallyin the ElectronicDataCapture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug 
Safety & Epidemiology immediately after investigator signature or 24 hours afterentry, 
whichever occurs first. Study site personnel must also informthe Clinical Trial Leader.
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subjectcontinued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported.Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
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9.3
Liver safety monitoring
To ensure subjectsafety 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 toTable 9-1and Table 9-2for 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 inTable 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 laboratoryto monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.
For the liver events:
Repeating the LFT to confirm elevation as appropriate
Discontinuation of the investigational drug(refer to Section 7.1,if appropriate
Hospitalizationof the subjectif 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 
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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 * 
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)


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Criteria
Actions required
Follow-up monitoring
> 3 ×ULN
accompanied by 
symptoms
b
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)
> 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 liverneoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1)return to baseline values, (2)stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.


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9.4
Renal safety monitoring
Renal events are defined as one of the following:
confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status
new onset (≥1+) proteinuria, hematuria or glucosuria; or as a
doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio 
(PCR) (if applicable).
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
Table 9-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
25 –49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Serum creatinine increase  50 % 
compared to baseline
Follow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Albumin-or Protein-creatinine ratio 
increase ≥ 2-fold
Albumin-creatinine ratio (ACR) ≥ 30 mg/g 
or ≥ 3 mg/mmol;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR )≥ 150 mg/g 
or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until one of the following:
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline) 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.


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9.5
Pregnancy reporting
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatmentin this study. Consent to report information regarding these 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.
9.6
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (C-SSRS), isa questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior. 
The C-SSRS, which uses a semi-structured interview to probe subjectresponses, will be 
administered by an individual who has received training and certification in its administration. 
At screening and baseline visits, 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 subjectmustbe referred to a mental health care professionalfor 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 professionalto whom the subjectis 
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 Behaviorsection) 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. 
Suchevaluations 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.


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When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
Duringthe studyNovartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. Themonitor will visit the site to check 
the completeness of subjectrecords, 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 eligibilitycriteria, 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 the CRO working on behalf of Novartis.TheInvestigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
Afterdatabase lock, the investigator will receive a CD-ROM or paper copies of the patient
data for archiving at the investigational site.


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Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule
Corporate Confidential Information
and canbe recorded directly on the CRFs.All other data captured for 
this study will have an external originating source (either written or electronic)withthe CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
CRO working on behalf of Novartis will 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 correctthe 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 theCRO working on behalf of Novartiswho will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes will be tracked using InteractiveResponse Technology (IRT). 
Thesystem will be supplied by a vendor, who will also manage the database. Thedatabase 
will be sent electronically to Novartis (or a designated CRO).
ABPM data will be collected by a designated CRO and the results will be sent electronically 
to Novartis and the data management CRO
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
Thecode break functionality will remain available until study shut down or upon request of 
Novartis.
Theoccurrence 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.
 
 
 
 
 


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10.3
Data Monitoring Committee
Not required.
10.4
Adjudication Committee
Not required.
11
Data analysis
All data analyses will be performed under the direction of Novartis personnel.  
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The full analysis set will include all subjects who received study treatment.
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 primary PD analysis set will include all subjects with available PD data. The secondary 
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 treatment group and 
subject. Summary statistics(mean[or geometric mean for log transformed data]), standard 
deviation, minimum, median and maximum)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 bytreatment group and subject.
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group andsubject.


