Conditions: Acute Heart Failure (AHF)
Keywords: AHF, RLX030, SOC, WHF, RELAX-AHF-EU Renal Impairment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2666
Healthy volunteers: no

Brief summary:
This was a multinational, multicenter, randomized, open-label study to confirm and expand the efficacy, safety and tolerability evidence of 48 hours intravenous infusion of serelaxin (30 micrograms/kg/day) when added to Standard of Care (SoC) in patients admitted to hospital for Acute Heart Failure (AHF).

Detailed description:
This study was aimed at generating clinical evidence, especially on the short term period (in-hospital and at 30 days) to complement existing and future serelaxin data sets in Acute Heart Failure (AHF).

Arms:
arm 1: Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care. arm 2: All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.

Interventions: intervention 1: Serelaxin intervention 2: Standard of Care
Intervention descriptions: intervention 1: 30 µg/kg/day IV infusion intervention 2: This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.

Protocol document:
Prot_000.pdf: 
Clinical Development & Medical Affairs
RLX030/Serelaxin
Clinical Trial Protocol CRLX030A3301 / NCT02064868
A multicenter, prospective, randomized, open label study to assess 
the effect of serelaxin versus standard of care in acute heart failure 
(AHF) patients
Authors:
 
 
Principal or Coordinating 
Investigator
 for the RLX030A3301 Executive 
Committee
Document type:
Amended Protocol Version
EUDRACT number:
2013-002513-35
Version number:
04 (Clean)
Development phase:
IIIb
Release date:
19 Oct 2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 30-April-2013
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations ...................................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 4 ...........................................................................................................................10
Amendment 3 ...........................................................................................................................12
Amendment 2 ...........................................................................................................................14
Amendment 1 (for Germany ONLY) .......................................................................................17
Protocol synopsis......................................................................................................................19
1
Introduction .......................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose ..................................................................................................................26
2
Study objectives.................................................................................................................26
2.1
Primary objective(s)...............................................................................................26
2.2
Secondary objectives .............................................................................................27
27
3
Investigational plan ...........................................................................................................28
3.1
Study design...........................................................................................................28
3.2
Rationale of study design.......................................................................................30
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....31
3.4
Rationale for choice of comparator .......................................................................31
3.5
Purpose and timing of interim analyses/design adaptations..................................31
3.6
Risks and benefits..................................................................................................31
4
Population..........................................................................................................................32
4.1
Inclusion criteria ....................................................................................................32
4.2
Exclusion criteria...................................................................................................33
5
Treatment...........................................................................................................................35
5.1
Protocol requested treatment .................................................................................35
5.1.1
Investigational treatment.......................................................................35
5.1.2
Additional study treatment....................................................................35
5.2
Treatment arms ......................................................................................................36
5.3
Treatment assignment, randomization...................................................................36
5.4
Treatment blinding.................................................................................................36
5.5
Treating the patient................................................................................................37
 


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5.5.1
Patient numbering .................................................................................37
5.5.2
Dispensing the investigational treatment ..............................................37
5.5.3
Handling of study treatment..................................................................37
5.5.4
Instructions for prescribing and taking study treatment........................38
5.5.5
Permitted dose adjustments and interruptions of study treatment ........39
5.5.6
Rescue medication ................................................................................40
5.5.7
Concomitant treatment..........................................................................40
5.5.8
Prohibited Treatment.............................................................................41
5.5.9
Discontinuation of study treatment .......................................................41
5.5.10
Withdrawal of consent ..........................................................................42
5.5.11
Loss to follow-up ..................................................................................42
5.5.12
Emergency breaking of assigned treatment code..................................42
5.5.13
Study completion and post-study treatment..........................................43
5.5.14
Early study termination.........................................................................43
6
Visit schedule and assessments .........................................................................................43
6.1
Information to be collected on screening failures..................................................46
6.2
Patient demographics/other baseline characteristics .............................................46
6.3
Treatment exposure and compliance .....................................................................47
6.4
Efficacy..................................................................................................................47
6.4.1
In-hospital Worsening Heart Failure/all-cause death through Day 5....47
6.4.2
In-hospital Worsening Heart Failure/all-cause death through Day 
14...........................................................................................................48
6.4.3
Index Length of hospital stay................................................................48
6.4.4
Appropriateness of efficacy assessments..............................................48
6.5
Safety.....................................................................................................................48
6.5.1
Physical examination ............................................................................49
6.5.2
Vital signs..............................................................................................49
6.5.3
Height and weight .................................................................................50
6.5.4
Laboratory evaluations..........................................................................50
6.5.5
Electrocardiogram (ECG) .....................................................................51
6.5.6
Appropriateness of safety measurements..............................................52
6.6
Other assessments..................................................................................................52
52
52
52
6.6.4
Health-related Quality of Life...............................................................52
6.6.5
Resource utilization...............................................................................53
 


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6.6.6
Echocardiography .................................................................................53
7
Safety monitoring ..............................................................................................................53
7.1
Adverse events.......................................................................................................54
7.2
Serious adverse event reporting.............................................................................56
7.3
Liver safety monitoring .........................................................................................58
7.4
Pregnancy reporting...............................................................................................60
8
Data review and database management.............................................................................60
8.1
Site monitoring ......................................................................................................60
8.2
Data collection.......................................................................................................60
8.3
Database management and quality control............................................................61
8.4
Data Monitoring Committee..................................................................................61
8.5
Adjudication Committee........................................................................................62
9
Data analysis......................................................................................................................62
9.1
Analysis sets ..........................................................................................................62
9.1.1
Full analysis set (FAS)..........................................................................62
9.1.2
Randomized (RAN) set.........................................................................63
9.1.3
Per Protocol (PP) set .............................................................................63
9.1.4
Safety population ..................................................................................63
9.2
Patient demographics and other baseline characteristics.......................................63
9.3
Treatments .............................................................................................................64
9.3.1
Investigational Treatment......................................................................64
9.3.2
Concomitant treatments ........................................................................64
9.4
Analysis of the primary variable(s) .......................................................................65
9.4.1
Variable(s).............................................................................................65
9.4.2
Statistical model, hypothesis and method of analysis...........................65
9.4.3
Handling of missing values/censoring/discontinuations.......................66
9.4.4
Supportive analyses...............................................................................66
9.5
Analysis of secondary variables ............................................................................66
9.5.1
Efficacy variables..................................................................................66
9.5.2
Safety variables .....................................................................................68
9.5.3
Resource utilization...............................................................................69
9.5.4
Health-related Quality of Life...............................................................69
9.5.5
Pharmacokinetics ..................................................................................70
9.5.6
Pharmacogenetics/pharmacogenomics .................................................70
70
9.5.8
PK/PD ...................................................................................................70
70
 


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70
9.6
Interim analyses .....................................................................................................70
9.7
Sample size calculation..........................................................................................70
10 Ethical considerations........................................................................................................71
10.1
Regulatory and ethical compliance........................................................................71
10.2
Informed consent procedures.................................................................................71
10.3
Publication of study protocol and results...............................................................72
11 Protocol adherence ............................................................................................................72
11.1
Protocol Amendments ...........................................................................................72
12 References (available on request)......................................................................................73
13 Appendix 1: Clinically notable laboratory values .............................................................78
14 Appendix 2: Liver laboratory trigger and liver event definitions and follow-up 
requirements ......................................................................................................................79
15 Appendix 3: Physician assessment of signs and symptoms ..............................................82
84
88
91
List of tables
Table 5-1
Weight-range adjusted dosing regimen of serelaxin.............................39
Table 5-2
Dosing adjustment of study drug administration in the event of 
systolic BP decrease through completion of study drug infusion.........40
Table 6-1
Assessment schedule.............................................................................44
Table 14-1
Definitions of liver laboratory triggers or liver events, which 
cannot be solely explained by apparent cardiac decompensation as 
the underlying cause (i.e., another etiology is suspected to cause or 
contribute to this event).........................................................................79
Table 14-2
Follow up requirements for liver laboratory triggers or liver events, 
which cannot be solely explained by apparent cardiac 
decompensation as the underlying cause (i.e., another etiology is 
suspected to cause or contribute to this event)......................................80
List of figures
Figure 3-1
Study design..........................................................................................28
 


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List of abbreviations
ACE 
Angiotensin-Converting Enzyme
AE 
Adverse Event 
AHF 
Acute Heart Failure
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BP 
Blood Pressure
CCU
Critical Care Unit
CEC
Central Event Committee
cGMP
cyclic Guanosine Monophosphate
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report/Record Form (paper)
CRO
Contract Research Organization
CSR 
Clinical Study Report
CV
Cardiovascular
DB
Double Blind
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form/Record Form
ED
Emergency Department
EDC
Electronic Data Capture
EGFR 
Estimated Glomerular Filtration Rate
EMS
Emergency Medical Services
ER
Emergency Room
ET-B
Endothelin receptor Type B
FAS 
Full Analysis Set
GDF-15
Growth Differentiation Factor 15
GI
Gastro-Intestinal
 


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HF 
Heart Failure
H-FABP
Heart-type Fatty Acid-Binding Protein
HPA
Hypothalamus-Pituitary-Adrenal
HR 
Heart Rate
HRQoL 
Health Related Quality of Life
HRU 
Health Care Resource Utilization
IB 
Investigator’s Brochure
ICF
Informed Consent Form
ICU
Intensive Care Unit
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee 
IN 
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
ITT 
Intent-to-Treat
IV
Intravenous
JVP 
Jugular Venous Pulse
LC-MS/MS
Liquid Chromatography Tandem Mass Spectrometry
LFT 
Liver Function Test
LOS 
Length of Stay
LVEF
Left Ventricular Ejection Fraction
MedDRA 
Medical Dictionary for Regulatory Activities
NGAL 
Neutrophile Gelatinase Associated Lipocalin
NO/NOx
Nitric Oxide
NOS
Nitric Oxide Synthase
NT-proBNP 
N-Terminal pro b-type Natriuretic Peptide
OL
Open Label
PP 
Per Protocol
PT
Preferred Term
PTX-3
Pentraxin-3
RCT
Randomized Controlled Trial
SAE
Serious Adverse Event
 


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SD 
Standard Deviation
SBP 
Systolic Blood Pressure
sMDRD 
Simplified Modification of Diet in Renal Disease
SOC 
Standard of Care; System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total Bilirubin
ULN
Upper Limit of Normal
VAS 
Visual Analog Scale
VAS AUC
Visual Analog Scale Area Under the Curve
WHF 
Worsening Heart Failure
WOCBP
Women of Child Bearing Potential
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Epoch 
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up after treatment has ended.
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
‘‘investigational new drug’’ or ‘‘investigational medicinal product’’.
Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage
Medication number
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system
Part
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part.
Period 
A subdivision of a cross-over study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up)
Randomization number
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later
Study drug/treatment
Any single drug or combination of drugs administered to the patient as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy 
Study/investigational treatment 
discontinuation
Point/time when patient permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of 
premature patient withdrawal
Subject Number 
A number assigned to each patient who enrolls into the study
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points.
 


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Amendment 4
Amendment rationale
This amendment to the protocol is necessary because the Executive Committee recommended 
during its meeting held on 15th of June 2016 to increase the number of randomized patients
from 2,685 to 3,183 patients. This decision was endorsed by the Data Monitoring Committee 
(DMC) during the meeting on 21st of June 2016. The rationale for the increase in sample size 
is provided below.
Although the rate of enrollment into the trial is in line with the planning, the number of events 
constitutive of the primary endpoint (i.e. patients with WHF events or death through Day 5) is 
lower than expected.
 
 
 
 
 
 
 
 
 
 
 
Ancillary changes introduced with the amendment
Clarification in reporting Adverse Events and Worsening of Heart Failure 
events
In-hospital Worsening of Heart Failure (WHF) within the first 5 days is one of two 
components of the primary endpoint. Some WHF events could represent an endpoint as well 
as a non-serious or serious AE. 
In order to avoid potential under-reporting of non-serious AEs indicative of cardiac failure 
due to inconsistency in event reporting by investigators, the WHF event and/or the related 
signs and symptoms should be always recorded on the Adverse Event eCRF page.
Patients treated with valsartan/sacubitril
When a patient treated with valsartan/sacubitril (Entresto®) is considered for randomization in 
to the trial, only NT-proBNP, and not BNP, should be assessed during the screening phase.
As reported in the SmPC (Summary of Product Characteristics) of Entresto®, BNP is not a 
suitable biomarker of heart failure in patients treated with Entresto® because BNP is a 
neprilysin substrate. NT-proBNP is not a neprilysin substrate and is therefore a more suitable 
biomarker.
 


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This specification relates only to the assessment method but does not affect the inclusion 
criterion.
Treatment Blinding
The previous versions of the protocol did not explain which study roles are blinded and which 
are unblinded. The current amendment clarifies that the clinical trial team (e.g. Clinical Trial 
Lead, Clinical Trial Manager, Medical Lead, Trial Statistician) are blinded throughout the 
study and that only roles specifically mentioned in the Safety Manual are unblinded. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Status
The recruitment in the study is ongoing.
 


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So far, more than two thousand three hundred and thirty (2337) patients have been 
randomized by Austria, Belgium, Bulgaria, Croatia, Czech Republic, Estonia, Finland, France, 
Germany, Greece, Hungary, Iceland, Italy, Latvia, Lithuania, Poland, Portugal, Romania, 
Russia, Serbia, Slovakia, Slovenia, Spain, Switzerland and United Kingdom in the study.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein affect the Informed Consent. Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment.
Changes to the protocol
Section 4.1 and Table 6.1 updated to clarify that only NT-proBNP should be assessed in 
patients under valsartan/sacubitril (Entresto®) therapy
Section 5.4 updated to clarify the management of the treatment blinding in the study
Section 6.5.4 updated to clarify the volume of the blood sample collection.
Section 7 updated to clarify the correct reporting of Worsening of Heart Failure events 
versus Adverse Events.
Section 9.7 updated in the sample size calculation.
 
Amendment 3
Amendment rationale
Acute Heart Failure is a complex and subjective clinical diagnosis. Since the diagnosis of 
AHF is primarily based on clinical observations that are interpreted bedside, in an urgent care 
environment, based on the clinical judgment of the investigator, the diagnosis is sometimes 
difficult to qualify.
Therefore, the study Executive Committee has recommended changes to better specify the 
criteria defining AHF in the patient population under investigation, correct inconsistencies 
and improve the overall clarity of the study. This has led to the following adjustments in 
inclusion and exclusion criteria:

Increase of required NT-proBNP level for inclusion of a patient from 1,400 to 2,000 
pg/mL in order to ensure that patients with cardiac dyspnea are included

Exclusion of patients with SBP above 180 mmHg at the end of screening in order to avoid 
pure hypertensive crisis

To ensure that patients suffering from non-cardiogenic dyspnea are not enrolled into 
RELAX-AHF-EU to ensure that patients with cardiac dyspnea are included, another 
 


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criteria has been added, the exclusion of patients with a known history of respiratory 
disorder (i.e. COPD) requiring the daily use of IV steroids. 

To ensure that an underlying malignancy does not interfere with the efficacy objectives 
(e.g. no treatment success) and to collect SAEs/safety data that are due the disease 
condition and/or the allocated study treatment and not associated with the malignancy, the 
exclusion of patients with history of malignancy of any organ system (other than localized 
basal cell carcinoma of the skin), treated or untreated (within the past year). 
Other changes in the protocol

The possibility to use a BNP level rather than a NT-proBNP level for inclusion of the
patient into the study will be introduced with the present amendment. At the start of the 
study, all sites without a local possibility to assess NT-proBNP levels were equipped with 
a bedside device of NT-proBNP assessment, the COBAS device. Feedback from a number 
of sites was that they would like to use their local laboratory to assess natriuretic peptide 
levels in order to gain time. Since some of these local laboratories only measure BNP 
levels, the possibility to include patients based on BNP  ≥500 pg/mL will now be added to 
the inclusion criteria

 
Study Status
The recruitment in the study is ongoing.
So far, more than one thousand (1000) patients have been randomized by Austria, Belgium, 
Bulgaria, Croatia, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, 
Italy, Latvia, Lithuania, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, 
Switzerland and United Kingdom in the study.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein affect the Informed Consent. Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment.
Changes to the protocol
Section 4.1: Inclusion criteria 
No. 4: NT-proBNP criterion has been increased to ≥2,000 pg/mL, and BNP criterion ≥500 
pg/mL has been added.
Section 4.2: Exclusion criteria
The following exclusion criteria have been added:
 


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No. 2: Known history of respiratory disorders requiring the daily use of IV steroids (does not 
include inhaled or oral steroids) at least 2 months prior to randomization; need for intubation 
or the current use of IV steroids for COPD.
No. 3: Patients with systolic blood pressure >180 mmHg at the end of screening or persistent 
heart rate >130 bpm.
No. 13: History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated (within the past year) has been added.
The following exclusion criteria have been updated:
No. 5: Diuretic has been added to the description of equivalent for IV furosemide. The use of
IV nitrates is permitted if the patient has systolic BP >150 mmHg at “the start of screening”.
Section 5.3 updated to clarify the management of mis-randomized patients.
Sections 5.5.9 and 5.5.10 updated to clarify patient withdrawal and continued patient 
follow-up.
Section 6.4.1.1 modified to indicate who, besides the PI, can assess AHF signs and 
symptoms.
 
 
Section 6.5.2 and Table 6-1 updated to clarify the time points for the collection of vital 
signs.
Section 6.6.4 clarifies the procedure for administering the EQ-5D-5L questionnaire.
Section 6.6.6: Echocardiography has been added to collect and record (into eCRF) the most 
recent data in the past 12 months if the evaluation is performed and the values obtained are 
available in the source documents.
Section 7.2: SUSAR reporting has been updated to clarify that pre-specified AEs commonly 
observed in the study population that also meet the criteria for SUSARs will be expedited to 
Health Authority (if specifically requested by local health authority).
Investigator 
Notifications (INs) will not be issued for these events.
Sections 6, 6.4.1.1, 6.5.1, 6.5.2, 6.5.3, 6.5.4, and Table 6-1 provide clarity and 
flexibility regarding the conduct and timing of the study visits and visit procedures.
Section 9 provides clarity on data analysis.
Amendment 2
Amendment rationale
This amendment is introduced based on the initial feedback gathered from the investigators 
already screening and recruiting patients, the request for clarification from some local health 
authorities, and further discussions with the Executive Committee Board. These changes aim 
 


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at further strengthening the protocol, facilitating the recruitment and ensuring possible data 
merging with other serelaxin studies like RELAX-AHF-2. 
The key changes introduced in this amendment are the following:

More background information has been provided about the clinical parameter in-hospital 
WHF-worsening of heart failure.

The inclusion criterion “pulmonary congestion” is now to be diagnosed by physical 
examination and chest X-ray as required by local clinical practice. Echocardiography is 
not anymore mentioned as a possible procedure for diagnosis of pulmonary congestion.

Refinement of inclusion of patients with renal dysfunction. Patients with significant renal 
dysfunction are most at risk of complicated AHF episodes. Concomitantly, these patients 
benefit potentially most from serelaxin, as shown by the available data. To ensure that 
these patients represent a large enough proportion in this practical trial, it was decided to 
allow inclusion of patients with an eGFR of 25 to 75 ml/min/1.73m2 (instead of 30 to 75 
ml/min/1.73m2). 

Streamline the exclusion criteria related to WOCBP changing the requirements from 
“effective” to “highly effective” methods of contraception to minimize the likelihood of 
pregnancies during dosing and for 5 days after cessation of study drug.  

A discharge assessment was added to collect valuable information about the real life 
clinical situation when the patient is sent back home. It has been shown that 24% of
patients hospitalized for HF in Europe have signs of congestion at discharge (Maggioni et 
al 2010). The primary endpoint is through Day 5, and we expect most patients to be 
discharged later than Day 5. The added discharge assessment would capture novel 
information about the residual AHF signs at discharge (and before the FU visit at Day 14).

The primary endpoint “time to in hospital WHF or death at Day 5” has been strengthened 
in that the time window allowed for in hospital WHF assessment is through Day 5 (which 
was previously +/- 1 day). 

Exclusion of patients with a body weight below 40 kg and >160 kg, which would have 
underlying medical conditions that would render this treatment most probably not 
effective in these two groups, for different reasons, the former (the first are a very selected 
subgroup of cachectic HF patients, the latter group of patients, expect to be very few in 
European countries) would have major associated dysmetabolic conditions. 

Exclusion criterion number #03 was clarified: it will now require that concomitant active 
therapies or procedures are not allowed “2 hours prior to randomization” (and not as was 
previously “2 hours prior to screening”).

The HIV, HBV and HCV testing of active or latent HIV, HBV or HCV infection were 
suppressed, based on current epidemiology and the available reassuring data, showing no 
signal of concern in terms of safety and tolerability.

The exclusion criterion of severe pulmonary disease is now deleted. It is already contained 
in the exclusion criteria #01 “dyspnea primarily due to non-cardiac causes” and exclusion 
criteria #16 (when patient is put at risk or deemed unsuitable for the study).
Additional points are also clarified through this amendment:

The justification for the open label design has been expanded
 


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
Time points at which vital signs are to be assessed, in patients randomized to Standard of 
Care (SOC) as compared to the serelaxin group. It now highlights that the reference time 
point for the assessments required in the serelaxin group is “start of the infusion”, whereas 
it is the “randomization time point” for the SOC group.

The handling of the serelaxin infusion when concomitant AHF therapies have to be started 
during the serelaxin infusion is clarified. 

The SBP measurements between screening and randomization and implications on 
serelaxin infusion were clarified.

The term mechanical ventilation, and the different categories of invasive and non-invasive 
assisted ventilation, are better defined.

The collection of EQ-5D-5L HRQOL questionnaires at Day 2 has been added.
Study Status
The recruitment in the study is ongoing.
So far, sixty-nine (69) patients have been randomized by Belgium, Bulgaria, Czech Republic, 
France, Germany, Hungary, Italy, Russia, Slovakia and United Kingdom in the study.
Changes to the protocol
Section 1
Text added to strengthen a meaningful definition of Worsening Heart Failure (WHF) and its 
significance for patients’ disease trajectory underlying the results of RELAX-AHF study in 
term of WHF.
Figure 3.1
Figure modified to correct inconsistencies with the rest of Section 3.1.
Section 3.2
Choice of Open-label design strengthened by adding details of pros and cons of an open-label 
design versus a double-blind design in Randomized Controlled Trials (RCT).
Section 4.1
Some changes to key inclusion criteria.
Section 4.2
Some changes to key exclusion criteria.
Section 5.5.4
Sentences added to align with the current version of the pharmacist manual.
Section 5.5.5
Instructions provided to clarify what to do in case of Systolic Blood Pressure (SBP) drop 
between randomization and start of serelaxin infusion.
 


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Section 5.5.7
Instructions provided to clarify what to do in case IV therapies have to be administered after 
randomization in both arms.
Section 5.5.8
Section amended to be consistent with the previous Section.
Section 6
Section amended to restrict the visit window of Day 5 (time point of the main efficacy 
endpoint).
Table 6.1
Table and footnotes amended to introduce a discharge visit if the patient is still hospitalized 
beyond Day 5, clarify whose frequency all the assessments will be performed in the Standard 
of Care (SoC) arm.
Section 8.5
Text amended to be consistent with the current version of the Clinical Endpoint Committee 
charter.
Section 9.5.1
Header amended to be consistent with the corresponding efficacy variable mentioned in 
Section 6.4.1.
Table 14.1 and Table 14.2
Tables amended to align the liver events monitoring according to the new Novartis liver 
guidance.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes here in affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 1 (for Germany ONLY)
Amendment rationale
This amendment is being initiated at the request of German Health Authorities & will be 
applicable only to German sites participating in this trial. As part of the review process, 
German health authorities have requested to amend the protocol with inclusion of the 
following 2 requirements:
 


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1. As part of additional safety measures & to avoid any potential risk of hypotension with the 
infusion of serelaxin, it was recommended to clarify the use of an infusion pump, a drip or 
any other controllable infusion systems to ensure a constant infusion rate of serelaxin at 
10ml/hour.
2. To further clarify the informed consent procedure related to the nature of the witness, an 
“independent second physician or nurse” is being added who will co-sign the ICF & 
thereby confirm that the patient has provided  informed consent according to his/her  own 
will following receipt of  all study related information based on his/her ability to 
understand  the  trial procedures.
Study status
The recruitment in the study has just started.
So far, one patient has been screened and randomized in Italy.
Changes to the protocol
Section 1
Text corrected to remove the reference to the status of the Marketing Authorization 
Application for serelaxin.
Section 5.5.4
Text added to specify how the infusion of the study drug will be maintained constant at a rate 
of 10 mL/hour.
Section 7.2
Text corrected to make reference to the most recent European Commission communication.
Section 10.2
Text added to clarify the independence of the witness from the trial group during the informed 
consent procedure
 


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Protocol synopsis
Protocol number
CRLX030A3301
Title
A multicenter, prospective, randomized, open label study to assess the 
effect of serelaxin versus standard of care in acute heart failure (AHF) 
patients.
Brief title
Effect of serelaxin versus standard of care in acute heart failure (AHF) 
patients. 
Sponsor and Clinical 
Phase
Novartis, IIIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The aim of this study is to assess the efficacy, safety and tolerability of 
intravenous infusion of 30 μg/kg/day serelaxin administered for 48 hours, 
when added to standard therapy in patients hospitalized for acute heart 
failure. Efficacy will be determined based on the combined primary end-
point of in-hospital worsening of heart failure requiring rescue therapy and 
all-cause death through Day 5. Patients will be followed-up for 30 days.  
The aim of this study is to generate clinical evidence, especially on the 
short-term period (in-hospital and at 30 days) that will complement existing 
and future serelaxin data sets in AHF.
Primary 
Objective(s) 
and 
Key 
Secondary 
Objective
The primary objective of the study is to evaluate the effect of serelaxin as 
add-on therapy to standard of care (SOC), versus SOC alone, in reducing 
in-hospital worsening heart failure (WHF) requiring rescue therapy or all-
cause death, from randomization through Day 5. 
Secondary Objectives
To assess the effect of serelaxin as add-on therapy to SOC versus SOC 
alone in reducing in-hospital WHF requiring rescue therapy or all-cause 
death or readmission for heart failure, from randomization through Day 14.
To assess the effect of serelaxin as add-on therapy to SOC versus SOC 
alone in reducing the number of patients with persistent signs or 
symptoms of HF / not showing an improvement versus baseline conditions 
from randomization through Day 5 (persisting need of IV therapy for HF).
To evaluate the effect of serelaxin as add-on therapy to SOC versus SOC 
alone in reducing the rate of renal deterioration (defined as ≥ 0.3 mg/dL 
increase in serum creatinine), from randomization through Day 5.
To evaluate the effect of serelaxin as add-on therapy to SOC versus SOC 
alone in modifying the index length of hospital stay (LOS) by location (e.g., 
ICU, CCU, cardiology department) in days (and hours for ICU).
To evaluate the safety and tolerability of intravenous serelaxin in AHF 
patients during a period of 30 days following exposure.
To collect data on health-related quality of life (HRQoL) and economic 
burden to provide a more comprehensive analysis of the burden of HF, 
beyond the clinical outcomes.
Study design
This is a multicenter, prospective, open-label, randomized study. 
 


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Population
The study population will consist of male and female patients ( ≥18 years 
old) admitted to the hospital for AHF, with systolic BP ≥125 mmHg and 
mild-to-moderate renal impairment.
Inclusion criteria

Able to provide written informed consent before any study-
specific assessment is performed

Male or female ≥ 18 years of age with body weight ≥40 Kg and ≤
160 Kg.

Systolic blood pressure >125 mmHg at the beginning of the 
screening period (after ICF signature) and at the end of the 
screening period (prior to randomization)

Admitted/hospitalized for AHF. AHF is defined as including all of 
the following measured at any time between presentation and the 
end of screening: 

Persistent dyspnea at rest or with minimal exertion, at 
screening and at the time of randomization, despite standard 
background therapy for acute decompensated heart failure 
including intravenous furosemide of at least 40 mg total (or 
equivalent)

Pulmonary congestion assessed through physical 
examination and chest X-Ray obtained during routine clinical 
practice at any time between presentation and the end of 
screening (prior to randomization)

BNP ≥500 pg/mL or N-terminal pro b-type natriuretic peptide 
(NT-proBNP) ≥2,000 pg/mL. For patients treated with 
valsartan/sacubitril (Entresto®), BNP is not a suitable 
biomarker and only NT-pro-BNP should be assessed

Able to be randomized within 16 hours from presentation to the 
hospital [presentation starts as the earliest of (1) time of 
presentation at either the ER/ED, ICU/CCU or ward; or (2) time of 
first IV loop diuretic for treatment of the current AHF episode prior 
to arrival at the hospital (this includes outpatient clinic, 
ambulance, or hospital including emergency department)]

Received intravenous furosemide of at least 40 mg (or 
equivalent) at any time between presentation and the start of 
screening for the study

Impaired renal function defined as an estimated glomerular 
filtration rate (eGFR) between presentation and randomization
defined as >25 and <75 mL/min/1.73 m2, calculated using the 
simplified Modification of Diet in Renal Disease (sMDRD) 
equation.
Exclusion criteria

Dyspnea primarily due to non-cardiac causes, such as acute or 
chronic respiratory disorders or infections (i.e., severe chronic 
obstructive pulmonary disease, bronchitis, pneumonia), or 
primary pulmonary hypertension sufficient to cause dyspnea at 
rest, which may interfere with the ability to interpret the primary 
cause of dyspnea

Known history of respiratory disorders requiring the daily use of 
IV steroids (does not include inhaled or oral steroids) at least 2 
months prior to randomization; need for intubation or the current 
use of IV steroids for COPD

Patients with systolic blood pressure >180 mmHg at end of 
screening or persistent heart rate >130 bpm
 


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
History of malignancy of any organ system (other than localized 
basal cell carcinoma of the skin), treated or untreated, within the 
past year

Women of child bearing potential unless they are using highly 
effective methods of contraception during dosing of study 
treatment and for 5 days after cessation of study drug or pregnant 
or nursing (lactating) women

Temperature > 38.5°C (oral or equivalent) or sepsis or active 
infection requiring IV anti-microbial treatment 

Current (within 2 hours prior to randomization) or planned 
treatment with any IV vasoactive therapies, including 
vasodilators, positive inotropic agents and vasopressors, or 
mechanical support, with the exception of IV furosemide (or 
equivalent diuretic) or IV nitrates at a dose of ≤0.1 mg/kg/hour if 
the patient has a systolic BP >150 mmHg at the start of the 
screening

Significant left ventricular outflow obstruction, uncorrected, such 
as obstructive hypertrophic cardiomyopathy or severe aortic 
stenosis (i.e., aortic valve area <1.0 cm2 or mean gradient >50 
mmHg on prior or current echocardiogram), severe aortic 
regurgitation and severe mitral stenosis

Clinical evidence of acute coronary syndrome currently or within 
30 days prior to enrollment. (Note that the diagnosis of acute 
coronary syndrome is a clinical diagnosis and that the sole 
presence of elevated troponin concentrations is not sufficient for a 
diagnosis of acute coronary syndrome, given that troponin 
concentrations may be significantly increased in the setting of 
AHF)

AHF due to significant arrhythmias, acute myocarditis or 
hypertrophic obstructive, restrictive, or constrictive 
cardiomyopathy

Known hepatic impairment or ASL / ALT > 3 ULN

Known presence of active or recurrent bacterial, fungal or viral 
infection at the time of enrollment
Investigational and 
reference therapy
Serelaxin according to a weight-range adjusted dosing regimen at a 
nominal dose of 30 µg/kg/day as a continuous intravenous infusion for 48 
hours as add-on therapy to Standard of Care (SOC)/SOC.
Efficacy assessments
The primary endpoint is time to in-hospital Worsening HF requiring rescue 
therapy or all-cause death through Day 5. 
In-hospital Worsening of heart failure (WHF) through Day 5 post 
randomization, includes worsening signs and/or symptoms of heart failure 
that require an intensification of intravenous therapy for heart failure or 
mechanical ventilation, renal or circulatory support.
The secondary efficacy endpoint is in-hospital Worsening HF requiring 
rescue therapy as defined above, or all-cause of death or readmission for 
heart failure through Day 14. 
Another secondary endpoint in this study is to evaluate the number of 
patients with persistent symptoms or signs of HF / not showing an 
improvement versus baseline conditions through Day 5 (persisting need of 
IV therapy for HF).
 


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Moreover, modification of index LOS by location will be evaluated.
Safety assessments
Safety will be assessed by comparing the serelaxin group to the standard 
of care only group with regard to the frequency of adverse events (AEs) / 
serious adverse events (SAEs), changes in vital signs, physical 
examination findings, and clinical laboratory test results (chemistry, 
hematology and urinalysis). 
All AEs will be assessed through Day 5
All SAEs will be assessed through Day 14 (regardless of causality). 
Any SAEs experienced after Day 14 should be reported to Novartis only if 
the investigator suspects a causal relationship to study treatment.
Other assessments
Health related Quality of Life. 
Healthcare resource utilization.
 
 
 
 
 
Data analysis
The primary efficacy variable of the study is the time to in-hospital 
Worsening of Heart Failure (WHF) requiring rescue therapy or all-cause 
death through Day 5 post randomization. 
The time to in-hospital WHF/all cause death will be computed as the 
number of hours from randomization to the earlier of the onset of WHF or 
death. Subjects without an event will be censored at the earlier of the last 
assessment or 120 hours after randomization. 
The primary statistical hypothesis is H0: λ2/λ1 ≥ 1 versus the one -sided 
alternative HA: λ2/λ1 < 1, where λ1 and λ2 are the hazard rates for WHF 
or all cause death in the Standard of Care group and serelaxin group, 
respectively. The hypothesis will be tested based on the Full Analysis Set 
(FAS) with a Gehan’s generalized Wilcoxon test at a significance level of 
0.025 (one-sided). 
 
 
 
 
 
 
 
 
 
 
 
Time to in-hospital WHF/all cause death/readmission through Day 14 post 
randomization will be analyzed using survival analysis as in the primary 
analysis. 
Treatments will be compared regarding proportions of patients with 
persistent signs or symptoms of HF/ not showing an improvement vs. 
 


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baseline through Day 5 by means of Chi square test / Fisher Exact test.
Index length of stay, overall and by location, in the two treatment groups 
will be compared using a Wilcoxon rank-sum test.  
Key words
Acute Heart Failure, Worsening of Heart Failure, standard of care.
 


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1
Introduction
1.1
Background
Acute heart failure (AHF) is recognized as a major and escalating public health problem with 
high disease prevalence associated with poor prognosis. It is the leading medical cause of 
hospitalization among patients over 65 years of age in the United States, European countries, 
Australia and New Zealand, with a significant cost burden for the health care systems 
(McMurray 1998, Fonarow 2008, Roger and Go 2012).
Despite the undoubted clinical importance of AHF, no universally accepted definition exists, 
but the condition is generally considered to represent the relatively abrupt onset of symptoms 
and signs secondary to abnormal cardiac function. The cardiac dysfunction can be related to 
systolic or diastolic myocardial dysfunction, to acute valvular dysfunction, to pericardial 
tamponade, to abnormalities in cardiac rhythm, or to preload and afterload mismatch. It is a 
life-threating condition that requires immediate medical attention, and usually leads to urgent 
admission to hospital (McMurray et al 2012). In most cases, AHF arises as a result of 
deterioration in patients with a previous diagnosis of heart failure (HF) (where the term acute 
decompensation is often applied), but it can also occur as the first manifestation of a failing 
heart (acute de novo heart failure) (McMurray et al 2012). AHF should be considered as a 
heterogeneous set of syndromes, characterized by reduced cardiac output, tissue 
hypoperfusion and increase in the pulmonary capillary wedge pressure and tissue congestion. 
Such set of syndromes induce metabolic abnormalities and organ damage, such as renal and 
liver damage (Metra et al 2010a; Metra et al 2012).
Epidemiological registries and surveys in Europe (Zűrich-Helsinki, EFICA, Italian Acute 
Heart Failure Survey, Euro Heart Survey I and II, British NHS survey) (Rudiger et al. 2005, 
Zannad et al 2006, Tavazzi et al 2006, Cleland et al 2003, Nieminen et al 2006, Nicol et al 
2008), in USA (ADHERE) (Adams et al 2005), in ASIA Pacific region (ATTEND) (Sato et al 
2010), and across 9 countries in 4 continents (ALARM-HF) (Follath et al 2011) provided
several clues for diagnosis and classification of AHF. These multicenter hospital-based 
registries and surveys have shown that the typical patient is elderly, with a history of heart 
failure, coronary artery disease and hypertension. Patient presentation may vary, 
encompassing worsening congestion, worsening chronic heart failure, pulmonary edema, 
hypertensive crisis, or cardiogenic shock. Patients typically spend several days in the intensive 
care unit, with longer admissions in Europe than the United States (Dar and Cowie 2008). The 
vast majority of patients symptomatically improve during hospitalization; however, their early 
post-discharge rehospitalization and mortality rates continue to be high (Gheorghiade et al 
2009, Bueno et al, 2010).
The main clinical challenges in managing AHF patients are to achieve the optimal and 
sustained resolution of patient congestion aiming for prevention of in-hospital worsening of 
heart failure (WHF) and organ damage.
The therapeutic approach of AHF has remained the same for decades, being the use of the 
most acute treatments empirical. Conventional treatment for AHF consists of loop diuretics to 
reduce fluid overload, plus the addition of nitrates (oral, sublingual or IV) where required to 
ease vasoconstriction. None of the currently available treatments can demonstrate positive 
 


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outcome benefits from randomized clinical trials and, according to the latest ESC-ESH 
guidelines, treatment in AHF remains largely opinion-based with little good evidence to guide 
therapy (McMurray et al 2012). 
In-hospital worsening of heart failure is considered a clinically relevant end-point in the 
evaluation of treatment success for AHF (Zannad et al 2013). WHF is defined as a persistence 
or worsening of symptoms during the acute phase of a heart failure episode requiring 
intensification of therapy in patients already hospitalized for their acute decompensation 
(similar to the RELAX-AHF WHF definition). Approximately 10–30% of patients may 
experience in-hospital WHF in the first few days following hospital admission for AHF 
(Cotter et al 2010; Weatherley et al 2009).
WHF is a distinct clinical event that represents a severe deterioration of AHF signs/symptoms 
requiring urgent intervention. Also, it is an event that profoundly alters the patient’s disease 
trajectory. Published data clearly demonstrate that the occurrence of WHF during the hospital 
phase is associated with a significantly increased risk (2-3 times) of re-hospitalization and 
mid- and long-term morbidity and mortality outcomes (Cotter et al 2010; Weatherley at al 
2009; Zannad et al 2013; Metra 2010; Teerlink et al 2013; Metra 2011; McMurray et al 2007).
Serelaxin is a recombinant form of human relaxin-2, a naturally occurring peptide hormone 
which is present in both men and women (Dschietzig et al 2006). The hormone rises to 
pharmacologic levels during pregnancy, being associated with many of the maternal 
hemodynamic and reno-vascular adjustments in response to the demands of pregnancy, such 
as increased cardiac output, increased renal blood flow, and increased arterial compliance
(Teichman et al 2010, Du et al 2010, Conrad and Shroff, 2011). More recently, cardiac 
pleiotropic effects at the tissue level, i.e. contractility increase, angiogenesis, anti-
inflammatory, prevention of ischemic-reperfusion injuries and extracellular matrix 
remodeling have been described. 
Serelaxin represents a new pharmacologic class (relaxin peptide family) that is thought to help 
in AHF by stimulating vasodilation and renal function, boosting cardiac output and decreasing 
systemic vascular resistance.
Its efficacy and safety in AHF patients has been demonstrated in two studies, the dose-finding 
phase II study Pre-RELAX-AHF (Teerlink et al 2009) and the phase III pivotal study 
RELAX-AHF (Teerlink et al 2013, Metra et al 2013). Both the Pre-RELAX-AHF and the 
RELAX-AHF 
were 
randomized, 
double-blind, 
placebo-controlled, 
parallel-group, 
international trials comparing the intravenous administration of serelaxin for up to 48 hours, 
started within 16 hours of presentation, added to conventional therapy with placebo in patients 
hospitalized for AHF with dyspnea, congestion on chest radiography, increased natriuretic 
peptide levels, mild to moderate renal insufficiency, and systolic blood pressure >125 mmHg. 
In the Pre-RELAX-AHF study 234 patients were enrolled, 230 of whom treated with serelaxin 
at 10, 30, 100 and 250 g/kg/day or placebo (n=61, 40, 42, 38, 49 patients, respectively). The 
results showed beneficial effects of serelaxin on both dyspnea and post-discharge clinical 
outcomes. Serelaxin rapidly improved shortness of breath at 6 hours which was sustained at 
12 and 24 hours, with 40% of subjects reporting moderate to marked improvement in the 30 
g/kg/day group, compared with 23% in the placebo group (p=0.044). Similar trends were 
seen with multiple outcomes including greater weight loss, lower intravenous (IV) loop 
diuretic use and lower incidence of in-hospital worsening heart failure in the serelaxin groups 
 


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(with the 30 g/kg/day dose group being optimal) compared with placebo. Serelaxin was well 
tolerated at all doses, the adverse events (AEs) being distributed across study groups without 
any consistent pattern, the majority of which represented the natural history of patients 
admitted with AHF.
In the RELAX-AHF study 1161 patients were enrolled, 1138 of whom treated with serelaxin 
at 30 g/kg/day or placebo (n=568 and 570 patients, respectively). The results showed a 
significant relief of dyspnea as measured by change from baseline on a 100-point visual 
analogue scale (VAS) over 5 days (p=0.0075), even though dyspnea reduction as measured 
using a 7-point, Likert scale over the first 24 hours (primary end-points) did not achieve 
statistical significance. The results also showed that, compared with conventional therapy, 
treatment with serelaxin improved signs and symptoms of patient congestion at Day 2 and 
significantly reduced WHF episodes through Day 5 and the overall length of index hospital 
stay, associated with a range of other in-hospital clinical benefits. WHF rates were 
significantly decreased by serelaxin in RELAX-AHF: significantly fewer patients in the 
serelaxin group experienced WHF event or death through Day 5 compared with the placebo 
group (6.5% vs. 12.0%, OR=0.51; 95% CI: 0.33, 0.77; RLX.CHF.003; data on file). Similar 
results were obtained for WHF through 14 days in placebo group 15.7% (KM) and serelaxin 
11.4% (KM), p=0.024 (Teerlink et al 2013). Serelaxin provided sustained benefits beyond the 
initial 48 hours of infusion leading to a clinically and statistically significant 37% reduction in 
the risk of both cardiovascular and all-cause-mortality through Day 180. Serelaxin had 
favorable effects on the short-term changes in multiple laboratory markers of cardiac, renal, 
and hepatic damage known to be associated with long-term mortality in AHF. Serelaxin was 
well tolerated with no notable difference in the overall AE profile; a lower rate of AEs related 
to renal impairment in the serelaxin treatment arm compared with placebo was noted.
Based on these data, serelaxin represents a new treatment option in AHF, in addition to 
standard therapy, that may provide rapid and sustained dyspnea relief and improvement of 
other symptoms and signs of congestion. The findings obtained suggest serelaxin holds 
promise as the first evidence-based therapy for AHF to substantially improve patients’ 
symptoms and clinical outcomes, including death.
1.2
Purpose 
This is a multinational, multicenter, prospective, randomized, open label study to confirm and 
expand the efficacy, safety and tolerability evidence of 48 hours intravenous infusion of 
serelaxin (30 g/kg/day) when added to Standard of Care (SOC), in patients admitted to 
hospital for AHF.
2
Study objectives
2.1
Primary objective(s)
The primary objective of the study is to evaluate the effect of serelaxin as add -on therapy to 
standard of care (SOC) versus SOC alone in reducing in-hospital worsening HF (WHF) 
requiring rescue therapy or all-cause death, from randomization through Day 5. 
 


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2.2
Secondary objectives
The secondary objectives of the study are the following: 
To assess the effect of serelaxin as add-on therapy to SOC versus SOC alone in reducing 
in-hospital WHF requiring rescue therapy or all-cause death or readmission for heart 
failure, from randomization through Day 14.
To assess the effect of serelaxin as add-on therapy to SOC versus SOC alone in reducing 
the number of patients with persistent symptoms or signs of HF / not showing an 
improvement versus baseline conditions from randomization through Day 5 (persisting 
need of IV therapy for HF).
To evaluate the effect of serelaxin as add-on therapy to SOC versus SOC alone in reducing 
the rate of renal deterioration (defined as ≥0.3 mg/dL increase in serum creatinine), from 
randomization through Day 5.

To evaluate the effect of serelaxin as add-on therapy to SOC versus SOC alone in 
modifying the index length of stay (LOS) by location (e.g., ICU, CCU, cardiology 
department) in days and hours (ICU).
To evaluate the safety and tolerability of intravenous serelaxin in AHF patients during a 
period of 30 days following exposure.
To collect data on health-related quality of life (HRQoL) and economic burden to provide a 
more comprehensive analysis of the burden of HF, beyond the clinical outcomes.
 


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3
Investigational plan
3.1
Study design
This study is a prospective, multinational, multicenter, randomized, open label clinical trial to 
evaluate the efficacy, safety and tolerability of serelaxin as add-on therapy to SOC versus 
SOC alone in AHF subjects on the primary composite end-point of in-hospital WHF or all-
cause-death through Day 5. The outcome defined as in-hospital WHF (with signs/symptoms 
of worsening conditions, requiring therapy intensification) will be adjudicated by an 
Independent Board.
After signing an Ethics Committee or Institutional Review Board approved Informed Consent 
Form, subjects will be asked to undergo screening procedures for study eligibility. It is 
essential that screening is completed in time to allow randomization within 16 hours from 
presentation. Investigators are invited to initiate the serelaxin treatment as soon as possible 
after randomization.
After assessing patient eligibility during the screening period, patients who meet the study 
inclusion and none of the exclusion criteria will be randomized in a 2:1 ratio to receive 
intravenous infusion of either serelaxin for up to 48 hours in addition to SOC or SOC alone 
(Figure 3-1). 
Figure 3-1
Study design
Presentation starts as the earliest of (1) time of presentation at either the ER/ED, ICU/CCU or 
ward (excludes EMS or other pre-hospital care); or (2) time of first IV loop diuretic for 
treatment of the current AHF episode prior to arrival at the hospital (this includes outpatient 
clinic, ambulance, or previous hospital including emergency department). Investigators will 
be encouraged to initiate therapy as soon as possible.
 