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11.4
Analysis of the primary variable(s)
The primary efficacy variable will be the change in the 12 hour average of systolic blood 
pressure measured by ambulatory blood pressure monitoring (ABPM) 28 days following the 
start of treatment.
11.4.1
Variable(s)
The primary efficacy variable will be the change in the 12 hour average of systolic blood 
pressure measured by ambulatory blood pressure monitoring (ABPM) 28 days following the 
start of treatment.This is defined as the 12 hour daytime average systolic blood pressure on 
day28 minus the 12 hour daytime average systolic blood pressure on day -1.
11.4.2
Statistical model, hypothesis, and method of analysis
The primary efficacy variable will be the change in the 12 hour average of systolic blood 
pressure measured by ambulatory blood pressure monitoring (ABPM) 28 days following the 
start of treatment. Out-of-office ABPM is a more reliable measure of a patient
's blood 
pressure than office-based BP readings which may be falsely elevated because of "white-coat" 
phenomena (Bakris et al 2010). The change from baseline in the placebo group will be 
compared to the change from baseline in the pooled LHW090 doses. The criteria to 
demonstrate efficacy (success) will be based on statistically significant (1-sided p<0.1) greater 
reduction from baseline in mean daytime SBP with active treatment (pooled doses) than with 
placebo, as well as an estimated median reduction on active treatment (pooled active doses) of 
at least 7 mmHg higher than on placebo. The threshold of a 7 mmHg reduction in 
placebo-adjusted systolic BP by ABPM is considered clinically significant since similar 
magnitude changes were observed in a phase 3 trial of an endothelin-receptor antagonist, 
darusentan, for the same indication (Weber et al 2009).
Study patients will be randomized into one of 3 groups,placebo, 100 mg LHW090 and 
200mg LHW090, as an add-on therapy toconventional background anti-hypertensive therapy. 
40 patients will be randomized to placebo, and 20 to each dose of active treatment. This will 
give around 32 completers in the placebo group and 16 on each active dose group. The 
primary analysis of change in mean daytime systolic blood pressure will be performed using 
the data collected during the period 0900 to 2100 consistent with recommendations from the 
European Society for Hypertension (O
'Brien et al 2013). The average of these 12hours of 
data will be produced using data from the baseline ambulatory blood pressure monitoring on 
Day -2 and Day 27.The change from baseline in mean daytime SBP will be estimated from a 
longitudinal model using all data collected for every patient until Day27. The model will 
include fixed effects for baseline, treatment (including dose), and visit, and a random effect 
for each patient. This analysis is unbiased under the assumption that the data are missing at 
random (MAR).
11.4.3
Handling of missing values/censoring/discontinuations
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11.4.4
Supportive analyses
As a supportive analysis, the difference in efficacy between the twoactive doses will be 
examined by computing the t-statistic associated with the difference in means.
11.5
Analysis of secondary and exploratory variables
The secondary objective variables are obtained from pharmacokinetic analyses, as described 
in Section 11.5.3.  These analyses of these data are describedin this section.  
11.5.1
Efficacy / Pharmacodynamics
There are no efficacy secondary variables.  
 
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
Adverse events
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All information obtained on adverse events will be displayed by treatment andsubject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment.A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.


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11.5.3
Pharmacokinetics
 
Descriptive summary statistics will beprovided by treatment and 
visit/sampling time point, includingthe frequency (n, %) of concentrations below the LLOQ 
and reported as zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Anexception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statisticsand for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values.Pharmacokinetic parameters will be calculated as 
described inSection 8.5and will be listed by treatment and subject.PK-PD relationships will 
be explored as relevant.
 
11.5.4
Pharmacokinetic / pharmacodynamics interactions
The relationship between PK and key PD parameters may be explored using a graphical
approach. Descriptive statistics may be provided. 
11.5.5
Other assessments
 
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11.7
Power for analysis of key secondary variables
There are no power analyses for the secondary safety variables.
11.8
Interim analyses
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
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Before initiating a trial, the investigator/institutionshould 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.


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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 
protocoldeviation 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/IECprior to 
implementation. 
Onlyamendments that areintended to eliminate an apparent immediate hazard to subjects 
may be implemented,provided the Health Authorities and the reviewing IRB/IEC are 
subsequentlynotified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases,the CTL 
should be informed and (serious) adverseevent reporting requirements (Section 9) followed 
as appropriate.


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14
References
Available upon request
Bakris GL, Lindholm LH, Black HR, et al (2010) Divergent results using clinic and 
ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension 
p. 824-30.
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, anovel 
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.
Mancia G, Fagard R, Narkiewicz K, et al (2013) ESH/ESC Guidelines for the management of 
arterial hypertension. J Hypertens 31:1281-1357.
O
'Brien E, Parati G, Stergiou G, et al (2013) European Society of Hypertension position paper 
on ambulatory blood pressure monitoring. J. Hypertens. p. 1731-68.
Ruilope LM, Dukat A, Bohm M, et al (2010) Blood-pressure reduction with LCZ696, a novel 
dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, 
placebo-controlled, active comparator study. Lancet 375:1255-56.
Valderrama AL, GillespieC, King SC, et al (2012) Vital Signs: Awareness and Treatment of
Uncontrolled Hypertension Among Adults — United States, 2003–2010Morbidity and 
Mortality Weekly Report. 61(35):703-709.
Vongpatanasin W (2014) Resistant hypertension: a review of diagnosis and management. 
JAMA p. 2216-24.
Weber MA, Black H, Bakris G, et al (2009) A selective endothelin-receptor antagonist to 
reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-
blind, placebo-controlled trial. Lancet p. 1423-31.