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Serelaxin drug infusion will be administered via continuous IV infusion for 48 hours
according to a weight-range adjusted dosing regimen at the nominal dose of 30 g/kg/day. 
Due to the potential risk of hypotension, blood pressure will be monitored regularly during the 
administration of study drug. If at any time during dosing, the subject’s systolic blood 
pressure is decreased by >40 mmHg from pre-treatment (i.e. just before the study drug 
infusion) but is ≥100 mmHg in 2 consecutive measurements 15 minutes apart, serelaxin 
infusion rate will be decreased by 50% for the remainder of the 48-hour study drug 
administration. Serelaxin administration will be permanently discontinued at any time if in 2 
consecutive measurements, 15 minutes apart, systolic blood pressure is reduced to <100 
mmHg. Measures may be taken by the investigator to address the decrease in blood pressure 
during the intervening 15 minutes, if clinically indicated. Should the study drug dose be 
decreased or the study drug be discontinued prematurely due to blood pressure decrease, then 
blood pressure measurements shall be taken every half hour through 2 hours following the 
blood pressure decrease event, and then hourly through 5 hours after the event onset. Upon 
completion of the 5-hour post event onset time point, heart rate and blood pressure 
measurements shall be resumed as outlined in Section 6.5.2. If hypotension persists beyond 
the 5-hour post event onset, continued hourly blood pressure monitoring should be considered 
by the investigator, if clinically indicated. Additional blood pressure data collected beyond the 
5-hour post event shall be reported in the source documents; only heart rate and blood 
pressure outlined in Section 6.5.2 will be entered into the case report form (eCRFs).
Patients will be monitored closely during the treatment infusion period (48 hours up to Day 2). 
The study includes a short-term follow-up through Day 5, discharge and through Day 14. An 
extension follow-up period up to Day 30, when all subjects will receive a phone call to 
ascertain vital status and the need for repeated hospitalization. 
Patients will undergo clinical evaluations including AHF symptom assessments, vital signs, 
physical examination emphasizing signs of HF, as well as the need for further IV or oral HF 
treatment and the occurrence of worsening HF events at least daily while hospitalized and 
then at Day 14. Subjects randomized to either serelaxin arm or SOC, and discharged prior to 
Day 5 will be required to return to the hospital/clinic for scheduled visits at Days 5 and 14.
Should the patient not be able to come for the scheduled visit at Day 14, every effort should 
be made to contact the patient via phone to obtain essential vital details (See Table 6-1).
Safety will be assessed by monitoring AEs and vital signs and performing physical 
examinations and routine clinical laboratory tests as per protocol, as well as tests felt to be 
clinically indicated by the investigator up to Day 30.
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and through Day 14 must be reported to Novartis within 24 hours 
of learning of its occurrence. Any SAEs experienced after Day 14 should be reported to 
Novartis only if the investigator suspects a causal relationship to study treatment.
Patients are required to receive standard of care treatment for HF during both the index 
hospitalization and post-discharge per local and institution practice guidelines.
 
 
 
 


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3.2
Rationale of study design
Choice of open-label design
The open label (OL), randomized design was chosen after careful considerations and the
possibility of a double blind (DB) design had been evaluated. The DB could have brought 
both benefits and challenges, the benefits based on a high credibility of the study results in the 
academic community (internal validity), while the challenges would have been operational 
and would have had an impact on complexity and recruitment speed.
The choice of a randomized OL design will offer a different balance of benefits, with 
emphasis on external validity (Juni et al., 2001), as literature supports randomization in an OL 
design as a sensible option when DB is not chosen (Casteels et al., 2007).
The aim of the RELAX-AHF-EU study is to generate evidence in the management of AHF in 
real-life settings that will complement existing and future serelaxin data sets based on DB-
RCT (double-blind randomized controlled trials) in AHF. 
Decision makers in Health Care are indeed increasingly interested in using high-quality 
scientific evidence to support clinical and health policy choices, and they welcome practical 
(or pragmatic) clinical trials (Tunis et al., 2003). 
These practical clinical trials are characterized by the 1) selection of clinically relevant 
alternative interventions to compare, 2) inclusion of a diverse population of study participants, 
3) recruitment of participants from heterogeneous practice settings, and 4) collection of data 
on a broad range of health outcomes.
The OL randomized controlled design of RELAX-AHF-EU will better reflect the way 
physicians really manage patients. A variety of different hospital settings will participate 
(cardiology departments, internal medicine wards, and emergency units) from a large 
selection of countries.
The OL nature of the study also creates an opportunity to reach out to a variety of clinica l 
institutions and structures, closely reflecting real-life clinical contexts.
To note that the primary endpoint, which contains elements of subjectivity, will be 
adjudicated in a blind way by a committee of experts (Adjudication Committee) appointed by
the study Executive Committee.
 


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3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
Previous results in the Phase II Pre-RELAX-AHF (a dose finding trial) and in Phase III 
RELAX-AHF support the selection of serelaxin 30 μg/kg/day as the dose to be used via 
intravenous infusion for 48 hours. 
In the RELAX-AHF study, serelaxin treatment significantly improved early signs and 
symptoms of congestion, reduced WHF through Day 5 and the length of index hospital stay in 
addition to a range of other in-hospital clinical benefits; it also demonstrated overall good 
safety and tolerability. The favorable efficacy and safety observed in the RELAX-AHF study 
support the adoption of the same dosing regimen of serelaxin administration in this study.
For patients who experience significant systolic blood pressure decrease during the 48-h 
serelaxin infusion, protocol-specified dosing adjustments and/or discontinuations rules must 
be followed to ensure patient safety (refer details in Section 3.1 and Section 5.5.5).
3.4
Rationale for choice of comparator
There is no evidence based therapy for the treatment of AHF and thus an active comparator is 
not available. All patients in this study will be required to receive standard of care HF 
management during the study. 
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits 
The management of AHF remains an area of unmet medical need, even though, therapies are 
available to improve AHF-related symptoms, no evidence based therapy for the treatment of 
AHF is currently available. 
Previous studies with serelaxin (Teerlink et al., 2011 and 2013) showed significant 
improvement in dyspnea and signs and symptoms of congestion, and demonstrated an
association of the drug with significant reductions in early worsening heart failure events and 
length of stay during the index hospitalization, including duration of intensive care. Moreover, 
pre-specified biomarker changes in previous studies suggest serelaxin therapy has a protective 
effect on both the heart and kidney. 
Serelaxin was generally well tolerated with no notable differences in the overall adverse event 
profile compared to placebo. Although a decrease in blood pressure can occur due to the 
vascular mechanism of action of the drug, worse outcomes were not observed. In order to 
ensure patient safety, the protocol provides instructions for the management of systolic blood 
pressure (SBP), including close and careful monitoring as well as mandatory dose adjustment 
or stopping rules.
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and close clinical monitoring. Since the potential of immunogenicity as a result of repeated 
intravenous dosing has not yet been fully characterized, those patients who participated in 
prior serelaxin clinical studies will be excluded. It is also important to note that all patients in 
 


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this study will be required to receive standard of care background HF management during 
hospitalization as well as the period of 30 days following exposure.
Refer to the Investigator’s Brochure (IB) for additional information regarding the safety 
profile of serelaxin.
4
Population
Similarly to the RELAX-AHF study, subjects will be selected among patients who have been 
admitted with AHF, who have normal to elevated blood pressure (SBP>125 mmHg at the start 
and at the end of the screening period) and have impaired renal function defined as an 
eGFR >25 and <75 ml/min/1.73m2 at screening (calculated using the sMDRD equation).
The study plans to randomize approximately 3183 patients in approximately 600 study centers 
mainly in Europe.
4.1
Inclusion criteria
Subjects must fulfill all of the following criteria at screening to be eligible for the study. The 
screening period is defined as that interval that begins at the time the informed consent is 
signed and ends with the qualification of the subject for entry into the study (i.e. when subject 
has met all eligibility criteria):
1. Able to provide written informed consent before any study-specific assessment is 
performed. The AHF diagnostic assessments performed as per current local 
institution/hospital standard practice or as part of routine clinical care can be used to 
support patient screening even if performed before obtaining informed consent.
2. Male or female ≥18 years of age with body weight ≥ 40 Kg and ≤ 160 Kg.
3. Systolic blood pressure >125 mmHg at the beginning of the screening period (after 
ICF signature) and at the end of the screening period (prior to randomization). 
4. Admitted/hospitalized for AHF. AHF is defined as including all of the following 
measured at any time between presentation and the end of screening:
a.
Persistent dyspnea at rest or with minimal exertion, at screening and at the 
time of randomization, despite standard background therapy for acute 
decompensated heart failure including intravenous furosemide of at least 40 
mg total (or equivalent)
b. Pulmonary congestion assessed through physical examination and chest X-
Ray obtained during routine clinical practice at any time between presentation 
and the end of screening (prior to randomization)
c.
N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥2,000 pg/mL or 
BNP ≥500 pg/mL. For patients treated with valsartan/sacubitril (Entresto®), 
BNP is not suitable and only NT-pro-BNP should be assessed
5. Able to be randomized within 16 hours from presentation to the hospital 
[presentation starts as the earliest of (1) time of presentation at either the ER/ED, 
ICU/CCU or ward; or (2) time of first IV loop diuretic for treatment of the current 
AHF episode prior to arrival at the hospital] (this includes outpatient clinic, ambulance, or 
previous hospital including emergency department).
 


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6. Received intravenous furosemide of at least 40 mg (or equivalent) at any time 
between presentation and the start of screening for the study
7. Impaired renal function defined as an estimated glomerular filtration rate (eGFR), 
between presentation and randomization of ≥ 25 and ≤ 75 mL/min/1.73 m2, calculated 
using the simplified Modification of Diet in Renal Disease (sMDRD) equation (Levey 
AS et al., 2007; Myers GL et al., 2006).
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this 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.
1. Dyspnea primarily due to non-cardiac causes, such as acute or chronic respiratory 
disorders or infections (i.e., severe chronic obstructive pulmonary disease, bronchitis, 
pneumonia), or primary pulmonary hypertension sufficient to cause dyspnea at rest, 
which may interfere with the ability to interpret the primary cause of dyspnea. 
2. Known history of respiratory disorders requiring the daily use of IV steroids (does not 
include inhaled or oral steroids) at least 2 months prior to randomization; need for 
intubation or the current use of IV steroids for COPD.
3. Patients with systolic blood pressure >180 mmHg at the end of screening or persistent 
heart rate >130 bpm
4. Temperature >38.5°C (oral or equivalent) or sepsis or active infection requiring IV 
anti-microbial treatment. 
5. Current (within 2 hours prior to randomization) or planned (through the completion of 
study drug infusion) treatment with any IV vasoactive therapies, including 
vasodilators (including nesiritide), positive inotropic agents and vasopressors, or 
mechanical support (intra-aortic balloon pump, endotracheal intubation, assisted 
(invasive or non-invasive) ventilation, or any ventricular assist device, or 
ultrafiltration, hemofiltration or dialysis), with the exception of IV furosemide (or 
equivalent diuretic) or IV nitrates at a dose of ≤0.1 mg/kg/hour if the patient has a 
systolic BP >150 mmHg at the start of the screening. 
6. Significant left ventricular outflow obstruction, uncorrected, such as obstructive 
hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <1.0 cm2
or mean gradient >50 mmHg on prior or current echocardiogram), severe aortic 
regurgitation and severe mitral stenosis. 
7. Clinical evidence of acute coronary syndrome currently or within 30 days prior to 
enrollment. (Note that the diagnosis of acute coronary syndrome is a clinical 
diagnosis and that the sole presence of elevated troponin concentrations is not 
sufficient for a diagnosis of acute coronary syndrome, given that troponin 
concentrations may be significantly increased in the setting of AHF). 
8. AHF due to significant arrhythmias, which include any of the following: sustained 
ventricular tachycardia, bradycardia with sustained ventricular rate <45 beats per 
 


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minute or atrial fibrillation/flutter with sustained ventricular response of >130 beats 
per minute. 
9. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of study treatment and for 5 days after cessation of study drug. Highly 
effective contraceptive methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of childbearing potential.
10. 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 
local laboratory test. 
11. Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive 
cardiomyopathy (does not include restrictive mitral filling patterns seen on Doppler 
echocardiographic assessments of diastolic function). 
12. Major surgery, including implantable devices (e.g. ICD, CRT), or major neurologic 
event including cerebrovascular events, within 60 days prior to screening. 
13. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated, within the past year.
 


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14. Hematocrit <25% or a history of blood transfusion within the 14 days prior to 
screening or active, life-threatening GI bleeding.
15. Known hepatic impairment or AST / ALT > 3 ULN.
16. Known presence of active or recurrent bacterial, fungal or viral infection at the time 
of enrollment.
17. Any organ transplant recipient, or patient currently listed for imminent transplant (i.e., 
do not exclude patients on an administrative transplant waiting list), or admitted for 
any transplantation. 
18. Any other medical conditions that may put the patient at risk or influence study 
results in the investigator’s opinion, or that the investigator deems unsuitable for the 
study, including drug or alcohol abuse or psychiatric, behavioral or cognitive
disorders, sufficient to interfere with the patient’s ability to comply with the protocol 
instructions or follow-up procedures. 
19. Administration of any investigational drug or implantation of investigational device, 
or participation in another trial, within 30 days before screening or previous treatment 
with serelaxin. 
20. Inability to follow instructions or comply with follow-up procedures. 
21. Known hypersensitivity to serelaxin or similar substances or to any of the excipients. 
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Serelaxin will be administered according to a weight-range adjusted dosing regimen at a 
nominal dose of 30 μg/kg/day (refer to the details in Section 5.5.4), as a continuous 
intravenous infusion for 48 hours. The study drug is provided as a 1 mg/mL solution in 6 mL 
vials (with 3.5 mL fill). For the randomized patients to receive the study drug infusion, it will 
be withdrawn from the vials contained in the kits, injected into a 250 mL intravenous bag of 5% 
dextrose solution and then infused through a dedicated IV line or port, using compatible 
tubing, infusion filters and IV bags according to instructions in the Pharmacy Manual.
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial. 
Nevertheless, all randomized patients will be required to receive standard of care background 
HF management during both the index hospitalization and post discharge, according to local 
guidelines/international standards. This treatment post-randomization can include but is not 
limited
to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) 
inhibitors/angiotensin receptor antagonists, blockers and aldosterone receptor antagonists, 
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5.2
Treatment arms
Subjects will be randomized in a 2:1 ratio to receive one of the following: 

Serelaxin (30 µg/kg/day) as continuous 48-h intravenous infusion plus standard of care.

Standard of care only. 
5.3
Treatment assignment, randomization 
At baseline, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number (for patients randomized to 
serelaxin only) for the first package of investigational treatment to be dispensed to the patient. 
The randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the 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, which in turn are linked to medication numbers (for serelaxin arm only). A separate 
medication list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to packs containing the investigational drug. 
The randomization scheme for patients will be reviewed and approved by the Randomization 
Office.
Mis-randomized patients are those who have not been qualified for randomization, have been 
inadvertently randomized into the study and who did not take study drug. Mis -randomized 
patients are defined as cases where IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the patient’s final randomization eligibility and 
administration of serelaxin, where applicable, was not performed. These patients should have 
been considered screen failures as they did not meet eligibility criteria and should
subsequently be discontinued from the study. Sites should notify IRT and contact their 
Novartis monitor as soon as possible if a patient is mis-randomized into the study.
5.4
Treatment blinding 
Treatment code will be open to patients, investigator staff, and persons performing the 
assessments. The clinical trial team (e.g. Clinical Trial Lead, Clinical trial Manager, Medical 
Lead, Trial Statistician) will be blinded to the identity of the treatment from the time of 
randomization until database lock. Randomization data will be kept strictly confidential until 
the time of unblinding, and will not be accessible by anyone else involved in the study with 
the exception of those mentioned in the Safety Manual.
 


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5.5
Treating the patient
5.5.1
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The assigned 
patient number should be entered in the field labeled ‘‘Subject ID’’ on the electronic Case 
Report Form (eCRF) data entry screen.
If a patient correctly randomized fails to be treated for any reason, the IRT must be notified 
immediately that the patient was not treated. The patient will be followed up to Day 30 and 
relevant information, together with the reason for not being treated, will be entered into the 
eCRF. 
5.5.2
Dispensing the investigational treatment
Each study site will be supplied by Novartis with investigational treatment in kits containing 1 
vial of serelaxin each, enough study drug for 24 hours of infusion. To receive the second 24 
hours of study drug, the investigator’s staff will contact the IRT again and request a second kit
(for patients randomized to serelaxin only).
The investigational treatment packaging has a 2-part label. Immediately before dispensing the 
package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
subject number.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment shall be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the patient number. The investigator must maintain an 
accurate record of the shipment and dispensing of investigational treatment in a drug 
accountability log. Monitoring of drug accountability will be performed by the field monitor 
during site visits and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels and a copy 
 


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of the completed drug accountability log to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
5.5.3.2
Handling of other study treatment
Patients will receive standard of care as per local clinical practice. The investigator will enter 
information on standard of care provided to the patient in the eCRF. 
5.5.4
Instructions for prescribing and taking study treatment
Serelaxin drug infusion will begin as soon as possible after randomization, but not later than 4 
hours after start of study drug preparation, and will be administered via continuous IV 
infusion for 48 hours. 
Serelaxin infusion solution must be prepared in infusion bags containing 5% dextrose as a 
diluent. Recommended infusion bags, which have been tested and qualified for use with 
serelaxin, are detailed in the Pharmacy Manual. However, there is no restriction of use of any 
other 250 mL infusion bag with 5% dextrose.
Compatible infusion filters which have been tested and qualified for use with serelaxin, must 
be used to administer the study drug and are detailed in the Pharmacy Manual.
For each randomized patient to receive the study drug according to a weight-range adjusted 
dosing regimen over a period of 24 hours (Table 5-1), the required amount of study drug will 
be withdrawn from the 6-mL vials (with stopper and crimp caps with 3.5 mL fill) contained in 
the kits, injected into a 250 mL intravenous bag of 5% dextrose solution recommended above 
and then infused at a constant rate of 10 mL/hour [via an infusion pump, a drip or any other 
controllable system for Germany only]. Details of study drug preparation and infusion can be 
found in the Pharmacy Manual.
Study drug will be dispensed only by study staff qualified to perform that function under 
applicable local laws and regulations for the study site(s), according to the protocol and 
Schedule of Events (see Table 6-1). 
Patients who do not meet any criteria for interruption after 24 hours of infusion and are 
therefore eligible to continue with other 24 hours of study drug infusion will be required to 
receive study drug prepared from a second kit or pair of kits also assigned via IRT, depending 
on the patient’s body weight.
The study drug kits, allocated to each randomized patient via IRT, containing one 6 -mL vial 
of serelaxin (with 3.5 mL fill), will be used to compound study drug for the first 24 hour s of 
infusion for all patients <115 kg in weight; in cases when the subject is ≥115 kg, two study 
drug kits will be assigned via IRT for the first 24 hours of infusion. The body weight 
determined between presentation and randomization, rounded up to the nearest 0.5 kg, will be 
used for the calculation of the dose for each patient, for the entire 48-hour infusion period. 
Study drug from a second kit or pair of kits, also assigned via IRT depending on the patient’s 
body weight as assessed between presentation and randomization, will be used to continue the 
infusion for the second 24 hours. The second study drug kit should be obtained by calling IRT 
close to the end of the 1st 24 hours of study drug infusion.
 


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Table 5-1
Weight-range adjusted dosing regimen of serelaxin 
All kits of investigational treatment assigned by the IRT will be recorded in the IRT.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Systolic Blood Pressure (SBP) has to be ≥ 125 mmHg for the patient to be eligible, and then ≥ 
125 mmHg during the screening period, in particular at the end of the screening period just 
before calling the IRT for randomization. In many centers, continuous cardiac monitoring will 
probably be applied and this will keep the site informed about SBP values.
Considering the high fluctuation of blood pressure in patients with decompensated HF, 
especially because the patient might be under the effect of nitrates (even at low dose) and 
diuretics, it is advised to minimize the time windows between the end of screening, the IRT 
call and start of the serelaxin infusion. 
In practice: 

BP has to be measured at the end of screening and SBP must be ≥ 125 mmHg before 
calling the IRT. Once the patient is randomized, the study drug should be prepared 
promptly (if the patient is in the serelaxin group). 

Just before the immediate start of study drug infusion, SBP must be assessed again. 
During that interval between randomization and infusion start, sometime will elapse (30 to 
60 minutes in most cases) and BP may fluctuate. 

It is not required that pre-infusion SBP be ≥125 mmHg (SBP ≥125 mmHg is an 
inclusion criterion and matters only up to randomization)

If at the immediate start of study drug infusion, SBP is below 100 mmHg (SBP <100 
mmHg), serelaxin should not be started, neither now nor later. The patient will remain 
in the study up to 30 days but will not have received serelaxin

If a blood pressure fall has occurred since randomization but SBP is still ≥100 mmHg, 
the decision to start or not the infusion remains at the discretion of the investigator,
based on the hemodynamic context of the patient (i.e. previous hemodynamic stability, 
DBP, concomitant medications, medical response to IV furosemide/diuretics, etc.).
Of note, there is no mandatory time window between randomization and start of the study 
drug infusion. This time span should be kept as short as possible. For microbiological reasons, 
there is a maximum time of 4 hours allowed between preparation (mixing) of the study drug 
and infusion start.
If at any time during the study drug infusion, the subject’s systolic blood pressure decreases 
by >40 mm Hg from just before the study drug infusion but is ≥100 mmHg in two consecutive 
measurements 15 min apart, the serelaxin infusion rate will be decreased by 50% for the 
Body weight (kg)
Serelaxin (mg)
Volume of serelaxin to be added to 250 mL IV bag of 
sterile 5% dextrose for intravenous infusion over a period 
of 24 hours
40-59 kg
2.0 mg
2.0 mL
60-74 kg
3.0 mg
3.0 mL
75-114 kg
3.5 mg
3.5 mL
115-160 kg
5.5 mg
5.5 mL (2 vials needed)
 


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remainder of the 48-hour study drug administration. Serelaxin administration will be 
permanently discontinued at any time if in 2 consecutive measurements; 15 minutes apart, 
systolic blood pressure is reduced to <100 mmHg.
Table 5-2 describes the actions required for a systolic BP decrease during the period of study 
drug infusion, which must be strictly followed.
Table 5-2
Dosing adjustment of study drug administration in the event of 
systolic BP decrease through completion of study drug infusion
* These systolic BP values should be confirmed by two measurements taken 15 minutes apart.
In addition, dosing may be discontinued at any time at the discretion of the investigator. 
Reasons the investigator may discontinue study drug administration include, but are not 
limited to, serious or intolerable AEs suspected to be related to study drug. If dosing is 
discontinued for BP decreases, or any safety reasons, it should not be restarted. Re-
administration of study drug once terminated for safety reasons is not allowed. The total time 
from initiation of study drug infusion to completion must not exceed 48 hours. In the event 
that study drug administration is discontinued, regardless of the reason, the patient will 
continue to be followed at all study visits defined in the protocol. These changes in study drug 
dose must be recorded on the Dosage Administration Record eCRF.
5.5.6
Rescue medication
The investigator may prescribe any medications and/or supportive care during the study based 
on clinical needs. Use of rescue medication must be recorded on the Concomitant 
medications/Significant non-drug therapies in the eCRF.
5.5.7
Concomitant treatment
To be eligible for the study, all patients must have received IV furosemide of at least 40 mg 
(or equivalent e.g. Torasemide 20 mg or Bumetanide 2 mg) at any time between presentation 
and the start of screening for the study. This total 40 mg IV furosemide or equivalent loop 
diuretic dose might include the dose that the patient has received in the emergency service 
ambulances. 
Patients will not be enrolled in the study if concomitant therapy for AHF includes current 
(within 2 hours prior to randomization) or planned (through the completion of study drug 
infusion) treatment with any cardiovascular IV therapies, including vasodilators (including 
nesiritide), positive inotropic agents and vasopressors, or mechanical support (intra-aortic 
balloon pump, endotracheal intubation, assisted (invasive or non-invasive) ventilation, or any 
Changes in systolic BP during infusion*
Adjustments of study drug administration
Decrease >40 mmHg from pre-treatment (i.e.,
measured just before the immediate start of 
study drug infusion), but systolic BP remains ≥ 
100 mmHg
Reduce the infusion rate by half for the 
remainder of the study drug administration, 
i.e., reduce infusion rate from 10 mL/hour to 5 
mL/hour for the remainder of 48-hour infusion
Decrease in absolute value of systolic BP to
<100 mmHg
Permanently terminate study drug infusion
 