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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

SAP_001.pdf: 
Biostatistics & Statistical Programming /
Novartis Institutes for BioMedical Research
LHW090
Study CLHW090X2202
A randomized, sponsor open, site and subject double blind, 
parallel group, placebo-controlled study to evaluate the 
safety and efficacy of LHW090 after 4 weeks treatment in 
patients with resistant hypertension
Statistical Analysis Plan(SAP)
Author(s):
Document type:
Statistical Analysis Plan: Detailed Statistical Methodology
Document status:
FinalAmendment 3
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................4
1 Introduction to RAP documentation....................................................................................5
1.1 
Scope........................................................................................................................5
2 Study objectives and design................................................................................................5
2.1
Study objectives.......................................................................................................5
2.1.1
Primary objectives...................................................................................5
2.1.2
Secondary objective................................................................................5
2.1.3
Exploratory objectives............................................................................5
2.2
Study design and treatment......................................................................................5
3 First interpretable results (FIR)...........................................................................................6
4 Interim analyses...................................................................................................................6
5 Statistical methods: Analysis sets........................................................................................7
6 Statistical methods for Pharmacokinetic (PK) parameters..................................................8
6.1
Variables..................................................................................................................8
6.2
Descriptive analyses................................................................................................8
6.3
Graphical presentation of results.............................................................................9
6.4
Pharmacokinetic / pharmacodynamics interactions.................................................9
7 Statistical methods for Pharmacodynamic (PD) parameters...............................................9
7.1
Analysis of the primary variables............................................................................9
7.1.1
Variable...................................................................................................9
7.1.2
Descriptive analyses................................................................................9
7.1.3
Statistical model, assumptions and hypotheses.......................................9
7.1.4
Handling of missing values/censoring/discontinuations.......................10
7.1.5
Supportive analyses...............................................................................10
7.1.6
Graphical presentation of results...........................................................10
7.2
Analysis of theexploratory efficacy variables......................................................10
8 Statistical methods for safety and tolerability data............................................................10
8.1.1
Variables...............................................................................................10
8.1.2
Descriptive analyses..............................................................................11
8.1.3
Graphical presentation of results...........................................................12
9 Statistical methods for Biomarker data.............................................................................
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List of tables
Figure 2-1
Study design............................................................................................6
Table 5-1
Protocol deviation severity codes and analysis sets................................8


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1
Introduction to RAPdocumentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLHW090X2202”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis
planned in the protocol.
2
Study objectives and design 
2.1
Study objectives
2.1.1
Primary objectives
To assess the safety and tolerability of LHW090 for 4 weeks on a background of 
conventional anti-hypertensive medications in patients with resistant hypertension.
To evaluate the effect of LHW090 on placebo-adjusted mean daytime systolic blood 
pressure (SBP) after 4 weeks in patients with resistant hypertension.
2.1.2
Secondary objective
To evaluate the pharmacokinetics (PK) of LHW090 and its active metabolite LHV527 
in patients with resistant hypertension.
2.1.3
Exploratory objectives
2.2
Study design and treatment
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This is a non-confirmatory, randomized, sponsor open, site and subject blind, parallel group, 
placebo-controlled study to evaluate the safety and efficacy of 4 weeks once daily treatment 
with LHW090 in patients with resistant hypertension. Patients with uncontrolled hypertension 
as defined as a mean daytime systolic blood pressure ≥ 135 mmHg by ambulatory blood 
pressure monitoring (ABPM) on a stable (at least 2 months) regimen of an angiotensin 
receptor blocker (ARB) plus a thiazide diuretic plus at least one of the following commonly 
used classes of anti-hypertensive medications—beta-blockers or calcium channel blockers—
will be considered for this trial. Patients with resistant hypertension will be randomized to 


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either placebo or 1 of 2 dose regimens of LHW090, i.e. LHW090 100 mg once dailyor
LHW090 200 mg once daily, as an add-on to their anti-hypertensive regimen at baseline.
Each patient will participate in an up to 3 week screening period, a 2-week single blind 
placebo run-in period, baseline assessments, a 4 week treatment period, and an end of study 
assessment as demonstrated in Figure 2-1. During the 2 week placebo run-in period, patients 
will receive regular reminders by the site to be compliant with their anti-hypertensive 
medications. At the end of this run-in period, patients who demonstrate ≥80% compliance 
with placebo will be randomized. Compliance will be established by pill count and review of 
medication diary. Patients will be advised that study entry cannot be fully determined until the 
completion of the run-in period.
Figure 2-1
Study design
3
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for this trial.
The study FIR template(mock slides)can be found in CREDI in the study RAP folder.
The template shows the analysis/ resultsto be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in the TFL shells documentand marked 
as “Key” in the Tracking sheet output list. 
4 
Interim analyses 
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5
Statistical methods: Analysis sets
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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 were randomizedwill 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 primary PD analysis set will include all subjects that received any study drug, with any 
available post-dose PD data.
The secondary PD analysis set will include all subjectsthatreceived any study drug, with any 
available post-dose PD dataand experienced no protocol deviations with relevant impact on 
PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 5-1
Protocol deviation severity codes and analysis sets
Protocol deviation severity code
Safety 
analysis 
set
PK 
analysis 
set
PD 
analysis 
set
Secondary
PD analysis 
set
Code
Text
5
Exclude subject from all safety analysis
- 
- 
-
-
8
Exclude from all analyses
- 
- 
-
-
20
Exclude subject from PK analysis set
+ 
- 
+
+
22
Exclude subject from PD analysis set
+ 
+ 
-
-
23
Exclude subject from PK and PD analysis set
+ 
- 
-
-
49
Report relevant protocol deviation –include 
subject in all analysis sets
+ 
+ 
+
+
+ = include in analysis set, -= exclude from analysis set, NA = not applicable
6
Statistical methods for Pharmacokinetic (PK) parameters
6.1
Variables 
 
 
 
 
 
 
 
6.2
Descriptive analyses
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6.3
Graphical presentation of results
 
6.4
Pharmacokinetic / pharmacodynamics interactions
The relationship between PK and key PD parameters may be explored using a graphical
approach. Descriptive statistics may be provided. 
 
 
7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Analysis of the primaryvariables
The first primary variables are adverse events, vital signs (blood pressure, pulse rate, body 
temperature), ECG intervals and laboratory measurements.
The second primary variable will be the change in the 12 hour average of SBPmeasured by 
ABPM 28 days following the start of treatment.
7.1.1
Variable 
The primary safety variables are definedin Section 8, below.    
The primary efficacy variable is defined as the 12 hour daytime average SBP on day 28 minus 
the 12 hour daytime average SBP on day -1.
7.1.2
Descriptive analyses
The descriptive analyses of the safety variables areshown in the safety analyses in Section 8.
Summary statistics of the ABPM data and change from baseline data will be provided by 
treatment and visit/time.
7.1.3
Statistical model, assumptions and hypotheses
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Analyses of the safety data will be descriptive, as shown in Section 8.
 
 
 
 
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 nformation
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7.1.4
Handling of missing values/censoring/discontinuations
Missing data will not be imputed. The longitudinal repeated measures mixed model analysis 
method allows missing values.
7.1.5
Supportive analyses
 
 
 
7.1.6
Graphical presentation of results
Arithmetic mean (SD) ABPM data will be plotted across time.
7.2
Analysis of the exploratory efficacy variables
 
 
8
Statistical methods for safety and tolerability data
8.1.1
Variables 
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Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
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8.1.2
Descriptive analyses
Subject demographicsand other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics(mean, standard deviation, minimum, median and maximum)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 bytreatment group and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group andsubject.  The number and percentage of subjects completing 
treatment for each treatment group and cohort will be tabulated.  For those not completing 
treatment, the reason for discontinuation will be listed by treatment group and subject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment andsubject.
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 systemand treatment.
The number and percentage of subjects with adverse events by maximum severity of adverse 
event will be tabulated by body system and preferred term with a breakdown by treatment.
Columbia-Suicide Severity Rating Scale(C-SSRS)
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All C-SSRSresults will be listed by subject and visit/time.


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8.1.3
Graphical presentation of results
 
9
Statistical methods for Biomarker data
 
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