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ventricular assist device), with the exception of IV nitrates at a dose of ≤0.1 mg/kg/hour if the 
patient has a systolic BP >150 mmHg at the start of the screening. Use of IV furosemide (at 
least 40 mg or equivalent) is an inclusion criterion. Further doses of IV or oral furosemide can 
be administered at any time after enrollment.
The investigator may prescribe any additional medications during the study as made necessary 
by the patients’ condition. Administration of any standard AHF treatment shall in no instance 
be delayed or withheld due to patient’s participation in the study. Standard AHF treatment 
includes, but is not limited to, administration of the major classes of cardiovascular 
medications, as well as administration of oxygen, analgesics, anxiolytics and sedatives, as 
needed.
Heart failure medications, procedures and significant non-drug therapies administered after 
the patient was enrolled into the study must be recorded. The investigator shall instruct the 
patient to notify the investigator or associated study personnel about any new medications 
he/she takes after discharge and up to Day 30.
Administration of any cardiovascular IV therapies, including vasodilators (including 
nesiritide), positive inotropic agents and vasopressors, or mechanical support (intra-aortic 
balloon pump, endotracheal intubation, assisted ventilation (invasive or non-invasive), or any 
ventricular assist device), is allowed when necessary in both groups. However, in the 
serelaxin group caution should be exercised and potential additive hypotensive effects be 
discussed, in order to decide whether to maintain or discontinue the serelaxin infusion during 
administration of the above mentioned additional AHF drugs or procedures.
Any concomitant treatment taken by a subject during the hospital stay and until Day 30 will 
be recorded.
5.5.8
Prohibited Treatment
Use of IV vasoactive therapies within 2 hours prior to randomization is an exclusion criterion 
with the exception of IV loop diuretics, or IV nitrates at a dose of ≤ 0.1 mg/kg/hour if the 
patient has a systolic BP >150 mmHg at the start of the screening. Thus, study drug shall be 
started concomitantly with IV nitrates only if at a low dose (≤ 0.1 mg/kg/hour) in a patient 
with high systolic BP (>150 mmHg).
Post-randomization, the investigator may prescribe any additional medication as made 
necessary by the patients’ condition. Administration of any standard AHF treatment shall
never be delayed or withheld due to patient’s participation in the study.
The investigator shall exercise caution when up-titrating or adding concomitant standard AHF 
therapies that might decrease BP during study drug infusion. Investigator may consider not 
administering all blood pressure (BP) lowering medication simultaneously. Changes to these 
medications during the index hospitalization shall be recorded on the eCRF.
5.5.9
Discontinuation of study treatment
The investigator shall discontinue the study drug infusion for a patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
In particular, the study drug administration must be discontinued under the following 
circumstances:
 


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
The patient’s systolic BP falls to <100 mmHg in two consecutive measurements 15 min 
apart. Measures may be taken by the investigator to address the decrease in blood pressure 
during the intervening 15 minutes, if clinically indicated 

Pregnancy

Any other protocol deviation that results in significant risk to the patient’s safety
During the study drug infusion, administration of any cardiovascular IV therapies, including 
vasodilators (including nesiritide), positive inotropic agents and vasopressors, or mechanical 
support (intra-aortic balloon pump, endotracheal intubation, assisted ventilation, or any 
ventricular assist device) is allowed. The continuation or discontinuation of study drug 
infusion will then be at the discretion of the investigator.
Of note, patients who discontinue investigational treatment shall NOT be considered 
withdrawn from the study, and are required to be followed per the visit/assessment schedules 
illustrated in Table 6-1 until the study is complete. The investigator must register the patient’s 
discontinuation from the study and/or investigational treatment in the eCRF.
Patients can also refuse to participate in specific aspects of the study and/or take study 
medication at any time without withdrawing consent. Investigators shall make every effort to 
accommodate the needs of the patients to make it possible for them to continue to participate 
in the remaining aspects of the study. This includes performing telephone visits to obtain vital 
status and/mortality information for patients who are unable to or refuse to return for clinic 
visits.
5.5.10
Withdrawal of consent
Patients may voluntary withdraw from the study for any reason at any time. Withdrawal of 
consent occurs only when a patient does not want to participate in the study anymore and does 
not want any further visits or assessments and does not want any further study related contacts 
and does not allow analysis of already obtained biologic material.
If a patient withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. All biological 
material that has not been analyzed at the time of withdrawal must not be used. Furt her 
attempts to contact the patient are not allowed unless safety findings require communicating 
or follow-up.
5.5.11
Loss to follow-up
The investigator should show ‘‘due diligence’’ by contacting the patient, family or family 
physician as agreed in the informed consent and by documenting in the source documents 
steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. to collect 
safety information, the vital status and hospitalizations at 30 days.
5.5.12
Emergency breaking of assigned treatment code
Not applicable.
 


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5.5.13
Study completion and post-study treatment
After randomization, patients will be followed up through Day 5 and 14 and then at Day 30. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
Any SAEs experienced after Day 14 should be reported to Novartis only if the investigator 
suspects a causal relationship to study treatment.  
5.5.14
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient shall be seen as soon as possible and treated as a prematurely withdrawn patient. 
The Executive Committee can also stop the study based on DMC recommendation; the final 
decision is up to Novartis. The investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing Institutional review 
boards (IRBs) and/or Ethics Committees (ECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and an ‘‘x’’ indicates when the visits are to be performed. 
Patients shall be seen daily through index hospitalization until Day 5, until discharge
(whichever occurs first), and then at Day 14. If for any good reason, the assessments at Day 5 
cannot be done on the designated day, a window of + 1 day is allowed. A “visit window” of 
+/- 2 days is allowed for Day 14 and for phone contact on Day 30.
Patients should be seen for all visits on the designated day or timepoint, or as close to it as 
possible. Patients are expected to return to the clinic for all scheduled study visits. Patients 
unable or unwilling to return to the hospital/clinic for scheduled visits will be contacted by 
telephone as close as possible to the expected visit to obtain information about their survival 
status.
Patients who prematurely discontinue the investigational treatment remain in the study and 
shall undergo all the assessments illustrated in Table 6-1. 
If a patient withdraws from participation in the study, refuses to return for study assessments 
or is unable to do so, every effort shall be made to contact them or a knowledgeable informant 
by telephone and/or other measures to determine the patient’s survival status during the 
follow-up period.
 


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Table 6-1
Assessment schedule
Visit number
0
0-1
1-1
1-2
1-3
1-4
1-5
1-6
2
3
4
Time of Visit
Screening
End of 
Screening/
Baseline
6h
12h
24h
48h
D3
D4
D512
Discharge13
D14
(± 2) 
D30
(± 2)
Phase
Drug Infusion0
Post-treatment daily 
assessment
Follow-
up
Obtain Informed 
Consent
X
Demographic data
X
Inclusion/Exclusion 
criteria
X
Medical history, 
including diagnostic of 
AHF, Alcohol, drug 
abuse, education 
level, living 
arrangement and
smoking histories
X
Physical examination 
with vital signs1
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight 
measurement1
X
X
X
X
X
X
X
X
Physician 
assessment of signs 
and symptoms of HF1
X
X
X
X
X
X
X
X
X
X
Worsening Heart 
Failure (WHF)2
X
X
X
X
X
X
X
X
X
ECG
X
X
X
Chest X-Ray3
X
BP and HR 
measurements4
X
X
X
X
X
X
X
X
X
X
X
NT-pro-BNP or BNP
for study entry5
X
Serum cTnT or cTnI6
for study entry
X
Pregnancy test6
X
eGFR (sMDRD)6
X
X
X
X
Laboratory tests 
(Local Laboratory)6,7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQoL questionnaire 
X
X
X
X
X
 


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Visit number
0
0-1
1-1
1-2
1-3
1-4
1-5
1-6
2
3
4
Time of Visit
Screening
End of 
Screening/
Baseline
6h
12h
24h
48h
D3
D4
D512
Discharge13
D14
(± 2) 
D30
(± 2)
Phase
Drug Infusion0
Post-treatment daily 
assessment
Follow-
up
(EQ-5D-5L)
Healthcare Resource 
Utilisation9
X
X
X
X
X
X
X
X
X
X
X
Contact IRT10
X
X
X
Administer study 
medication
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
Non-serious Adverse 
Events11
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events11
X
X
X
X
X
X
X
X
X
X
X
X
Vital Status
X
X
X
X
0 Study drug will be administered as an IV infusion for 48 hours. If at any time during dosing, the subject’s systolic blood 
pressure is decreased by >40 mm Hg from baseline but is ≥100 mm Hg in 2 consecutive measurements 15 minutes apart, the 
study drug treatment infusion rate will be decreased by 50% for the remainder of the study drug administration. If at any time 
during dosing, the subject’s systolic blood pressure is <100 mm Hg in 2 consecutive measurements 15 minutes apart, the study 
drug infusion will be terminated. 
1Physical examination includes assessment of vital signs. Following randomization, all physical examinations should be 
performed daily at approximately the same time of day. Daily vital signs may be m easured and recorded by trained study 
personnel as well as trained healthcare personnel as part of their rout ine clinical duties. For details of assessment see Section 
6.5.1, Section 6.5.2.
2 WHF is defined as worsening signs and/or symptoms of heart failure that require an intensification of intravenous therapy for 
heart failure or mechanical ventilation or circulatory support. Such treatment can include the institution or up -titration of IV 
furosemide, IV nitrates or any other IV medication for heart failure or institution of mechanical support such as assisted
(invasive/non-invasive) ventilation, IABP, etc.  
3Chest X-Ray is not considered a study-related procedure. It should be done according to local diagnostic practice. Patients 
may only enter the trial with pulmonary congestion on a chest X -Ray obtained during routine clinical practice at any time 
between presentation and the end of screening (prior to randomization). If the chest X-Ray from routine clinical assessments is 
not available, the patient may not enter the trial.
4 BP and HR measurements should be performed for all patients at the beginning of the screening period (after ICF signature) 
and at the end of the screening period (prior to randomization). For serelaxin patients, frequent BP and HR measurements 
should be performed between randomization and immediate start of study drug administration, 30 and 60 minutes after start of 
study drug administration, then every hour for the first 6 hours and then every 3 hours during study drug infusion, including night 
time hours. Post-infusion, BP and HR should be measured every 3 hours until 12 hours following end of infusion, then every 6 
hours for 48 hours and then every 24 through the index hospitalization, at discharge, at Day 5 and then at Day 14.For patients 
randomized to the SOC group, BP and HR measurements should be performed at 6, 12, 24, 48 hours post-randomization, daily 
through the index hospitalization, at discharge, at Day 5 and then at Day 14. All measurements should be performed as close 
as possible to specified timepoints. BP and HR should be measured with the patient in the same position and with the same 
equipment using the same arm. These measurements may be made and recorded by trained study personnel, as well as 
trained healthcare personnel as part of their routine clinical duties.
5 Measured through a point of care device provided by Sponsor required only if the site is not able to obtain local lab test results 
within the 16-hour timeframe or if local lab does not offer it at all. When a patient treated with valsartan/sacubitril (Entresto®) is 
considered for randomization into the trial, only NT-proBNP and not BNP should be assessed during the screening phase. BNP 
is not a suitable biomarker of heart failure in patients treated with Entresto® because BNP is a neprilysin substrate. NT-proBNP 
is not a neprilysin substrate and is therefore a more suitable biomarker.
6 Measured at local laboratory. Following randomization, local laboratory collections can be adjusted to conform to the hospital’s 
routine laboratory collection schedule and can be collected at any time of the day.
7 Clinical laboratory tests include hematology and chemistry and will be performed locally. Urinalysis will be conducted at 
baseline, 24 and 48 hours only to rule out any conditions that might be requiring further diagnostic evaluation or treatment. See 
Section 6.5.4 for details.
9 Throughout the index hospitalization, the level of healthcare resource utilization shall be assessed by the overall length of stay, 
length of time in specific inpatient care units and procedures rendered during hospital stay. There may be circumstances when 
the collection of the data after completion of the study may be warranted.
 


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Visit number
0
0-1
1-1
1-2
1-3
1-4
1-5
1-6
2
3
4
Time of Visit
Screening
End of 
Screening/
Baseline
6h
12h
24h
48h
D3
D4
D512
Discharge13
D14
(± 2) 
D30
(± 2)
Phase
Drug Infusion0
Post-treatment daily 
assessment
Follow-
up
10 Investigational treatment kits containing 1 vial of serelaxin each is enough for 24 hours of study infusion. To receive the 
second 24 hours of study drug, the investigator’s staff will contact the IRT again and request a second kit. For SOC patients, 
the contact with IRT at Visit 1-3 is not necessary.
11 Non-serious Adverse Events will be collected through Day 5 and all Serious Adverse Events will be collected through Day 14, 
regardless of suspected causality. After Day 14 only suspected Serious Adverse Events will be collected and databased.
12 If for any good reason, the assessments at Day 5 cannot be done in the designated day, a window of + 1 day is allowed.
13 If discharge assessments coincide with a scheduled visit, only the assessments of the scheduled visit will have to be 
performed. If discharge occurs at any time after Day 5, all discharge assessments have to be performed.
 
6.1
Information to be collected on screening failures
All patients who have signed informed consent but are not entered into the next epoch (study 
phase) will have the study completion page for the screening epoch, demographics, 
inclusion/exclusion, and SAE data collected. AEs that are not SAEs will be followed by the 
investigator and collected only in the source data.
All patients who have signed informed consent and are entered into the next epoch of the 
study will have all AEs occurring after informed consent is signed recorded on the Adverse 
Event eCRF.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever, in their judgment, the test abnormality occurred prior to the informed 
consent signature.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include 
date of birth, age, sex, race, ethnicity, education level, living arrangement, weight and height, 
relevant medical history/current medical condition present before signing informed consent. If 
patient body weight cannot be measured at screening because of the patient’s physical 
condition, a verbal weight will be acceptable (weight should be obtained as soon as the patient 
is physically able to). Where possible, diagnoses and not symptoms will be recorded.
Baseline HF medications and other CV medications will be recorded in eCRFs separately 
from other medications. Likewise, detailed HF history and other relevant CV medical history 
will be recorded on eCRFs separately from other medical history.
Chest X-Ray will not be considered a study related procedure and shall be performed 
according to local clinical practice. Pulmonary congestion should be present upon clinical 
assessment and chest X-Ray as per local clinical practice.
Patients may only enter the trial with pulmonary congestion on a chest X-Ray obtained during 
routine clinical practice at any time between presentation and the end of screening (prior to 
randomization). If the chest X-Ray from routine clinical assessments is not available, the 
patient may not enter the trial.
 


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Physical examination, assessment of signs and symptoms of HF and its worsening will be also 
performed. Relevant documentation shall be filed in the patient’s medical record and available 
information entered in the eCRF. 
The eGFR to determine eligibility of the patient for screening into the trial will be calculated 
at screening from the serum creatinine concentration measured locally. 
Serum cTnT or cTnI and NT-proBNP or BNP will be performed only at screening by local 
laboratory (cTnT or cTnI). Values prior to the screening but performed within the index 
hospitalization can be used. NT-proBNP assessed specifically by point of care device is only 
required if the site is not able to obtain local lab test results within the 16-hour timeframe or if 
local lab does not offer NT-pro BNP or BNP at all.
At screening, a locally-analyzed urine/serum pregnancy test (according to the local practice) 
will be performed for all females of childbearing potential. Any subject with a positive 
pregnancy test at Screening will be excluded from the study.
Baseline information on healthcare resource utilization (HRU) and HRQoL will be collected
also.
6.3
Treatment exposure and compliance 
Information on study drug administration, infusion time and rates and possible discontinuation 
of intravenous infusion will be reported in the eCRF. 
Study drug accountability will also be verified by the site monitor while performing routine 
site visits and at the completion of the study. 
6.4
Efficacy
6.4.1
In-hospital Worsening Heart Failure/all-cause death through Day 5
The primary endpoint is time to in-hospital Worsening Heart Failure (WHF) requiring rescue 
therapy or all-cause death through Day 5. 
In-hospital WHF through Day 5 post randomization includes worsening signs and/or 
symptoms of heart failure that require an intensification of intravenous therapy for heart 
failure or mechanical ventilation, renal or circulatory support. Such treatment can include the 
institution or up-titration of IV furosemide, IV nitrates or any other IV medication for heart 
failure, or institution of mechanical support such as assisted (invasive or non-invasive) 
ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or ventricular assist device, 
etc. This endpoint also includes patients who die in this 5-day period of any cause before 
experiencing episode(s) of WHF.
Relevant evaluations will be performed in the serelaxin arm at 6, 12, 24 and 48 hours from 
start of study drug infusion, daily through index hospitalization, at Day 5 and discharge and 
then at Day 14. For patients in the SOC arm, relevant evaluations will be performed at 6, 12, 
24 and 48 hours from randomization, daily through index hospitalization, at Day 5 and
discharge, and then at Day 14.
 


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6.4.1.1
Assessment of signs and symptoms of heart failure
The investigator or appropriate qualified designee will evaluate the symptoms and signs of 
heart failure, including dyspnea on exertion or at rest, orthopnea, rales, jugular venous pulse 
(JVP) and peripheral edema. These evaluations will be performed at baseline, 6, 12, 24 and 48 
hours from start of study drug infusion, daily through index hospitalization, at Day 5, at 
discharge and then at Day 14 for serelaxin arm. For patients in the SOC arm, relevant 
evaluations will be performed at baseline, at 6, 12, 24 and 48 hours from randomization, daily 
through index hospitalization, at Day 5, at discharge, and then at Day 14.
These evaluations should be done at approximately the same time of the day, each day, in the 
same position and hospital/clinic setting, preferably by the same assessor.
For details of assessment see Appendix 3.
6.4.2
In-hospital Worsening Heart Failure/all-cause death through Day 14
The secondary efficacy endpoint is Time to Worsening HF requiring rescue therapy as 
defined above, or death or readmission for heart failure through Day 14. 
In this study we are also collecting information on the number of patients with persistent 
symptoms or signs of HF / not showing an improvement versus baseline conditions through
Day 5 (persisting need of IV therapy for HF).
6.4.3
Index Length of hospital stay
Changes in index length of hospital stay and per location (emergency ward, emergency care 
unit, etc.) will be evaluated by treatment group.
6.4.4
Appropriateness of efficacy assessments 
The efficacy assessments selected are standard for this indication/patient population. In-
hospital WHF is a clinically meaningful efficacy variable that gives the investigator an 
indication of the evolution of the clinical condition of the patients as well as information on 
treatment efficacy. Mortality in AHF patients remains high despite contemporary standard-of-
care HF management, and all-cause death is a robust and established efficacy endpoint to 
assess the effect of pharmacologic interventions on clinical outcomes of HF patients. The 
various assessments planned during the in-hospital phase, as well as at 14 and 30 days follow-
up, will provide useful and complementary information on serelaxin efficacy in acute HF 
patients.
6.5
Safety 
Safety will be assessed by comparing the serelaxin group to the standard of care only group 
with regard to the frequency of AEs/SAEs, changes in vital signs, physical examination 
findings, and clinical laboratory test results (chemistry, hematology, and urinalysis). All non-
serious AEs will be collected through Day 5 and SAEs (regardless of causality) through Day
14. Any SAEs experienced after Day 14 should be reported to Novartis only if the investigator 
suspects a causal relationship to study treatment.
 


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6.5.1
Physical examination 
An overall physical examination will be performed by the investigational staff at screening 
and includes the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and vascular and 
neurological examination. An abbreviated physical examination will be performed at 6, 12, 24 
and 48 hours after start of study drug infusion in the serelaxin arm and daily through index 
hospitalization, at Day 5, at discharge and then Day 14, and includes the examination of 
general appearance and vital signs (SBP/DBP and pulse). For patients in the SOC arm, an 
abbreviated physical examination will be performed at 6, 12, 24 and 48 hours from 
randomization, daily through index hospitalization, at Day 5, at discharge, and then at Day 14, 
and includes the examination of general appearance and vital signs (SBP/DBP and pulse).
Following randomization, all physical examination should be performed at approximately the 
same time of day. Information for all physical examinations must be included in the source 
documentation at the study site. Significant findings that are present prior to signing informed 
consent must be included in the Medical History part of the eCRF. Significant findings after 
signing the informed consent, up to and including Day 5, which meet the definition of a non-
serious AE, must be recorded on the Adverse Event section of the eCRF (Section 7.1). 
Significant findings after signing the informed consent, up to and including Day 14, which 
meet the definition of a SAE, must be recorded on the Serious Adverse Event section of the 
eCRF (Section 7.2), and a completed signed Serious Adverse Event form must be faxed to the 
local Novartis Drug Safety and Epidemiology Department (DS&E) within 24 hours after 
awareness of the SAE.
Subjects discharged after 48 hours from start of drug infusion for serelaxin arm/from 
randomization for SOC arm, but prior to Day 5, will be required to return for a physical 
examination as an outpatient at Days 5 and 14.
6.5.2
Vital signs 
Body temperature and respiratory rate will be measured at Screening, at 6, 12, 24 and 48 
hours after start of study drug infusion in serelaxin arm and daily through index 
hospitalization, at Day 5, at discharge, and then at Day 14. Patients discharged prior to Day 5 
will return to the hospital/clinic for Day 5 procedures. For the SOC patients, body temperature 
and respiratory rate will be measured at Screening, at 6, 12, 24 and 48 hours after 
randomization and daily through index hospitalization, at Day 5, at discharge, and then at Day 
14, according to the scheduled visits. 
Daily measurements may be made and recorded by trained study personnel as well as trained 
healthcare personnel as part of their routine clinical duties.
BP and HR measurements should be performed for all patients at the beginning of the 
screening period (after ICF signature) and at the end of the screening period (prior to 
randomization).
For serelaxin patients, BP and heart rate (HR) measurements will be also performed before 
the immediate start of study drug administration (0 hours pre infusion start), throughout study 
drug infusion at 30 and 60 minutes, then every hour for the first 6 hours, and then every 3 
hours, including night time hours. Post-infusion BP and HR are to be measured every 3 hours 
until 12 hours following end of infusion, then every 6 hours for 48 hours and then every 24 
 


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hours through index hospitalization, at Day 5, at discharge, and then at Day 14. For patients 
randomized to the SOC group, BP and HR measurements should be also performed at 6, 12, 
24, 48 hours, including night time hours, daily through index hospitalization, at Day 5, at 
discharge, and then at Day 14.
All measurements should be performed as close as possible to specified timepoint.
BP and HR are to be measured with the patient in the same position and with the same 
equipment using the same arm throughout study drug infusion. These measurements may be 
made and recorded by trained healthcare personnel as part of their routine clinical duties, as 
well as trained study personnel.
If at any time during dosing, the subject’s systolic blood pressure decreases by >40 mmHg 
from the systolic blood pressure measured just before the start of study drug infusion but is ≥ 
100 mmHg in two consecutive measurements 15 min apart, serelaxin infusion rate will be 
decreased by 50% for the remainder of the 48 hour study drug administration. Serelaxin 
administration will be permanently discontinued at any time if in two consecutive 
measurements 15 minutes apart, systolic blood pressure is reduced to <100 mmHg (also see 
details in Section 5.5.5).
Should the study drug dose be decreased or the study drug be discontinued prematurely due to 
blood pressure decrease, measurements should be taken every half hour through 2 hours 
following the blood pressure decrease event, and then hourly through 5 hours after event onset. 
Upon completion of the 5-hour post event onset time point, heart rate and blood pressure 
measurements should be resumed as outlined above.
6.5.3
Height and weight 
Height in centimeters (cm) or inches (inch) will be measured at screening only.
Body weight (to the nearest 0.1 kilogram [kg] or 0.1 pounds [lbs] in indoor clothing, but 
without shoes) will be measured at Screening and at 24 and 48 hours after study drug infusion 
in serelaxin arm, and daily through index hospitalization, at discharge, and at Day 5 and then 
at Day 14. For the SOC patients, body weight will be measured at screening, 24 and 48 hours 
after randomization and daily through index hospitalization, at discharge, and at Day 5, and 
then at Day 14. These measurements during hospitalization can be performed at any time of 
the day.
If patient’s body height/weight cannot be measured at Screening because of the patient’s 
physical condition, verbal height/weight will be acceptable. Height/weight measurements 
shall be obtained as soon as the patient is physically able. 
6.5.4
Laboratory evaluations 
All screening, baseline and post-baseline specimens 
 
 
will be analyzed by the local laboratory.
Following randomization, local laboratory collections can be adjusted to conform to the 
hospital’s routine laboratory collection schedule and can be collected at any time of day. 
 


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Laboratory values that exceed the boundaries of a notable laboratory abnormality should be 
assessed for AEs and additional evaluations should be performed, as judged appropriate by 
the investigator. If the laboratory abnormality induces clinical signs and symptoms or requires 
therapeutic intervention, then the diagnosis or medical condition must be entered on the AE 
screen of the patient’s eCRF. If the laboratory abnormality is the primary reason for an 
unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then the 
procedure for immediate notification of SAEs must be followed. Likewise, if the laboratory 
abnormality leads to discontinuation from the study, then the patient must be followed until 
the abnormality resolves or is judged to be permanent.   
Clinical laboratory tests including hematology and chemistry will be performed locally at 
screening, at 24 and 48 hours, at Day 5, at discharge and then Day 14 (in both arms). The tests 
done at each visit are standard medical tests. A total of approximately 10 mL will be collected 
when each blood sample is taken.
Urinalysis will be conducted at baseline, 24 and 48 hours only and analyzed locally.
In those sites in which markers of cardiac injury or stress are measured as per local practice 
the values should be entered into the eCRF ONLY in the context of a WHF event.
6.5.4.1
Hematology
Clinical hematology evaluations will include measurement of hemoglobin, hematocrit,  red 
blood cell count, white blood cell count, differential cell count (monocytes, neutrophils, 
eosinophils, lymphocytes, basophils), and platelet count. 
6.5.4.2
Clinical chemistry
Serum chemistry evaluations will include measurement of blood urea nitrogen (BUN) or urea, 
serum creatinine, total bilirubin, phosphate, ALT, AST, alkaline phosphatase, sodium, 
potassium, calcium, total cholesterol, triglycerides, LDL, HDL, glucose, uric acid, albumin 
and total protein. In addition, hemoglobinA1c will be measured at screening only. For Liver 
Events only, fractionated bilirubin, which includes testing for total bilirubin, direct bilirubin, 
and indirect bilirubin, should be performed in accordance with Table 14-2.
6.5.4.3
Urinalysis
Urinalysis will include measurement of glucose, ketones, pH, protein and specific gravity.
The analysis will be performed according to local lab methods /procedures.
6.5.5
Electrocardiogram (ECG) 
ECGs will be performed and interpreted locally at screening and at Day 5 and at discharge.
The ECG interpretation and the person interpreting the ECG must be recorded in the source 
documents.
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula 
(QTcF) should be used for clinical decisions.
 


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Single 12 lead ECGs are collected. The original ECGs on non-heat-sensitive paper or a 
certified copy on non-heat sensitive paper, appropriately signed, should be collected and 
archived at the study site.
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings prior to dosing with investigational treatment must be discussed with 
the sponsor.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate.
6.5.6
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments 
 
 
 
 
 
 
 
 
6.6.4
Health-related Quality of Life
The EQ-5D-5L is a widely used, self-administered questionnaire designed to assess health 
status in adults. The measure is divided into two distinct sections. The first section includes 
one item addressing each of five dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression). The second section of the questionnaire measures 
self-rated (global) health status utilizing a vertically oriented visual analogue scale where 100 
represents the “best possible health state” and 0 represents the “worst possible health state”. In 
 


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this study the first administration of the EQ-5D-5L questionnaire will occur at baseline visit. 
If, for whatever reason, the patient is not able to fill in the questionnaire at baseline, it is 
possible to collect retrospectively these data on Day 2. If this is the case, on Day 2 two 
questionnaires need to be filled in at this visit: first one asking the patient to retrospectively 
describe how he/she felt on the day of admission, and second one asking the patient to 
describe how he/she feels today. A special permission was provided by EuroQoL for the use 
with 2-day recall of the questionnaire.
The EQ-5D-5L quality of life assessment will be completed by all study patients (both 
serelaxin and SOC groups) at baseline, at Day 2, at Day 5, at discharge and Day 14.
Completed questionnaires will be reviewed by the investigator before the clinical examination 
for responses that may indicate potential AEs or SAEs. The investigator shall review not only 
the responses to the questions in the questionnaires but also any unsolicited comments written 
by the patient.
If the occurrence of AEs or SAEs is confirmed, the physician must record the events as per 
instructions given in Section 7 of the protocol. Investigators shall not encourage the patients 
to change the responses reported in the questionnaire.
6.6.5
Resource utilization 
Analyses will be undertaken, as appropriate, to assess the effects of treatments on healthcare 
resource utilization (RU) parameters.
Throughout the index hospitalization, the level of healthcare resource utilization shall be 
assessed by the overall length of stay, length of time in specific inpatient care units and 
procedures rendered during hospital stay. 
Data for a health economic analysis will be collected from eCRFs, most notably Hospital 
Discharge, Re-hospitalization and Death. Data on medical resource use will be collected for 
all enrolled patients from the index hospitalization at discharge and at Day 5, and then at Day 
14 and through phone contact at Day 30. 
The endpoints and methods of the health economic analysis will be detailed separately in the 
statistical analysis plan.
6.6.6
Echocardiography
Echocardiography evaluation is not a mandatory requirement of the protocol; in case the 
evaluation is performed and the values obtained are available in the source documents, they 
need to be entered into eCRF. Most recent data up to the last 12 months can be entered.
7
Safety monitoring 
All AEs will be collected through Day 5, and all serious adverse events will be collected 
through Day 14, regardless of suspected causality. After Day 14 only suspected SAEs will be 
collected and databased.
Specific handling of the Study Endpoint WHF:
WHF events should be recorded not only as an endpoint but systematically as an AE as well. 
All WHF endpoints should thus be reported as AEs/SAEs in the AE eCRF page. 
 


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Non-serious WHF event should be reported through Day 5 and serious (SAE) WHFs should 
be reported through Day 14. After Day 14, only those study endpoints that qualify for SAEs 
and are also suspected to be related to the study medication should be reported in the AE 
eCRF page. It is recommended but not mandatory that the same verbatim should be used for 
an individual event for both the endpoint reporting and the AE reporting, i.e. “Worsening of 
Heart Failure”.
7.1
Adverse events 
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of AEs shall be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events may also be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of the 
individual patient and identifying AEs. Alert ranges for lab test abnormalities are included in
Appendix 1.
AEs shall be recorded in the Adverse Events eCRF under the signs, symptoms or diagnosis 
associated with them accompanied by the following information.

the severity grade
o mild: usually transient in nature and generally not interfering with normal activities
o moderate: sufficiently significant to interfere with normal activities
o severe: prevents normal activities

its relationship to the investigational treatment (no/yes)

its duration (start and end dates). If the event is ongoing, an outcome of not recovered/not 
resolved shall be reported.

whether it constitutes a SAE

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
whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; unknown)
An SAE is any AE (appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s) or medical conditions(s) which meets any one of the following criteria 

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
o 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 
o social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under ‘‘medically significant’’ if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All AEs shall be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e. further observation only); investigational treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the AE shall be recorded 
on the Adverse Event eCRF. 
Once an AE is detected, it shall be followed until its resolution or until it is judged to be 
permanent an assessment shall be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the investigational treatment, the 
interventions required to treat it and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated through IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and shall be discussed with the patient during the study as needed.
 


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The investigator shall also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information shall be recorded in the 
investigator’s source documents. If the AE meets the criteria of a SAE, it must however be 
reported to Novartis.
7.2
Serious adverse event reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent through Day 14 must be reported to Novartis within 24 hours of 
learning of its occurrence. Any SAEs experienced after the 14 days period should only be 
reported to Novartis if the investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one shall be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to study drug, complete the SAE Report Form in English, and send the completed, 
signed form by fax within 24 hours after awareness of the SAE to the local Novartis Drug 
Safety and Epidemiology Department. The telephone and fax numbers of the contact persons 
in the local department of Drug Safety and Epidemiology, specific to the site, are listed in the 
investigator folder provided to each site. The original copy of the SAE Report Form and the 
fax confirmation sheet must be kept with the case report form documentation at the study site. 
Follow-up information shall be provided using a new paper SAE Report Form stating that this 
is a follow-up to a previously reported SAE.
Follow- up information shall describe whether the event has resolved or continues, if and how 
it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event shall 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 Directive 2001/20/EC or as per national 
regulatory requirements in participating countries, except for SUSARs that are also efficacy 
endpoints and exempted from such expedited reporting as detailed below.
 


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Study-specific expediting rules for SUSARs that are also efficacy endpoints
In studies such as this one, where the efficacy endpoints potentially meet the requirements for
SUSAR reporting, the integrity of the study may be compromised if the endpoints are 
systematically expedited to competent authorities/relevant ECs and investigators. In such 
cases, regulations allow an exemption from SUSAR expediting aimed at ensuring the validity 
of an outcome study (European Commission: Communication from the Commission CT-3 
(2011/C 172/01); FDA Guidance 2012). Therefore, the rules for expediting SUSARs during 
the 14-day SAE collection period will be applied as follows.
1. Endpoint events that will not be expedited
A SUSAR will not be expedited, if the event is considered consistent with one of the efficacy 
endpoints: 

From randomization through Day 5: renal deterioration (defined as >0.3 mg/dL increase in 
serum creatinine)

From randomization through Day 14: in-hospital worsening heart failure (WHF) requiring 
rescue therapy (see endpoint definition in Section 2), or all cause death, or readmission for 
heart failure (HF)

Definitions:

In-hospital WHF includes worsening signs and/or symptoms of heart failure that 
require an intensification of intravenous therapy for heart failure or assisted (invasive 
or non-invasive) ventilation, renal or circulatory support. Such treatment can include 
the institution or up-titration of IV furosemide, IV nitrates or any other IV medication 
for heart failure, or institution of mechanical support such as assisted (invasive or non-
invasive) ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or 
ventricular assist device, etc. 

HF signs and symptoms include, but are not limited to, dyspnea on exertion or at rest, 
orthopnea, rales, jugular venous pulse (JVP) and peripheral edema.
In addition, Novartis will not expedite a report to competent authorities/relevant ECs and will 
not issue an IN.
If specifically requested by a local Health Authority, pre-specified endpoints (see above) that
also meet the criteria for SUSARs will be expedited to this Health Authority. Investigator 
Notifications will not be issued for these events.
2. Endpoint events that will be expedited
There is a subset of SAEs, which will require expedited reporting to
competent 
authorities/relevant ECs and investigators, if these meet SUSAR and/or endpoint criteria and 
are indicative of one of the following events:

Fatal events, which are often associated with drug toxicity and which include SAEs 
indicative of anaphylaxis, angioedema, blood dyscrasias (including agranulocytosis, 
aplastic anemia, bone marrow failure, pancytopenia and bicytopenia), hepatic injury, 
inflammatory lung disorders (including allergic, fibrosing, necrotizing alveolitis, 
eosinophilic pneumonia and interstitial lung disease), rhabdomyolysis, and serious 
cutaneous skin reactions (including Stevens-Johnson syndrome, toxic epidermal 
necrolysis and erythema multiforme) torsade de pointes and prolonged QT interval.
 


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
Efficacy endpoints, for which the investigator considers that the character and the 
severity of the endpoint is not consistent with the expected presentation or course of 
that endpoint and the investigator considers that the study drug and/or study 
procedures may have contributed to this abnormal presentation. 
Study-specific expediting rules for SUSARs that are commonly observed in the 
study population 
In clinical trials evaluating treatments for high morbidity and/or high mortality disease states, 
SAEs that are known consequences of the underlying disease or condition under investigation, 
or events common in the study population, are anticipated to occur with some frequency 
during the course of the trial, regardless of drug exposure. While the investigator must still 
report all non-serious AEs and SAEs through Day 5, and through Day 14, respectively, 
SUSARS considered consistent with the following SAE Preferred Terms (PTs) will not be 
reported in an expedited timeframe to regulatory agencies, ECs or investigators during the 
course of the study:
abdominal pain, acute coronary syndrome, acute pulmonary edema, anaemia,  angina pectoris 
*, anxiety, arthralgia, asthenia, azotaemia, back pain, blood creatinine *, blood pressure *, 
blood urea nitrogen *, bronchitis *, cardiac arrest, cardiac arrhythmias (all PTs presenting any 
type of arrhythmia excluding electrocardiogram QT interval abnormal, electrocardiogram QT 
prolonged, long QT syndrome, torsade de pointes), cardiac asthma, cardiac failure *, cardiac 
output *, cardiac pacemaker *, cardiac tamponade, cardiogenic shock, cardiorenal syndrome, 
cerebrovascular accident, chest pain, chronic obstructive pulmonary disease, confusional state, 
constipation, cor pulmonale *, cough *, creatinine renal clearance *, delirium, diarrhea, 
dizziness, dyspnea *, ejection fraction *, fatigue, generalized oedema, glomerular filtration 
rate *, gout, headache , hepatic congestion, hyperglycemia, hyperkalemia, hyperlipidemia, 
hypertension *, hyperuricaemia, hypoglycemia, hypokalemia, hypernatremia, hypotension *, 
implantable defibrillator *, influenza *, insomnia, loss of consciousness, muscle spasm, 
musculoskeletal pain, myocardial infarction*, nasopharyngitis, nausea, edema, edema due to 
cardiac disease, edema peripheral, osteoarthritis, pain in extremity, pericardial effusion, 
pleural effusion, pneumonia *, presyncope, pulmonary hypertension, pulmonary edema, renal 
failure *, renal impairment, respiratory distress *, respiratory failure *, respiratory tract 
infection *, stroke *, syncope, transient ischemic attack, urinary tract infection, valve *, 
ventricular failure *, vomiting, weight increased. 
*More than one PT can contain this term.
If specifically requested by a local health authority, pre-specified AEs commonly observed in 
the study population (see above) that also meet the criteria for SUSARs will be expedited to 
this Health Authority. Investigator Notifications will not be issued for these events. 
7.3
Liver safety monitoring
Hepatotoxicity clinical safety standard guideline
Hepatic dysfunction as sequelae of HF, even with modest cardiac compromise, has long been 
recognized. Passive hepatic congestion due to increased central venous pressure and low 
hepatic perfusion, reflecting impaired hemodynamics due to decreased cardiac output and 
profound hypotension, are considered causative mechanisms. Subsequent atrophy of liver 
 


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cells and edema of the peripheral hepatic parenchyma both lead to hepatocellular hypoxia.
PaO2 alterations can also add to hepatic injury. These events may be both acute with cardiac 
decompensation and chronic with low-grade hepatic compromise resulting in fibrosis or 
cirrhosis (Alvarez and Mukherjee 2011; Nikolau et al 2013).
Since cardiac-induced hepatic injury can mask hepatotoxic events, it is important to clearly
determine the underlying cause of elevations of liver function tests (LFTs) that may occur 
during the course of this study. Therefore, to ensure patient safety and enhance reliability in 
determining the hepatotoxic potential of an investigational drug, a standardized process for 
identification, monitoring and evaluation of hepatic events has to be followed.
The following two categories of abnormalities/liver 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 cannot be solely explained by apparent cardiac decompensation 
as the underlying cause (i.e., another etiology is suspected to cause or contribute to 
this event) and which will require close observation, follow-up monitoring and 
completion of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every laboratory trigger or liver event that cannot be solely explained by apparent cardiac 
decompensation as the underlying cause and as defined in Table 14-1 of Appendix 2 shall 
be followed up by the investigator or designated personnel at the trial site as summarized 
below. Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation
Repeat laboratory tests should be entered on the appropriate unscheduled local laboratory 
CRF page.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the hepatic event that needs to be followed until resolution.
These investigations can include serology tests, imaging and pathology assessments and a 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on the appropriate eCRF pages, including the 
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7.4
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
shall be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment.
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
8
Data review and database management 
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
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. Web based software will be used: no installation procedure will 
be needed. Each site will be authorized by the Administrator to access into the eCRF. Each 
investigator site qualified personnel would be allowed to access to the eCRF by means of a 
 


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‘login mask’ requiring User ID and Password and it would be possible to read, modify and 
update only the information he/she had previously reported. All pages should report site code 
and patient code. On-line 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 Contract Research Organization (CRO) working on behalf of Novartis. The 
Investigator must certify that the data entered into the Electronic Case Report Forms are 
complete and accurate. After database lock, the investigator will receive a CD-ROM with 
patient data for archiving at the investigational site. 
8.3
Database management and quality control
The 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. The Data Manager of the CRO working on behalf of 
Novartis will perform the cleaning session reviewing the warning messages raised by on-line 
checks and running post-entry checks by means of validation programs. During this process, 
if clarifications are needed, the Data Manager will raise queries by means of data query forms 
through the WEB application. Designated investigator site staff is required to respond to the 
query and the Data Manager will make the correction to the database on the basis of the query 
response. The data collection and the Queries flow as well as the on-line and off-line control 
checks will be detailed in the Data Management Plan and Data Validation documents
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.
 
Randomization codes 
and data about the study drug dispensed to the patient will be tracked using an Interactive 
Response Technology (IRT). The system will be supplied by a vendor. The IRT database will 
be sent electronically to Novartis (or a designated CRO). The occurrence of any protocol 
deviations will be reported during the conduct of the study until database lock.
After the database has been declared to be complete and accurate, it will be locked and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis Development management.
8.4
Data Monitoring Committee
An external independent Data Monitoring Committee (DMC) will be appointed to monitor the 
safety of study participants and to ensure that the program is being conducted with highest 
scientific and ethical standards. This DMC will review the safety data throughout the trial. 
Should the DMC make recommendations on the conduct of the trial that are considered to 
have significant bearing on the benefit-risk of the trial, these will be communicated by DMC 
to Executive Committee members and Novartis. The final decisions will be communicated to 
the investigators within an appropriate timeframe.
 


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8.5
Adjudication Committee
To strengthen the efficacy findings and interpretation, a Central Event Committee will be 
instituted and will oversee the adjudication of in-hospital WHF events and the cause of death.   
A charter of responsibilities and a specific dataset to evaluate clinical cases will be available 
before study initiation (Endpoint Manual).
The adjudication committee will review and adjudicate all in-hospital WHF that occur 
through Day 5 for endpoint determination in a blind way, as well as the causes of death events.
The detailed definitions of the endpoints, required documentation, and the adjudication 
process will be provided to all sites in a separate Endpoint Manual.     
9
Data analysis
All the data collected in this study will be listed and summarized as appropriate as described 
below. The data from all countries and all centers will be pooled and summarized. Continuous 
data will be summarized by the mean, standard deviation (SD), median, first and third 
quartiles, minimum and maximum. Categorical data will be presented by absolute and relative 
frequencies (n and %) or contingency tables. 
Subjects will be included in each efficacy analysis based on available assessments, after the 
data handling conventions have been applied. The prevalence approach, if not differently 
indicated, will be applied.
Unless stated otherwise, two-sided p values <0.05 will be considered statistically significant. 
All statistical tables, listings and analyses will be produced using SAS® release 9.2 or later 
(SAS Institute, Inc, Cary, NC, USA).
More details about data analysis will be provided in the Statistical Analysis Plan.
9.1
Analysis sets
The following analysis populations will be defined for statistical analysis. 
Patients without a valid or adequately obtained Informed Consent Form (ICF) will be 
excluded from any analysis population.
9.1.1
Full analysis set (FAS)
The Full Analysis Set (FAS) will include randomized patients who were not mis-randomized.
Following the intent-to-treat (ITT) principle, patients are analyzed according to the treatment 
they have been assigned to at randomization. Mis-randomized patients are those who have not 
qualified for randomization, have been inadvertently randomized into the study but who did 
not enter the treatment phase and who did not receive serelaxin. Mis-randomized patients are 
defined as cases where randomizations were made by the site either prematurely or 
inappropriately prior to confirmation of the patient’s final randomization eligibility. These 
patients should subsequently be discontinued from the study. The primary analysis and the 
analyses of all secondary and exploratory efficacy variables will be based on the FAS. 
 


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9.1.2
Randomized (RAN) set
All patients who received a randomization number, regardless of receiving trial medication
and including mis-randomized patients.
9.1.3
Per Protocol (PP) set
The Per Protocol (PP) set will include all patients in the FAS without major protocol 
deviations, as will be defined in the Patient Validation Document. Results of the primary 
efficacy endpoints conducted in the PP set will be considered as supportive.
In addition to the primary analysis, the primary efficacy variable will also be analyzed using 
the same primary analysis model on the PP set as supportive information.
9.1.4
Safety population
The safety population will include all patients who received any amount of study treatment or 
standard of care treatment and who have at least one post-baseline safety assessment. Of note, 
the statement that a patient had no adverse events also constitutes a safety assessment. 
Patients will be analyzed according to treatment received. The analyses on safety parameters 
will be conducted in the Safety set.
9.2
Patient demographics and other baseline characteristics 
All data about patient demographics and baseline characteristics, including derived variables, 
will be summarized in the FAS, overall and by treatment group, by means of summary 
descriptive statistics. Continuous data will be summarized by the mean, standard deviation 
(SD), median, first and third quartiles, minimum and maximum. Categorical data will be 
presented by absolute and relative frequencies (n and %) or contingency tables.
In order to interpret the results adequately, the homogeneity of patients’ distribution between 
treatment groups will be tested on demographics and anamnestic variables. P-values will have 
a descriptive meaning and any warnings of heterogeneity will be evaluated considering the 
clinical relevance of the involved variables. The p-values will not be considered to define any 
formal basis for determining factors to be included in statistical models. If an imbalance of 
treatment groups with respect to some variables does occur, supplemental analyses with 
addition of these variables in model may be performed to assess the potential impact on 
efficacy as appropriate. For continuous variables, the homogeneity of data will be tested by 
means of t-test. If data do not respect normality assumption a Wilcoxon rank sum test will be 
applied. For categorical variables chi-square test will be used. Fisher exact test in case of cell 
frequencies less than 5 will be applied. 
Whenever necessary, normality will be assessed by means of Shapiro-Wilk test and with 
graphical methods. In case of non-normality, appropriate transformation of data will be 
applied or a non-parametric test/model will be adopted. 
The number and percentages of subjects meeting all eligibility criteria at screening will be 
provided. The number of the analysis populations will be described and the reasons excluding 
the patient from any particular population will be provided with the number of protocol 
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A complete description of patient disposition will be provided, overall and by treatment group 
specifying the number of randomized patients, number of patients at each visit, completed and 
discontinued patients, and the reason for the discontinuation. 
The difference between treatment groups with respect to protocol violations and reasons for 
drop-out will be examined.
Medical history data will be presented by System Organ Class and Preferred Term, overall 
and by treatment group.
9.3
Treatments
9.3.1
Investigational Treatment
Overall study treatment administration details will be summarized for the FAS and the Safety 
population in the serelaxin arm only. This will include time from presentation to 
randomization (in hours), time from randomization to study treatment initiation (in hours), 
time from presentation to study treatment initiation (in hours), study treatment administered 
(yes/no), reason study treatment not administered, actual treatment received, and the number 
of days study treatment infused (one or two). The duration of study treatment administratio n 
(in hours) and the total volume of study treatment administered (estimated from the total time 
and rate of infusion) will be summarized. In addition, the number of subjects whose study 
medication dose was lowered or discontinued prematurely, and the reasons for discontinuation, 
will be summarized. Logistic regression models will be fitted considering demographics and 
anamnestic factors in order to identify main predictors for drug discontinuation. Odds ratio
and 95% confidence intervals will be provided. 
9.3.2
Concomitant treatments
Concomitant treatment administration details will be collected at any time between start of 
screening and randomization as well as by day from randomization. It will be summarized for 
the FAS and the Safety population. In addition, concomitant treatment administration details 
collected overall during index hospitalization and after discharge will also be summarized for 
the FAS and the Safety population.
As a patient may have taken more than one medication, the total number of medications could 
be greater than the total number of subjects. Continuous variables will be summarized with 
standard summary statistics (number of observations, mean, standard deviation, median, first 
and third quartiles, minimum and maximum), categorical variables with the number and 
percentage of subjects taking at least one dose of medication. Percentages will be computed 
on patients included in the analysis population. 
The total dose of IV loop diuretic and oral loop diuretic administered during the index 
hospitalization will be compared between treatment groups using a t-test. Doses will be 
converted to furosemide equivalents for analysis. 
Any standard of care treatment given according to local guidelines/international standards will
be summarized by preferred term. 
 


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This treatment can include but is not limited to intravenous and/or oral diuretics, ACE 
inhibitors/angiotensin receptor antagonists, blockers, and aldosterone receptor antagonists, 
etc. Summary tables will also be provided by country. 
As to the rescue medication usage summary statistics will be provided by treatment group. 
The rescue medication can include the institution or up-titration of IV furosemide, IV nitrates 
or any other IV medication for heart failure, or institution of mechanical support such as 
assisted (invasive or non-invasive) ventilation, ultrafiltration, hemodialysis, intra-aortic 
balloon pump or ventricular assist device, etc.
The use of other non-cardiovascular concomitant medications and significant non-drug 
therapies, prior to and after the randomization date, respectively, will be summarized by 
treatment group, therapeutic class, and preferred term for the FAS and the Safety population.
9.4
Analysis of the primary variable(s)
The primary analysis and the analyses of all secondary and exploratory efficacy variables will 
be based on the FAS. 
9.4.1
Variable(s)
The primary efficacy variable of the study is the time to in-hospital Worsening of Heart 
Failure (WHF) requiring rescue therapy or all-cause death through Day 5 post randomization. 
In-hospital worsening of heart failure (WHF) through Day 5 post randomization, includes 
worsening signs and/or symptoms of heart failure that require an intensification of intravenous 
therapy for heart failure or mechanical ventilation, renal or circulatory support. Such 
treatment can include the institution or up-titration of IV furosemide, IV nitrates or any other 
IV medication for heart failure, or institution of mechanical support such as assisted (invasive 
or non-invasive) ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or 
ventricular assist device, etc. This endpoint also includes patients who die in this 5-day period 
of any cause before experiencing episode(s) of WHF.
A central event adjudication committee will be appointed and will oversee the WHF primary 
endpoint adjudication. 
9.4.2
Statistical model, hypothesis and method of analysis
Time to in-hospital WHF/all-cause death through Day 5 post randomization will be analyzed 
using survival analysis. 
The time to in-hospital WHF/all-cause death will be computed as the number of hours from 
randomization to the earlier of the onset of in-hospital WHF or death. The onset of in-hospital
worsening heart failure through Day 5 will be the first assessment point, in terms of date and 
time, at which the investigator reported worsening heart failure (either during the initial 
hospitalization or re-hospitalization for heart failure). Subjects without an event will be 
censored at the earlier of the last assessment or 120 hours after randomization. 
The primary statistical hypothesis is:
H0: λ2/λ1 ≥ 1, i.e., the rate of primary event of in-hospital WHF or all cause death is greater or 
equal in the serelaxin group relative to the standard of care group versus the one-sided 
 


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alternative HA: λ2/λ1 < 1, i.e., the rate of in-hospital WHF or all cause death is smaller in the 
serelaxin group relative to the standard of care group, where λ1 and λ2 are the hazard rates for
in-hospital WHF or all cause death in the standard of care group and serelaxin group, 
respectively. The ratio λ2/λ1 is also called the hazard ratio of serelaxin to standard of care. 
The hypothesis will be tested based on the FAS with a Gehan’s generalized Wilcoxon test at a 
significance level of 0.025 (one-sided). Patients without an event will be censored at the 
earlier of the last contact date or 120 hours after randomization. 
The Kaplan-Meier estimates of the survival functions for each treatment group will be plotted
and Kaplan-Meier estimates for selected time points with 95% confidence intervals will be 
tabulated. 
The hazard ratio (relative risk) and its associated two-sided 95% confidence interval will be 
estimated based on a Cox proportional hazards model with treatment assignment as a factor. 
Absolute frequencies and proportions of patients with in-hospital WHF or all-cause death 
through Day 5 in each treatment group will be also provided.
9.4.3
Handling of missing values/censoring/discontinuations
In the analysis on time to in-hospital WHF/all-cause death through Day 5, patients without 
any event will be censored at the earlier of the last assessment or 120 hours post 
randomization. 
The proportions of patients with in-hospital WHF/all-cause death through Day 5 in each 
treatment group will be presented on all patients included in the efficacy analysis set.
9.4.4
Supportive analyses 
In addition to the primary analysis, the primary efficacy variable will also be analyzed using 
the same primary analysis model on the PP set as supportive information. Subgroup (age [65 
and 75 cut off], gender, race, region, naïve vs. prior history of HF) analyses will be performed 
for the primary endpoint.
9.5
Analysis of secondary variables
The additional efficacy endpoints will be analyzed in the FAS. Standard descriptive statistics 
will be presented for each treatment group at each time point the endpoint was measured. 
Two-sided p-values <0.05 will be considered statistically significant; no adjustment for 
multiple comparisons will be adopted.
9.5.1
Efficacy variables 
Time to in-hospital WHF/All-cause death/readmission for heart failure through Day 14 
post randomization
Time to in-hospital WHF/all-cause death/readmission for heart failure through Day 14 post 
randomization will be analyzed using survival analysis. 
The time to in-hospital WHF/all-cause death/readmission will be computed as the number of 
hours from the randomization to the earlier of the onset of in-hospital WHF or death or 
readmission. The onset of in-hospital WHF through Day 14 will be the first assessment point, 
 


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in terms of date and time, at which the investigator reported worsening heart failure (either 
during the initial hospitalization or re-hospitalization for heart failure). Subjects without an 
event will be censored at the earlier of the last assessment or 336 hours after randomization. 
Treatment groups will be compared with a Gehan’s generalized Wilcoxon test.
The Kaplan-Meier estimates of the survival functions for each treatment group will be plotted. 
The Kaplan-Meier estimates of the cumulative event rate will also be presented in tables by 
treatment group for each day and also by time interval. 
Absolute frequencies and proportions of patients with in-hospital WHF/all-cause 
death/readmission through Day 14 in each treatment group will be also provided. 
Persistent signs or symptoms of HF/ non-improvement
Absolute frequencies and proportions of patients with persistent symptoms or signs of HF / 
not showing an improvement vs. baseline through Day 5 (persisting need of IV therapy for HF) 
and at discharge in each treatment group will be provided, together with standard errors, 
asymptotic (Wald) and exact (Clopper-Pearson) confidence limits. The rates in the two groups 
will be compared by means of Chi square test at each time point. In case of cell frequencies 
less than 5, Fisher Exact test will be used. A time-to-event analysis will be applied to provide 
treatment comparisons. Hazard ratios of being a responder for each of the signs and symptoms 
variables will be estimated using a Cox regression model with treatment as factor.
Renal deterioration
Renal deterioration will be assessed as the proportion of patients with an increase of ≥0.3 
mg/dL from screening in serum creatinine levels. Absolute frequencies and proportions of 
patients with renal deterioration at each day until Day 5, at discharge and at Day 14 in each 
treatment group will be provided, together with standard errors, asymptotic (Wald) and exact 
(Clopper-Pearson) confidence limits. The rate of renal deterioration in the two groups will be 
compared by means of Chi square test at each time point. In case of cell frequencies less than 
5, Fisher Exact test will be used.
Index length of hospital stay
Index length of hospital stay (in hours) will be defined as the index discharge date and time 
minus the index hospitalization start date and time. 
Subjects still in the hospital at Day 30 will be censored at the end of Day 30. Subjects who die 
during the initial hospitalization will be assigned the maximum length of stay (including those 
censored at Day 30) plus 24 hours. Treatment groups will be compared using a Wilcoxon 
rank-sum test. Descriptive statistics by treatment group will be presented. Analysis will be 
done overall and by location (e.g. ICU, CCU, cardiology department).
Death through Day 30
The time (in days) from randomization to the event will be used for analysis. Subjects without 
an event will be censored at the earlier of the last contact date or Day 30. Treatment groups 
will be compared using a generalized Wilcoxon test. The Kaplan-Meier estimates of the 
survival functions for each treatment group will be plotted. 
 


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Re-hospitalization post-discharge
The number of re-hospitalizations per patients by treatment group will be described. 
Treatment groups will be compared using a Wilcoxon rank-sum test. The number of patients 
with 1, 2, ≥2 re-hospitalization will be summarized and treatment groups will be compared 
with a Chi-Square test. In case of cell frequencies less than 5, Fisher Exact test will be used.
Time to first re-hospitalization (in days) will be defined as the re-hospitalization date minus 
the randomization date. Subjects still in hospital at Day 30 will be censored at Day 30. 
Subjects who die when not hospitalized will be assigned as the date of death as their time to 
re-hospitalization. Treatment groups will be compared using a generalized Wilcoxon test. The 
Kaplan-Meier estimates for each treatment group will be plotted. Descriptive statistics by 
treatment group will be presented. 
9.5.2
Safety variables 
All the safety analyses will be done on the Safety population. 
Physical examination
As reported in Section 6.5.1, significant findings that are present prior to signing informed 
consent will be included in the Medical History part of the eCRF: they will be summarized by 
treatment group by means of usual descriptive statistics for categorical variables. Significant 
findings after signing the informed consent, up to and including Day 5, which meet the 
definition of an AE or of a SAE, will be recorded on the Adverse Event section of the eCRF. 
Adverse events
The incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) recorded during 
all the study will be presented. 
For patients in SOC group, time of randomization will considered as time of treatment 
initiation. Incident AEs will be considered those AEs with an onset date and time after 
treatment initiation. Adverse events with an onset between informed consent and treatment 
initiation will be listed separately. AEs will be summarized by System Organ Class and 
Preferred Term. Additionally, a summary of AEs by preferred term and severity using the 
worst reported severity grade for each event for the subject will be provided. For analysis 
purposes, all AEs defined as ‘‘definite’’, ‘‘probable’’ or ‘‘possible’’ will be considered as 
related. If the relationship to study drug is unknown or missing, the AE will be considered to 
be drug-related. All study-drug-related AEs, AEs with an outcome of death, AEs leading to 
discontinuation of treatment will be summarized by percentages and frequencies. SAEs will 
be summarized similarly. Percentages will be based on the number of subjects in the Safety 
population.
Adverse Events will be further characterized and presented according to the definitions of 
monitored safety risks and events of interest.
Laboratory data
Summary statistics of raw data and change from screening at each assessment time point and 
for each laboratory parameter will be presented by treatment group. Treatment groups will be 
compared for changes from screening using t-tests.
 


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Laboratory data will also be summarized by presenting shift tables for each laboratory 
parameter showing the number and percentage of subjects in each treatment group with the 
most extreme post-screening value that falls outside extended normal ranges by the 
classification of subjects at screening. 
Laboratory values will be presented for each subject in a data listing with an indication of 
whether the value is above (H) or below (L) the normal reference range and if it is notable.
Vital signs
Summary statistics of raw data and change from the start of screening for all patients, and 
from the end of screening for patients where the data are available will be provided by 
treatment group at each common assessment time point for vital signs, using t-tests.
Signs and symptoms of HF
Summary statistics for data about signs and symptoms of HF will be provided at each 
assessment time point by treatment group.
Blood pressure decrease events
Blood pressure values collected at various time-points only in serelaxin group during study 
drug infusion will be summarized by means of descriptive statistics for continuous variables.
The number and proportion of subjects who experience a confirmed blood pressure decrease 
event (i.e. CBPDE) during study drug infusion in the serelaxin group will be provided. 
Among subjects who experience a confirmed blood pressure decrease event, the events will be 
further characterized. Summaries will be provided separately for those confirmed events both 
symptomatic and asymptomatic that resulted in study drug dose reduction, and those that 
resulted in study drug discontinuation. The possible interaction between the effect of serelaxin 
and the effect of IV nitrate administration within the first 48 hours will be examined.
Pregnancy test results
Any pregnancies reported will be listed and outcome reported.
9.5.3
Resource utilization
Summary statistics on data about healthcare resource utilization collected through the index 
hospitalization, at discharge and at Day 5, and then at Day 14 and through phone contact at 
Day 30 will be provided by treatment group. Summary statistics for length of stay (overall and 
for specific inpatients care units) as well as for procedures rendered tthroughout the index 
hospitalization will be provided by treatment group. Additional information will be provided 
in the Statistical Analysis Plan.
9.5.4
Health-related Quality of Life
Health-related quality of life assessments, by means of the EuroQoL EQ-5D-5L questionnaire, 
will be used to derive pre-specified quality of life scores according to the EuroQoL EQ-5D-5L
questionnaire manual. For these scores summary statistics will be provided at each assessment 
by treatment group. 
To compare treatment groups in quality of life change from baseline, a mixed model for 
repeated measures will be fitted to overall health score absolute changes (score at time of 
 


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assessment - score at screening), at Day 2, at Day 5, at discharge and Day 14 and considering 
value at baseline as covariate. Additional analyses will also be conducted to generate utilities 
per treatment group, separately for patients hospitalized and not hospitalized at study visit.
9.5.5
Pharmacokinetics
Not applicable.
9.5.6
Pharmacogenetics/pharmacogenomics
Not applicable.
9.5.8
PK/PD
Not applicable.
9.6
Interim analyses 
No formal interim analyses are planned.
9.7
Sample size calculation
The primary endpoint of the study is the time to in-hospital adjudicated outcome Worsening 
of Heart Failure (WHF) requiring intensification of therapy, or to all-cause death through Day 
5 post randomization. 
 
 
 
 
 
 
 
 
 
 


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10
Ethical considerations 
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the International Conference for Harmonization (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.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed [by a 
study team independent physician or nurse for Germany only], where required by law or 
regulation), IRB/IEC-approved informed consent, or, if incapable of doing so, after such 
consent has been provided by a legally acceptable representative of the patient. In cases where 
the patient’s representative gives consent, the patient shall be informed about the study to the 
extent possible given his/her understanding. If the patient is capable of doing so, he/she shall 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. 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 shall be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP 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 and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of childbearing potential shall be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
 


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Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. 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 Clinical 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.
10.3
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.
11
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances shall the investigator contact Novartis or its agents, if any, monitoring the trial 
to request approval of a protocol deviation, as requests to approve deviations will not be 
granted.
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Under no circumstances shall an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs. 
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the clinical study report (CSR).
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis shall be notified of this action and the IRB/IEC at the study site shall be 
informed within 10 working days or less, if required by local regulations.
 


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12
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[Mantovani A, Valentino S, Gentile S, et al. (2013)] The long pentraxin PTX3: a paradigm for 
humoral pattern recognition molecules. Ann N Y Acad Sci.;1285:1-14.
[Manzano-Fernández S, López-Cuenca A, Januzzi JL, et al. (2012)] Usefulness of β-trace 
protein and cystatin C for the prediction of mortality in non ST segment elevation acute 
coronary syndromes. Am J Cardiol.;110(9):1240-8.
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public and private health burden. Eur Heart J.;19 Suppl P:P9-16.
[McMurray JJ, Adamopoulos S, Anker SD, et al. (2012)] ESC Guidelines for the diagnosis 
and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. 
Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart 
J.;33(14):1787-847.
[McMurray JJV, Teerlink J, Cotter G, et al (2007)] Effects of tezosentan on symptoms and 
clinical outcomes in patients with acute heart failure. The VERITAS randomized controlled 
trials. JAMA; 298:2009-19.
[Metra M, Felker GM, Zaca V, et al (2010)] Acute heart failure: multiple clinical profiles and 
mechanisms require tailored therapy. Int J Cardiol; 144:175-9.
[Metra M, O’Connor CM, Davison BA, et al (2011)] Early dyspnoea relief in acute heart 
failure: prevalence, association with mortality, and effect of rolofylline in the PROTECT 
Study. Eur Heart J; 32:1519-34. 
[Metra M, Cotter G, Davison BA, et al. (2013)] Effect of serelaxin on cardiac, renal, and 
hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development 
program: correlation with outcomes. J Am Coll Cardiol.;61(2):196-206.
[Metra M, Ponikowski P, Cotter G, et al. (2013)] Effect of serelaxin in subgroups of patients 
with acute heart failure: results from RELAX-AHF. Eur Heart J.;34(40):3128-36.
[Motiwala SR et al. (2013)] Serial measurements of galectin-3 in patients with chronic heart 
failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy 
(PROTECT). Eur J Heart Fail.;15(10):1157-63 or acute heart failure (RELAX-AHF1, 
unpublished).
[Myers GL, Miller GW, Coresh J, et al (2006)] Recommendations for improving serum
creatinine measurement: a report from the Laboratory Working Group of the National Kidney
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[Nicol ED, Fittall B, Roughton M, et al. (2008)] NHS heart failure survey: a survey of acute
heart failure admissions in England, Wales and Northern Ireland. Heart.;94(2):172-7.
[Nieminen MS, Brutsaert D, Dickstein K, et al. (2006)] EuroHeart Failure Survey II (EHFS 
II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart 
J.;27(22):2725-36.
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T to detect the ongoing myocardial damage in chronic heart failure patients. J Card Fail; 
13:120-127.
[Pellicori P, Cleland J (2015)] Update on management of heart failure with preserved ejection 
fraction. Curr Opin Cardiol;30:173-8
 


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[Rehman SU, Mueller T, Januzzi JL Jr. (2008)] Characteristics of the novel interleukin family 
biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol.;52(18):1458-65.
[Reiter M et al. (2008)] Heart-type fatty acid-binding protein in the early diagnosis of acute 
myocardial infarction. Heart 2013; 99:708-714.
[Roger VL, Go AS, Lloyd-Jones DM, et al. (2012)] Heart disease and stroke statistics – 2012 
update: a report from the American Heart Association. Circulation; 125:e2-e220.
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one-year mortality and prognostic factors. Eur J Heart Fail; 7:662-670.
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(ATTEND) registry. A prospective observational multicenter cohort study: rationale, design, 
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cardiology ward services in Italy. Eur Heart J; 27:1207-1215.
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for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. 
Lancet.;381(9860):29-39.
[Teichman SL, Unemori E, Teerlink JR, et al. (2010)] Relaxin: review of biology and 
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[Zannad F, Mebazaa A, Juillière Y, et al. (2006)] Clinical profile, contemporary management 
and one-year mortality in patients with severe acute heart failure syndromes: The EFICA 
study. Eur J Heart Fail.;8(7):697-705.
[Zannad F, Garcia AA, Anker SD, et al (2013)] Clinical outcome endpoints in heart failure 
trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J 
Heart Fail 15:1082-94.
[Zimmers TA et al. (2006)] Growth differentiation factor-15: induction in liver injury through 
p53 and tumor necrosis factor-independent mechanisms. J Surg. Res.; 130:45-51.
 


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Appendix 1: Clinically notable laboratory values
Clinically notable laboratory abnormalities for selected tests based on a percent change from
baseline:
Hematology
RBC count
>50% increase, >25% decrease
Hemoglobin
>50% increase, >25% decrease
Hematocrit 
>50% increase, >25% decrease
WBC count
>100% increase, >50% decrease
Platelet count
>100% increase, >50% decrease
Blood Chemistry
ALT (SGPT)
See Section 7.3 Liver safety monitoring and Tables 14-1, 14-2 in 
Appendix 2
AST (SGOT) 
See Section 7.3 Liver safety monitoring and Tables 14-1, 14-2 in 
Appendix 2
BUN
>100% increase
Creatinine
>100% increase
Total bilirubin 
See Section 7.3 Liver safety monitoring and Tables 14-1, 14-2 in 
Appendix 2
Alkaline phosphatase >100% increase
Potassium
>25% increase, >25% decrease
Calcium
>20% increase, >20% decrease
Uric acid
>100% increase
 


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Appendix 2: Liver laboratory trigger and liver event
definitions and follow-up requirements
Table 14-1
Definitions of liver laboratory triggers or liver events, which cannot be 
solely explained by apparent cardiac decompensation as the underlying 
cause (i.e., another etiology is suspected to cause or contribute to this 
event)
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)
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia
Any adverse event potentially indicative of a liver toxicity * 
 


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Table 14-2
Follow up requirements for liver laboratory triggers or liver events, 
which cannot be solely explained by apparent cardiac decompensation 
as the underlying cause (i.e., another etiology is suspected to cause or 
contribute to this event)
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, fractionated bilirubind, 
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, fractionated bilirubind, 
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, fractionated bilirubind, 
Alb, PT/INR, ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, fractionated bilirubind, 
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, fractionated bilirubind, 
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

Repeat LFT within the next week

If elevation is confirmed, initiate 
Investigator discretion
Monitor LFT within 1 to 4 weeks 
 


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Criteria
Actions required
Follow-up monitoring
(patient is 
asymptomatic)
close observation of the patient
or at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, fractionated bilirubind, 
Alb, PT/INR, ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
Any AE 
potentially 
indicative of a 
liver toxicity*

Consider study drug interruption or 
discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage-related conditions; the non-infectious hepatitis; the benign, malignant and unspecified 
liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
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.
dFractioned bilirubin includes testing for total bilirubin, direct bilirubin, and indirect bilirubin
 


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Appendix 3: Physician assessment of signs and symptoms
The following criteria are to be used to assess patient’s signs and symptoms of heart failure.
Exertional Dyspnea: The subject should be queried as to the extent of dyspnea noted over the
preceding 1-3 hours as follows:
0
No exertional dyspnea (NYHA Class I equivalent)
1
Mild exertional dyspnea, occurring with moderate exertion (climbing stairs or 
equivalent-NYHA Class II equivalent)
2
Moderate exertional dyspnea, occurring with only mild exertion (walking-
NYHA Class III equivalent)
3
Severe exertional dyspnea, occurring at rest (NYHA Class IV)
Orthopnea: The subject should be observed after being in the lowest recumbent position for 
10-15 minutes or queried in order to determine the minimum number of “pillows” required to 
obtain/maintain comfort while supine. This should be graded on a 0 - 4 scale as follows:
0
Comfortable with no pillow or very minimal elevation of head  
1
Comfortable with no less than one pillow to elevate head (approx 10 cm 
elevation)
2
Comfortable with no less than two pillows to elevate head (approx 20 cm 
elevation)
3
Comfortable with head no less than at 30 degree elevation 
Rales: Auscultation of the lungs applying a 4-point scale:
0
No rales heard, either moist or dry, after clearing with cough anywhere in
the lung fields
<1/3
Moist or dry rales heard in the lower 1/3 of either or both lung fields that persist 
after a cough in attempt to clear
1/3-2/3 
Moist or dry rales heard throughout the lower half to 2/3 of either or both
lung fields
>2/3 
Moist or dry rales heard throughout both lung fields
 


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Jugular venous pulse (JVP): With the subject supine at approximately a 45-degree angle, 
examination of the JVP is performed and the estimation, in cm H2O, is converted into one of 
3 categories:
<6 cm 
H2O 
Complete absence of discernable venous wave throughout respiratory cycle 
above the clavicle, even with hepatic compression (HJR)
6-10 cm 
H2O
Venous wave detectable above the clavicle, at least during expiration and 
possibly throughout respiratory cycle but less than 4 cm above the clavicle (<10 
cm H2O). Presence of venous wave only with mild HJR should be graded in this 
category.
>10 cm 
H2O  
Presence of venous wave throughout respiratory cycle with wave sometimes ≥ 4 
cm H2O above clavicle and typically increased with HJR. Patients with values 
of 6-10 cm H2O and positive HJR should be graded in this category.
NA
Examination could not be performed/result unobtainable
Peripheral Edema, Pre-sacral Edema: Edema should be examined in any dependent area 
including the lower extremities or the sacral region. The range to be applied is 0 - 3 (4 point 
scale).
0
The complete absence of edema, as determined by applying mild digital  
pressure in all dependent areas and failing to elicit any indentation of skin and 
subcutaneous tissues.
1+  
Detection of limited areas where mild digital pressure elicits an indentation of 
skin and subcutaneous tissues that resolves over approximately 10-15 seconds. 
Edema of this grade is typically limited to only the lower extremities or only the 
sacrum, not both.
2+   
Detection of moderate surface area in one or both areas (sacrum and lower 
extremities) where indentations of skin and subcutaneous tissues are easily 
created with limited pressure and these indentations disappear slowly (15-30 
seconds or more). 
3+  
Large areas of lower extremities (and sacrum if subject has been recumbent), 
often to mid-calf or higher, having easily produced and slowly resolving (more 
than 30 seconds) indentations. This extent of edema is sometimes associated 
with acute or subacute skin changes including weeping of skin and/or skin break 
down.
Patient’s assessment of dyspnea: Patient should be asked to assess their level of shortness of 
breath compared to admission using a scale from 0 to 10 where 0=none to 10=very very 
severe (maximal).
 


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SAP_001.pdf: 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301
FRM-STA003-01 
Rev.01 
Page 1 of 66 
RLX030/Serelaxin 
Clinical Trial Protocol CRLX030A3301 / NCT02064868
A multicenter, prospective, randomized, open label study 
to assess the effect of serelaxin versus standard of care in 
acute heart failure (AHF) patients 
Author: 
 
Document 
status: 
Final version 2.0 
Release date: 
27-Feb-2017


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 2 of 66 
 
 
Document History 
Status and 
Version 
Release Date 
Change Description 
Reason/Comment 
Draft Version 
0.1 
26/06/2015 
Initial release. 
Not applicable. 
Draft Version 
0.2 
25/09/2015 
Aligned Section 1.2 and 2.3 with Study 
Protocol Amendment # 3. 
Added protocol deviation details in 
Section 3. 
Redefined categories for LFT in 
Section 5.3. 
Added categorical values for ECG in 
Section 5.3. 
Aligned Section 5.1, 5.2 and 5.3 with 
CRLX030A2301 RAP Module 3. 
Editorial changes and minor 
corrections. 
Sponsor’s and Statistician’s 
review. 
Draft Version 
0.3 
20/04/2016 
Major revision of the entire document 
together with the preparation of table 
shells. 
Sponsor’s and Statistician’s 
review. 
Draft Version 
0.4 
09/06/2016 
Added new non-PD in Section 3. 
Added new age cutoff and 
clarification of baseline definition in 
Section 5.1. 
Added supportive analysis for primary 
endpoint in Section 5.2. 
Added definition and summary of 
adverse event associated with 
worsening of HF and BP decrease 
event in Section 5.3. 
Added plots for vital signs over time 
and changed categorical analyses for 
laboratory parameters in Section 5.3. 
Sponsor’s and Statistician’s 
review. 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 3 of 66 
 
Status and 
Version 
Release Date 
Change Description 
Reason/Comment 
Draft Version 
0.5 
17/06/2016 
Added comments from the Health 
Economics group in HRQoL sections. 
Further updates following statistical 
review of updated draft version 0.4: 
• 
Visit, baseline and post 
baseline definitions 
• 
Action taken “dose adjusted 
then permanently 
discontinued” for SBPDE 
Sponsor’s review 
Final Version 
1.0 
20/06/2016 
First final release 
Sponsor’s approval 
Draft Version 
1.1 
19/01/2017 
Added details to CBPDE analysis to 
reflect changes to Table Shells. 
Updated improvement in signs and 
symptoms of HF analysis. 
Updated re-hospitalization post 
discharge analysis. 
Updated sample size section to reflect 
changes in protocol amendment 4. 
Updated summaries for concomitant 
medications. 
Sponsor’s comments and 
protocol amendment 4 
Final Version 
2.0 
27/02/2017 
Second final release 
Sponsor’s approval 
 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 4 of 66 
 
 
Authorization 
 
The signatures on this page indicate review and approval of the Statistical Analysis Plan, version 
2.0, dated 27/02/2017. 
 
 
 
Name  
Function 
Signature 
Date 
 
Author 
 
 
 
 
 
 
 
Reviewer 
 
 
 
 
 
Novartis 
Approver 
 
 
 
 
 
Novartis 
Approver 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 5 of 66 
 
TABLE OF CONTENTS 
 
 
 
LIST OF ABBREVIATIONS ......................................................................................................................... 6 
1. 
STUDY OBJECTIVES ..................................................................................................................... 9 
1.1. PRIMARY OBJECTIVE ............................................................................................................................. 9 
1.2. SECONDARY OBJECTIVES ...................................................................................................................... 9 
 9 
2. 
BACKGROUND/INTRODUCTION ................................................................................................ 10 
2.1. STUDY DESIGN .................................................................................................................................... 10 
2.2. TREATMENT GROUPS AND RANDOMIZATION ................................................................................... 11 
2.3. STUDY POPULATION ........................................................................................................................... 12 
2.4. STUDY DRUG AND DOSING ................................................................................................................ 16 
2.5. SAMPLE SIZE ....................................................................................................................................... 17 
2.6. SCHEDULE OF TIME AND EVENTS ....................................................................................................... 18 
3. 
POPULATIONS OF ANALYSIS ..................................................................................................... 23 
4. 
VARIABLES ............................................................................................................................... 26 
4.1. EFFICACY PARAMETERS ...................................................................................................................... 26 
4.2. SAFETY PARAMETERS ......................................................................................................................... 29 
5. 
STATISTICAL METHODOLOGY ................................................................................................... 32 
5.1. GENERAL METHODOLOGY .................................................................................................................. 32 
5.2. EFFICACY DATA ................................................................................................................................... 41 
5.3. SAFETY DATA ...................................................................................................................................... 53 
5.4. INTERIM ANALYSIS.............................................................................................................................. 65 
6. 
APPENDIX ................................................................................................................................ 66 
 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 6 of 66 
 
LIST OF ABBREVIATIONS 
 
ACE 
 
 
Angiotensin-Converting Enzyme 
ACS 
 
 
Acute Coronary Syndrome 
AE 
 
 
Adverse Event 
AHF 
 
 
Acute Heart Failure 
ALP 
 
 
Alkaline Phosphatase 
ALT 
 
 
Alanine Aminotransferase 
AST 
 
 
Aspartate Aminotransferase 
ATC 
 
 
Anatomical Therapeutic Chemical 
BMI 
 
 
Body Mass Index 
BNP 
 
 
Brain Natriuretic Peptide 
BP 
 
 
Blood Pressure 
BSA 
 
 
Body Surface Area 
BUN 
 
 
Blood Urea Nitrogen 
CBPDE  
 
Confirmed Blood Pressure Decrease Event 
CCU 
 
 
Coronary Care Unit 
cGMP  
 
Current Good Manufacturing Practice 
CI 
 
 
Confidence Interval 
CMQ  
 
Customized MedDRA Query 
COPD  
 
Chronic Obstructive Pulmonary Disease 
CRS 
 
 
Case Retrieval Strategy 
CRT 
 
 
Cardiac Resynchronization Therapy 
CSR 
 
 
Clinical Study Report 
CTT 
 
 
Clinical Trial Team 
DBP 
 
 
Diastolic Blood Pressure 
DMC  
 
Data Monitoring Committee 
DS&E  
 
Novartis Drug Safety and Epidemiology Department 
ECG 
 
 
Electrocardiogram 
eCRF  
 
electronic Case Report Form 
ED 
 
 
Emergency Department 
eDISH  
 
evaluation of Drug-Induced Serious Hepatotoxicity 
EF 
 
 
Ejection Fraction 
e.g. 
 
 
Exempli Gratia 
eGFR  
 
Estimated Glomerular Filtration Rate 
EMS 
 
 
Emergency Medical Service(s) 
ER 
 
 
Emergency Room 
EU 
 
 
European Union 
FAS 
 
 
Full Analysis Set 
GI 
 
 
Gastrointestinal 
HBA1c  
 
Glycated hemoglobin 
HDL 
 
 
High Density Lipoprotein 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 7 of 66 
 
HF 
 
 
Heart Failure 
HLGT  
 
High Level Group Term 
HR 
 
 
Heart Rate 
HRQoL  
 
Health related Quality of Life 
IABP 
 
 
Intra-Aortic Balloon Pump 
ICD 
 
 
Implantable Cardioverter Defibrillator 
ICF 
 
 
Informed Consent Form 
ICU 
 
 
Intensive Care Unit 
i.e. 
 
 
Id Est 
Inc. 
 
 
Incorporation 
IRT 
 
 
Interactive Response Technology 
ITT 
 
 
Intent-To-Treat 
IUD 
 
 
Intrauterine Device 
IUS 
 
 
Intrauterine System 
IV 
 
 
Intra Venous 
JVP 
 
 
Jugular Venous Pulse 
LA 
 
 
Left Atrium 
LDL 
 
 
Low Density Lipoprotein 
LOS 
 
 
Length Of Stay 
LV 
 
 
Left Ventricular 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MI 
 
 
Myocardial Infarction 
NC 
 
 
North Carolina 
NMQ  
 
Novartis MedDRA Query 
NT-proBNP 
 
N-Terminal prohormone of Brain Natriuretic Peptide 
NYHA  
 
New York Heart Association 
PD 
 
 
Protocol Deviation 
PO 
 
 
Per Oral 
PP 
 
 
Per Protocol Set 
PR 
 
 
Pulse Rate 
PVD 
 
 
Patient Validation Document 
RAN 
 
 
Randomized Set 
RBC 
 
 
Red Blood Cell 
RU 
 
 
Resource Utilization 
SAE 
 
 
Serious Adverse Event 
SAF 
 
 
Safety Set 
SAP 
 
 
Statistical Analysis Plan 
SCR 
 
 
Screened Set 
SBP 
 
 
Systolic Blood Pressure 
SD 
 
 
Standard Deviation 
SGOT  
 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT  
 
Serum Glutamic Pyruvic Transaminase 
SMQ  
 
Standard MedDRA Query 


 
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sMDRD 
 
Simplified Modification of Diet in Renal Disease 
SOC 
 
 
Standard Of Care 
TBL 
 
 
Total Bilirubin 
TP 
 
 
Trial Programmer 
TS 
 
 
Trial Statistician 
ULN 
 
 
Upper Limit of Normal 
USA 
 
 
United States of America 
VAS 
 
 
Visual Analogue Scale 
WBC  
 
White Blood Cell 
WHF  
 
Worsening Heart Failure 
WHO  
 
World Health Organization 


 
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1. STUDY OBJECTIVES 
1.1. PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the effect of serelaxin as add-on therapy to 
standard of care (SOC) versus SOC alone in reducing in-hospital Worsening Heart Failure (WHF) 
requiring rescue therapy or all cause death, from randomization through Day 5. 
1.2. SECONDARY OBJECTIVES 
The secondary objectives of the study are the following: 
• To assess the effect of serelaxin as add-on therapy to SOC versus SOC alone in reducing 
in-hospital WHF requiring rescue therapy or all cause death or readmission for heart 
failure, from randomization through Day 14. 
• To assess the effect of serelaxin as add-on therapy to SOC versus SOC alone in reducing 
the number of patients with persistent symptoms or signs of Heart Failure (HF) / not 
showing an improvement versus baseline conditions from randomization through Day 5 
(persisting need of IV therapy for HF). 
• To evaluate the effect of serelaxin as add-on therapy to SOC versus SOC alone in 
reducing the rate of renal deterioration (defined as ≥ 0.3 mg/dL increase in serum 
creatinine), from randomization through Day 5. 
• To evaluate the effect of serelaxin as add-on therapy to SOC versus SOC alone in 
modifying the index length of stay (LOS) by location (e.g., ICU, CCU, cardiology 
department) in days and hours (ICU). 
• To evaluate the safety and tolerability of intravenous serelaxin in Acute Heart Failure 
(AHF) patients during a period of 30 days following exposure. 
• To collect data on health-related quality of life (HRQoL) and economic burden to 
provide a more comprehensive analysis of the burden of HF, beyond the clinical 
outcomes. 


 
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2. BACKGROUND/INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to detail the planned analyses for the 
clinical study report (CSR) for study CRLX030A3301. 
2.1. STUDY DESIGN 
This study is a prospective, multinational, multicenter, randomized, open label clinical trial to 
evaluate the efficacy, safety and tolerability of serelaxin as add-on therapy to SOC versus SOC 
alone in AHF subjects in the primary composite end-point of in-hospital WHF or all cause 
deaths through Day 5. The outcome defined as in-hospital WHF (with signs/symptoms of 
worsening conditions, requiring therapy intensification) is adjudicated by an Independent 
Board. 
After signing an Ethics Committee or Institutional Review Board approved Informed Consent 
Form, subjects are asked to undergo screening procedures for study eligibility. It is essential 
that the screening is completed in time to allow the randomization within 16 hours from 
presentation. Investigators are invited to initiate the serelaxin treatment as soon as possible 
after randomization. 
After assessing patient eligibility during the screening period, patients who meet the study 
inclusions and none of the exclusion criteria are randomized in a 2:1 ratio to receive 
intravenous infusion of either serelaxin for up to 48 hours in addition to SOC or SOC alone. 
Presentation starts as the earliest of (1) time of presentation at either the ER/ED, ICU/CCU or 
ward (excludes EMS or other pre-hospital care); or (2) time of first IV loop diuretic for 
treatment of the current AHF episode prior to arrival at the hospital (this includes outpatient 
clinic, ambulance, or hospital including emergency department). 
Serelaxin treatment will begin as soon as possible after randomization; it is administered via 
continuous intravenous (IV) infusion for 48 hours according to a weight-range adjusted dosing 
regimen at the nominal dose of 30 μg/kg/day. Due to the potential risk of hypotension, blood 
pressure is monitored regularly during the administration of study drug. 


 
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The study includes a short-term follow-up through Day 5, discharge and through Day 14, and 
an extension follow-up period up to Day 30, when all subjects receive a phone call to ascertain 
vital status and the need for repeated hospitalization. 
 
Figure 2.1-1: Study design 
 
In addition to the core study, the following sub-studies are planned: 
• 
 
• 
 
• 
 
The analyses of these sub-studies will be described in a separate SAP for each sub-study. 
2.2. TREATMENT GROUPS AND RANDOMIZATION 
Subjects are randomized in a 2:1 ratio to receive one of the following: 
• Serelaxin (30 μg/kg/day) as continuous 48-hour intravenous infusion plus standard of 
care. 
• Standard of care only. 
At baseline, all eligible patients who fulfill all inclusion/exclusion criteria are randomized via 
Interactive Response Technology (IRT) to one of the treatment arms. 


 
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The IRT assigns a randomization number to the patient, which links the patient to a treatment 
arm, and specifies a unique medication number (for patients randomized to serelaxin only) for 
the first package of investigational treatment to be dispensed to the patient. The 
randomization number is not communicated to the caller. 
The randomization numbers are generated using the following procedure to ensure an 
unbiased treatment assignment. A patient randomization list is produced by the 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, which in turn are linked to medication numbers (for serelaxin arm only). A separate 
medication list is produced by or under the responsibility of Novartis Drug Supply Management 
using a validated system that automates the random assignment of medication numbers to 
packs containing the investigational drug. 
Mis-randomized patients are those who have not been qualified for randomization, have been 
inadvertently randomized into the study and who did not take study drug. Mis-randomized 
patients are defined as cases where IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the patient’s final randomization eligibility and 
administration of serelaxin, when applicable, was not performed. These patients should have 
been considered screen failures as they did not meet eligibility criteria and should 
subsequently be discontinued from the study. Sites should notify IRT and contact their 
Novartis monitor as soon as possible if a patient is mis-randomized into the study. 
2.3. STUDY POPULATION 
Similarly to the RELAX-AHF study, subjects are selected among patients who have been 
admitted with AHF, who have normal to elevated blood pressure (SBP ≥ 125 mmHg at the start 
and at the end of the screening period) and have impaired renal function defined as an eGFR ≥ 
25 and ≤ 75 ml/min/1.73m2 at screening (calculated using the sMDRD equation). 
The study plans to randomize approximately 3,183 patients in approximately 450 study sites 
mainly in Europe. 
Inclusion criteria 
Subjects must fulfill all of the following criteria at screening to be eligible for the study. The 
screening period is defined as the interval that begins at the time the informed consent is 
signed and ends with the qualification of the subject for entry into the study (i.e., when subject 
has met all eligibility criteria): 
1. Able to provide written informed consent before any study-specific assessment is 
performed. The AHF diagnosis assessments performed as per current local 
institution/hospital standard practice or as part of routine clinical care can be used to 
support patient screening even if performed before obtaining informed consent. 
2. Male or female ≥ 18 years of age with body weight ≥ 40 Kg and ≤ 160 Kg. 


 
Statistical Analysis Plan 
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3. Systolic blood pressure ≥ 125 mmHg at the beginning of the screening period (after ICF 
signature) and at the end of the screening period (prior to randomization). 
4. Admitted/hospitalized for AHF. AHF is defined as including all of the following 
measured at any time between presentation and the end of screening: 
• Persistent dyspnea at rest or with minimal exertion, at screening and at the 
time of randomization, despite standard background therapy for acute 
decompensated heart failure including intravenous furosemide of at least 40 mg 
total (or equivalent) 
• Pulmonary congestion assessed through physical examination and chest X-Ray 
obtained during routine clinical practice at any time between presentation and 
the end of screening (prior to randomization) 
• N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥ 2,000 pg/mL or BNP ≥ 
500 pg/mL. For patients treated with valsartan/sacubitril (Entresto®), BNP is not 
suitable and only NT-pro-BNP should be assessed. 
5. Able to be randomized within 16 hours from presentation to the hospital [presentation 
starts as the earliest of (1) time of presentation at either the ER/ED, ICU/CCU or ward; 
or (2) time of first IV loop diuretic for treatment of the current AHF episode prior to 
arrival at the hospital] (this includes outpatient clinic, ambulance, or previous hospital 
including emergency department). 
6. Received intravenous furosemide of at least 40 mg (or equivalent) at any time between 
presentation and the start of screening for the study. 
7. Impaired renal function defined as an estimated glomerular filtration rate (eGFR), 
between presentation and randomization of ≥ 25 and ≤ 75 mL/min/1.73 m2, calculated 
using the simplified Modification of Diet in Renal Disease (sMDRD) equation (Levey AS 
et al., 2007; Myers GL et al., 2006). 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in 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: 
• Dyspnea primarily due to non-cardiac causes, such as acute or chronic respiratory 
disorders or infections (i.e., severe chronic obstructive pulmonary disease, bronchitis, 
pneumonia), or primary pulmonary hypertension sufficient to cause dyspnea at rest, 
which may interfere with the ability to interpret the primary cause of dyspnea. 
• Known history of respiratory disorders requiring the daily use of IV steroids (does not 
include inhaled or oral steroids) at least 2 months prior to randomization; need for 
intubation or the current use of IV steroids for COPD. 


 
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• Patients with blood pressure > 180 mmHg at the end of screening or persistent heart 
rate > 130 bpm. 
• Temperature > 38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-
microbial treatment. 
• Current (within 2 hours prior to randomization) or planned (through the completion of 
study drug infusion) treatment with any IV vasoactive therapies, including vasodilators 
(including nesiritide), positive inotropic agents and vasopressors, or mechanical support 
(intra-aortic balloon pump, endotracheal intubation, assisted (invasive or non-invasive) 
ventilation, or any ventricular assist device, or ultrafiltration, hemofiltration or dialysis), 
with the exception of IV furosemide (or equivalent diuretic) or IV nitrates at a dose of ≤ 
0.1 mg/kg/hour if the patient has a systolic BP > 150 mmHg at the start of the 
screening. 
• Significant left ventricular outflow obstruction, uncorrected, such as obstructive 
hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area < 1.0 cm2 
or mean gradient > 50 mmHg on prior or current echocardiogram), severe aortic 
regurgitation and severe mitral stenosis. 
• Clinical evidence of acute coronary syndrome currently or within 30 days prior to 
enrollment. (Note that the diagnosis of acute coronary syndrome is a clinical diagnosis 
and that the sole presence of elevated troponin concentrations is not sufficient for a 
diagnosis of acute coronary syndrome, given that troponin concentrations may be 
significantly increased in the setting of AHF). 
• AHF due to significant arrhythmias, which include any of the following: sustained 
ventricular tachycardia, bradycardia with sustained ventricular rate < 45 beats per 
minute or atrial fibrillation/flutter with sustained ventricular response of > 130 beats 
per minute. 
• Women of child bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of study treatment and for 5 days after cessation of study drug. Highly 
effective contraceptive methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment 


 
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• Male sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the sole partner for that 
subject 
• Combination of any two of the following (a+b, or a+c, or b+c): 
a) Use of oral, injected or implanted hormonal methods of contraception 
or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal 
hormone contraception 
b) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c) Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
• 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 
local laboratory test. 
• Acute 
myocarditis 
or 
hypertrophic 
obstructive, 
restrictive, 
or 
constrictive 
cardiomyopathy (does not include restrictive mitral filling patterns seen on Doppler 
echocardiographic assessments of diastolic function). 
• Major surgery, including implantable devices (e.g., ICD, CRT), or major neurologic event 
including cerebrovascular events, within 60 days prior to screening. 
• History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past year. 
• Hematocrit < 25% or a history of blood transfusion within the 14 days prior to screening 
or active, life-threatening GI bleeding. 
• Known hepatic impairment or AST / ALT > 3 ULN. 
• Known presence of active or recurrent bacterial, fungal or viral infection at the time of 
enrollment. 


 
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• Any organ transplant recipient, or patient currently listed for imminent transplant (i.e., 
do not exclude patients on an administrative transplant waiting list), or admitted for 
any transplantation. 
• Any other medical conditions that may put the patient at risk or influence study results 
in the investigator’s opinion, or that the investigator deems unsuitable for the study, 
including drug or alcohol abuse or psychiatric, behavioural or cognitive disorders, 
sufficient to interfere with the patient’s ability to comply with the protocol instructions 
or follow-up procedures. 
• Administration of any investigational drug or implantation of investigational device, or 
participation in another trial, within 30 days before screening or previous treatment 
with serelaxin. 
• Inability to follow instructions or comply with follow-up procedures. 
• Known hypersensitivity to serelaxin or similar substances or to any of the excipients. 
2.4. STUDY DRUG AND DOSING 
Serelaxin is administered according to a weight-range adjusted dosing regimen at a nominal 
dose of 30 μg/kg/day, as a continuous intravenous infusion for 48 hours. 
The study drug is provided as a 1 mg/mL solution in 6 mL vials (with 3.5 mL fill). For the 
randomized patients to receive the study drug infusion, it can be withdrawn from the vials 
contained in the kits, injected into a 250 mL intravenous bag of 5% dextrose solution and then 
infused through a dedicated IV line or port, using compatible tubing, infusion filters and IV 
bags according to instructions in the Pharmacy Manual. 
Each study site is supplied by Novartis with investigational treatment in kits containing 1 vial of 
serelaxin each, enough study drug for 24 hours of infusion (for all patients < 115 kg in body 
weight). At randomization time, the IRT specifies the first package of investigational treatment 
to be dispensed to the patient; to receive the study drug for the second 24 hours of infusion, 
the investigator’s staff contacts the IRT again and requests a second kit (for patients 
randomized to serelaxin only). In case the subject is ≥ 115 kg in body weight, two study drug 
kits are assigned via IRT for each 24 hour of infusion. 


 
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Table 2.4-1: Weight-range adjusted dosing regimen of serelaxin 
Body weight (kg) 
Serelaxin (mg) 
Volume of serelaxin to be added 
to 250 mL IV bag of sterile 5% 
dextrose for intravenous infusion 
over a period of 24 hours 
40-59 kg 
2.0 mg 
2.0 mL 
60-74 kg 
3.0 mg 
3.0 mL 
75-114 kg 
3.5 mg 
3.5 mL 
115-160 kg 
5.5 mg 
5.5 mL (2 vials needed) 
All kits of investigational treatment assigned by the IRT will be recorded in the IRT. 
 
Due to the potential risk of hypotension, blood pressure is monitored regularly during the 
administration of study drug. If at any time during dosing, the subject’s systolic blood pressure 
decreases by > 40 mm Hg from just before the study drug infusion but is ≥ 100 mmHg in 2 
consecutive measurements 15 minutes apart, serelaxin infusion rate is decreased by 50% for 
the remainder of the 48 hour study drug administration. Serelaxin administration is 
permanently discontinued at any time if in 2 consecutive measurements, 15 minutes apart, 
systolic blood pressure is reduced to < 100 mmHg. In addition, dosing may be discontinued at 
any time at the discretion of the investigator. Reasons the investigator may discontinue study 
drug administration include, but are not limited to, serious or intolerable adverse events (AEs) 
suspected to be related to study drug. If dosing is discontinued for hypotension or any safety 
reasons, re-administration of study drug is not allowed. For non-safety reasons (problems with 
the infusion line, etc.), dosing may be interrupted once for each patient for up to 1 hour. Time 
from initiation of study drug infusion to completion must not exceed 48 hours (i.e., if the 
infusion is interrupted or delayed, it must be terminated after 48h from the start, regardless of 
the actual infusion time). In the event that study drug administration is discontinued for any 
reason, the patient will continue to be followed at all study visits defined in the protocol. 
No additional treatment beyond investigational treatment is requested for this trial. All 
patients are required to receive standard of care background HF management during the 
study, according to local guidelines/international standards. This treatment can include but is 
not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) 
inhibitors/angiotensin receptor antagonists, β blockers and aldosterone receptor antagonists, 
etc. 
2.5. SAMPLE SIZE 
The primary end point of the study is the time to in-hospital adjudicated outcome Worsening 
of Heart Failure (WHF) requiring intensification of therapy, or all cause death through Day 5 
post randomization. 
 
 


 
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2.6. SCHEDULE OF TIME AND EVENTS 
Each patient is uniquely identified by a Subject Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
patient, the Subject Number will not be reused. Upon signing the informed consent form, the 
patient is assigned the next sequential number by the investigator. 
The patient is followed up to Day 30 and relevant information is entered into the eCRF. 
Table 2.6-1 lists all of the assessments and indicates with an ‘‘x’’ when the visits are to be 
performed. 
Patients shall be seen daily through index hospitalization until Day 5, until discharge 
(whichever occurs first), and then at Day 14. If for any good reason, the assessments at Day 5 
cannot be done on the designated day, a window of + 1 day is allowed. A “visit window” of +/- 
2 days is allowed for Day 14 and for phone contact on Day 30. 
Patients should be seen for all visits on the designated day or timepoint, or as close to it as 
possible. Patients are expected to return to the clinic for all scheduled study visits. Patients 
unable or unwilling to return to the hospital/clinic for scheduled visits will be contacted by 
telephone as close as possible to the expected visit to obtain information about survival status. 


 
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Patients who prematurely discontinue the investigational treatment will remain in the study 
and shall undergo all the assessments illustrated in Table 2.6-1. If a patient withdraws from 
participation in the study, or refuses to return for study assessments, or is unable to do so, 
every effort shall be made to contact them or a knowledgeable informant by telephone and/or 
other measures to determine the patient’s survival status during the follow-up period. 


 
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Table 2.6-1: Assessment schedule 
 
Visit number 
0 
0-1 
1-1 
1-2 
1-3 
1-4 
1-5 
1-6 
2 
 
3 
4 
Time of Visit 
Screening 
End of 
Screening/
Baseline 
6h 
12h 
24h 
48h 
D3 
D4 
D512 
Discharge13 
D14 
(± 2)  
D30 
(± 2) 
Phase 
 
 
Drug Infusion0 
Post-treatment daily 
assessment 
Follow-
up 
Obtain Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history, 
including diagnostic of 
AHF, Alcohol, drug 
abuse, education 
level, living 
arrangement and 
smoking histories 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
with vital signs1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
measurement1 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Physician 
assessment of signs 
and symptoms of HF1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Worsening Heart 
Failure (WHF)2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Chest X-Ray3 
X 
 
 
 
 
 
 
 
 
 
 
 
BP and HR 
measurements4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NT-pro-BNP or BNP 
for study entry5 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum cTnT or cTnI6 
for study entry 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test6 
X 
 
 
 
 
 
 
 
 
 
 
 
eGFR (MDRD)6 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
Laboratory tests 
(Local Laboratory)6,7 
X 
 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 


 
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X 
 
 
 
X 
 
 
X 
 
 
 
HRQoL questionnaire 
(EQ-5D-5L) 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Healthcare Resource 
Utilisation9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact IRT10 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Administer study 
medication 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-serious Adverse 
Events11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serious Adverse 
Event11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Status 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
0 Study drug will be administered as an IV infusion for 48 hours. If at any time during dosing, the subject’s systolic blood 
pressure is decreased by > 40 mm Hg from baseline but is ≥ 100 mm Hg in 2 consecutive measurements 15 minutes apart, the 
study drug treatment infusion rate will be decreased by 50% for the remainder of the study drug administration. If at any time 
during dosing, the subject’s systolic blood pressure is < 100 mm Hg in 2 consecutive measurements 15 minutes apart, the 
study drug infusion will be terminated. 
1 Physical examination includes assessment of vital signs. Following randomization, all physical examinations should be 
performed daily at approximately the same time of day. Daily vital signs may be measured and recorded by trained study 
personnel as well as trained healthcare personnel as part of their routine clinical duties. For details of assessment see Section 
6.5.1, Section 6.5.2 of the Study Protocol. 
2 WHF is defined as worsening signs and/or symptoms of heart failure that require an intensification of intravenous therapy for 
heart failure or mechanical ventilation or circulatory support. Such treatment can include the institution or up-titration of IV 
furosemide, IV nitrates or any other IV medication for heart failure or institution of mechanical support such as assisted 
(invasive/non-invasive) ventilation, IABP, etc. 
3Chest X-Ray is not considered a study-related procedure. It should be done according to local diagnostic practice. Patients 
may only enter the trial with pulmonary congestion on a chest X-Ray obtained during routine clinical practice at any time 
between presentation and the end of screening (prior to randomization). If the chest X-Ray from routine clinical assessments is 
not available, the patient may not enter the trial. 
4 BP and HR measurements should be performed for all patients at the beginning of the screening period (after ICF signature) 
and at the end of the screening period (prior to randomization). For serelaxin patients, frequent BP and HR measurements 
should be performed between randomization and immediate start of study drug administration, 30 and 60 minutes after start of 
study drug administration, then every hour for the first 6 hours and then every 3 hours during study drug infusion, including night 
time hours. Post-infusion, BP and HR should be measured every 3 hours until 12 hours following end of infusion, then every 6 
hours for 48 hours and then every 24 through the index hospitalization, at discharge, at Day 5 and then at Day 14.For patients 
randomized to the SOC group, BP and HR measurements should be performed at 6, 12, 24, 48 hours post-randomization, daily 
through the index hospitalization, at discharge, at Day 5 and then at Day 14. All measurements should be performed as close 
as possible to specified time points. BP and HR should be measured with the patient in the same position and with the same 
equipment using the same arm. These measurements may be made and recorded by trained study personnel, as well as 
trained healthcare personnel as part of their routine clinical duties, 
5 Measured through a point of care device provided by Sponsor required only if the site is not able to obtain local lab test results 
within the 16-hour timeframe or if local lab does not offer it at all. 
6 Measured at local laboratory. Following randomization, local laboratory collections can be adjusted to conform to the hospital’s 
routine laboratory collection schedule and can be collected at any time of the day. 
7 Clinical laboratory tests include hematology and chemistry and will be performed locally. Urinalysis will be conducted at 
baseline, 24 and 48 hours only to rule out any conditions that might be requiring further diagnostic evaluation or treatment. See 
Section 6.5.4 for details of the Study Protocol. 
 
 
9 Throughout the index hospitalization, the level of healthcare resource utilization shall be assessed by the overall length of stay, 
length of time in specific inpatient care units and procedures rendered during hospital stay. There may be circumstances when 
the collection of the data after completion of the study may be warranted. 
10 Investigational treatment kits containing 1 vial of serelaxin each is enough for 24 hours of study infusion. To receive the 
second 24 hours of study drug, the investigator’s staff will contact the IRT again and request a second kit. For SOC patients, 
the contact with IRT at Visit 1-3 is not necessary. 
11 Non-serious Adverse Events will be collected through Day 5 and all Serious Adverse Events will be collected through Day 14, 


 
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regardless of suspected causality. After Day 14, only suspected Serious Adverse Events will be collected and databased. 
12 If for any good reason, the assessments at Day 5 cannot be done in the designated day, a window of + 1 day is allowed. 
13 If discharge assessments coincide with a scheduled visit, only the assessments of the scheduled visit will have to be 
performed. If discharge occurs at any time after Day 5, all discharge assessments have to be performed. 
 
 
 
 


 
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3. POPULATIONS OF ANALYSIS 
Analysis population 
Patients without a valid or adequately obtained Informed Consent Form (ICF) will be excluded 
from any analysis population. 
The following analysis populations are defined: 
• Screened set (SCR): all patients who signed the informed consent. 
• Randomized set (RAN): all patients who received a randomization number, regardless 
of receiving trial medication and including mis-randomized patients. 
• Full analysis set (FAS): all randomized patients who were not mis-randomized. 
Following the intent-to-treat (ITT) principle, patients will be analyzed according to the 
treatment they have been assigned to at randomization. Mis-randomized patients are 
those who have not qualified for randomization, have been inadvertently randomized 
into the study but who did not enter the treatment phase and who did not receive 
serelaxin. Mis-randomized patients are defined as cases where randomizations were 
made by the site either prematurely or inappropriately prior to confirmation of the 
patient’s final randomization eligibility. These patients should subsequently be 
discontinued from the study. 
• Per Protocol set (PP): all patients in the FAS without major protocol deviations, as 
defined in the Patient Validation Document (PVD). 
• Safety set (SAF): all patients who received any amount of study treatment or standard 
of care treatment and who have at least one post-baseline safety assessment. Of note, 
the statement that a patient had no adverse events also constitutes a safety 
assessment. Patients will be analyzed according to treatment received. 
Protocol deviation 
The protocol deviation concerning the mis-randomization will be detected during the course of 
the study and reported by means of the specific tool developed on eCRF. 
All cases of prospectively defined protocol deviations (PD) will be identified prior to clinical 
database lock/unblinding and entered into a dedicated data panel as part of the locked 
database. Certain deviations may stipulate that data collected from the subjects will be 
excluded from analysis population(s). All exceptional cases, problems and the final decisions on 
the allocation of subjects to populations will be fully defined, documented and approved by 
the Novartis study team before data base lock (in particular before breaking the blind where 
applicable) and will be fully identified and summarized in the Patient Validation Document.  
The major protocol deviations resulting in exclusion of subjects from an analysis population are 
outlined in the table below: 
Table 3-1: Deviations resulting in exclusion of subjects from analysis populations 


 
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Deviation 
Exclusion from analysis set 
Category 
Description 
Code(s) * 
SCR RAN FAS PP SAF 
Selection 
criteria not 
met 
Lack of written informed consent (Inclusion criteria 
#1) 
IC001 
IC001_A1 
X 
X 
X 
X 
X 
Systolic blood pressure <125 mmHg at the 
beginning and at the end of the screening period 
(Inclusion criteria #3) 
IC003 
IC003_M1 
 
 
 
X 
 
Patient hospitalized for reasons of non-AHF event 
(Inclusion criteria #4) 
IC004 
IC004_M1 
IC004_A1 
 
 
 
X 
 
Lack of randomization within 16 hours from 
presentation to the hospital (Inclusion criteria #5) 
IC005 
IC005_M1 
 
 
 
X 
 
Lack of intravenous furosemide of at least 40 mg 
(or equivalent) at any time between presentation 
and the start of screening for the study (Inclusion 
criteria #6) 
IC006 
IC006_M1 
 
 
 
X 
 
Lack of impaired renal function defined as eGFR 
between presentation and randomization of  ≥ 25 
and ≤ 75 mL/min/1.73 m2 (Inclusion criteria #7) 
IC007 
IC007_M1 
 
 
 
X 
 
Persistent dyspnea at rest or with minimal exertion, 
at screening and at the time of randomization, 
despite standard background therapy for acute 
decompensated heart failure including intravenous 
furosemide of at least 40 mg total (or equivalent) 
(Exclusion criteria #1) 
EC001 
EC001_M1 
 
 
 
X 
 
Known significant pulmonary disease (obsolete 
exclusion criteria of original protocol) 
EC005 
EC006 
 
 
 
X 
 
Patients with systolic blood pressure >180 mmHg 
at the end of screening or persistent heart rate 
>130 bpm (Exclusion criteria #3) 
EC034 
 
 
 
X 
 
Sepsis or active infection requiring IV anti-microbial 
treatment (Exclusion criteria #4) 
EC003 
 
 
 
X 
 
Current or planned treatment with any IV 
vasoactive therapies or mechanical support, with 
the exception of IV furosemide (or equivalent 
diuretic) or IV nitrates at a dose of ≤0.1 mg/kg/hour 
if the patient has a SBP >150 mmHg at the start of 
the screening (Exclusion criteria #5) 
EC004 
EC004_M1 
EC004_A1 
EC004_M2 
 
 
 
X 
 
Significant left ventricular outflow obstruction, 
uncorrected, such as obstructive hypertrophic 
cardiomyopathy or severe aortic stenosis  severe 
aortic regurgitation and severe mitral stenosis 
(Exclusion criteria #6) 
EC007 
EC008_M1 
EC009_M1 
EC010_M1 
 
 
 
X 
 
Clinical evidence of acute coronary syndrome 
currently or within 30 days prior to enrollment. 
(Exclusion criteria #7) 
EC011 
 
 
 
X 
 
AHF due to significant arrhythmias, which include 
any of the following: sustained ventricular 
tachycardia, bradycardia with sustained ventricular 
rate <45 beats per minute or atrial fibrillation/flutter 
with sustained ventricular response of >130 beats 
per minute (Exclusion criteria #8) 
EC012 
EC013 
EC014 
 
 
 
X 
 


 
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Deviation 
Exclusion from analysis set 
Category 
Description 
Code(s) * 
SCR RAN FAS PP SAF 
Treatment 
deviation 
Drug infusion not administered according to a 
weight-range adjusted dosing regimen at the 
nominal dose of 30 μg/kg/day. 
DRUG02 
DRUG02_A3 
DRUG03 
 
 
 
X 
 
Study drug not injected into a 250 mL intravenous 
bag of 5% dextrose solution or not infused through 
a dedicated IV line or port, using compatible tubing, 
infusion filters and IV bags or not following 
instructions in the Pharmacy Manual. 
DRUG05 
 
 
 
X 
 
Investigational treatment not handled and stored 
properly (including temperature control). 
DRUG06 
 
 
 
X 
 
Expired investigational treatment 
DRUG07 
 
 
 
X 
 
Serelaxin infusion began later than 4 hours after 
start of study drug preparation. 
DRUG011 
 
 
 
X 
 
Serelaxin administered despite patient randomized 
in SOC arm 
DRUG12 
 
 
 
X 
 
Serelaxin administered despite patient not 
randomized with IRT 
DRUG13 
 
X 
X 
X 
 
Serelaxin not administered despite patient 
randomized in Serelaxin arm and SBP pre-infusion 
≥ 100 mmHg. 
DRUG14 
 
 
 
X 
X 
Other 
Subject does not undergo any clinical evaluations 
of AHF signs/symptom and subject does not report 
any information about the need for further IV or oral 
HF treatment and about the occurrence of 
worsening HF events through Day 5 
PROC03 
 
 
 
X 
 
Subject does not perform the scheduled visit at Day 
5 
PROC03_A1 
 
 
 
X 
 
Subject not randomized but entered the treatment 
phase 
PROC06 
 
X 
X 
X 
 
Subject mis-randomized (i.e. subject who has not 
been qualified for randomization, has been 
inadvertently randomized into the study, who did 
not enter the treatment phase and who did not 
undergo Serelaxin administration) 
PROC07 
 
 
X 
X 
X 
* Deviations codes as defined in the Protocol Deviation Handling Document (blind & unblind). Codes could possibly change 
before database lock. 
 
In addition, deviations not defined in the protocol resulting in exclusion of subjects from an 
analysis population are outlined in the table below. 
Table 3-2: Non-protocol deviations resulting in exclusion of subjects from analysis 
populations 
Non-Protocol Deviation 
Exclusion from analysis set 
Category 
Description 
SCR RAN FAS PP SAF 
Non-protocol 
deviation 
Subject has no post-baseline safety assessment. 
 
 
 
 
X 


 
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Non-Protocol Deviation 
Exclusion from analysis set 
Category 
Description 
SCR RAN FAS PP SAF 
Non-protocol 
deviation 
Subject randomized to Serelaxin group but not receiving any dose 
of study medication 
 
 
 
X 
X 
 
4. VARIABLES 
4.1. EFFICACY PARAMETERS 
Primary efficacy parameter 
Worsening of Heart Failure/all cause death through Day 5 
The primary efficacy variable of the study is the time to in-hospital Worsening of Heart Failure 
(WHF) requiring rescue therapy or all cause death through Day 5 post randomization. 
In-hospital WHF through Day 5 post randomization includes worsening signs and/or symptoms 
of heart failure that require an intensification of intravenous therapy for heart failure or 
mechanical ventilation, renal or circulatory support. Such treatment can include the institution 
or uptitration of IV furosemide, IV nitrates or any other IV medication for heart failure, or 
institution of mechanical support such as assisted (invasive or non-invasive) ventilation, 
ultrafiltration, haemodialysis, intra-aortic balloon pump or ventricular assist device, etc. This 
endpoint also includes patients who die in this 5-day period of any cause before experiencing 
episode(s) of WHF. 
A central event adjudication committee is appointed to oversee the WHF primary endpoint 
adjudication. 
Relevant evaluations to detect in-hospital WHF are performed in the serelaxin arm at 6, 12, 24 
and 48 hours from start of study drug infusion, daily through index hospitalization, at Day 5 
and discharge, and then at Day 14. For patients in the SOC arm, relevant evaluations are 
performed at 6, 12, 24 and 48 hours from randomization, daily through index hospitalization, 
at Day 5 and discharge, and then at Day 14. 
Death information is collected in a dedicated eCRF section. 
 
Secondary efficacy parameters 
In-hospital Worsening of Heart Failure/all cause death/hospital readmission for HF through 
Day 14 
The secondary efficacy endpoint is time to worsening HF requiring rescue therapy as defined 
above, or all cause death, or hospital readmission for heart failure through Day 14 post 
randomization. 


 
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Relevant evaluations to detect in-hospital WHF are performed in the serelaxin arm at 6, 12, 24 
and 48 hours from start of study drug infusion, daily through index hospitalization, at Day 5 
and discharge, and then at Day 14. For patients in the SOC arm, relevant evaluations are 
performed at 6, 12, 24 and 48 hours from randomization, daily through index hospitalization, 
at Day 5 and discharge, and then at Day 14. 
Death and re-hospitalization information are collected in dedicated eCRF sections. 
Persistent signs and symptoms of HF/non-improvement 
The number of patients with persistent symptoms or signs of HF / not showing an 
improvement versus baseline conditions through Day 5 (persisting need of IV therapy for HF) 
will be evaluated. 
Patients with persistent symptoms or signs of HF / not showing an improvement versus 
baseline conditions through Day 5 are those patients who take any IV therapy for HF at each 
assessment time point as reported in the eCRF sections “IV Loop Diuretic Medication for Heart 
Failure” and “IV Medications Other than Loop Diuretics”. 
Moreover, the investigator or appropriate qualified designee evaluates the symptoms and 
signs of heart failure, including dyspnea on exertion or at rest, orthopnea, rales, jugular venous 
pulse (JVP) and peripheral edema. These evaluations are performed at baseline, 6, 12, 24 and 
48 hours from start of study drug infusion, daily through index hospitalization, at Day 5, at 
discharge and then at Day 14 for the serelaxin arm. For patients in the SOC arm, relevant 
evaluations are performed at baseline, at 6, 12, 24 and 48 hours from randomization, daily 
through index hospitalization, at Day 5, at discharge, and then at Day 14. 
These evaluations should be done at approximately the same time of the day, each day, in the 
same position and hospital/clinic setting, preferably by the same assessor. 
Renal deterioration 
Renal deterioration is defined as an increase of ≥ 0.3 mg/dL from screening in serum creatinine 
levels. Rate of renal deterioration at 24 hours, at 48 hours, at Day 5, at discharge, and at Day 
14 post randomization will be evaluated. 
Serum creatinine evaluations are performed locally at screening, at 24 and 48 hours, at Day 5, 
at discharge, and then at Day 14 post randomization. 
Index length of hospital stay 
Index length of hospital stay (in hours) is defined as the index hospitalization discharge date 
and time minus the index hospitalization admission date and time + 1 minute. 
Index length of hospital stay, from admission to discharge, will be evaluated by location 
(emergency ward, emergency care unit, etc.). 
Index hospitalization details are collected in eCRF at Screening, Day 5, discharge visit, Day 14 
and Day 30 post randomization. 


 
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Death through Day 30 
All deaths (adjudicated or not) occurring from randomization through Day 30 will be used in 
the analysis. 
Re-hospitalization post-discharge 
The number of re-hospitalizations per patient post-discharge will be described. 
The time to first re-hospitalization (in days) will be defined as the first re-hospitalization 
admission date minus the randomization date + 1 day. 
Health-related Quality of Life 
The EQ-5D-5L is a widely used, self-administered questionnaire designed to assess health 
status in adults. The measure is divided into two distinct sections. The first section includes 
one item addressing each of five dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression). The second section of the questionnaire measures 
self-rated (global) health status utilizing a vertically oriented visual analogue scale where 100 
represents the “best possible health state” and 0 represents the “worst possible health state”. 
In this study, the first administration of the EQ-5D-5L questionnaire occurs at baseline visit. If, 
for whatever reason, the patient is not able to fill in the questionnaire at baseline, it is possible 
to collect retrospectively these data on Day 2. If this is the case, on Day 2, two questionnaires 
need to be filled in at this visit: the first one asking the patient to retrospectively describe how 
he/she felt on the day of admission, and the second one asking the patient to describe how 
he/she feels today. A special permission was provided by EuroQoL for the use with 2-day recall 
of the questionnaire. 
The EQ-5D-5L quality of life assessment is completed by all study patients (both serelaxin and 
SOC groups) at baseline (i.e., randomization), at Day 2, at Day 5, at discharge, and at Day 14 
post randomization. 
Resource utilization 
Analyses will be undertaken, as appropriate, to assess the effects of treatments on healthcare 
resource utilization (RU) parameters. 
Throughout the index hospitalization, the level of healthcare resource utilization shall be 
assessed by the overall length of stay, length of time in specific inpatient care units and 
procedures rendered during hospital stay. In addition, number of re-hospitalizations (events), 
number of patients with 1, 2, 3 re-hospitalization(s) and time to first (and recurrent) re-
hospitalization(s) (in days) will be evaluated. 
Moreover, the details about emergency/urgent care >24 hours not resulting in admission, 
including tests performed, will be provided. 
Data for a health economic analysis are collected from eCRFs, most notably Hospital Discharge, 
Re-hospitalization and Death. Data on emergency/urgent care >24 hours not resulting in 
admission are collected in dedicated eCRF sections. Data on medical resource use are collected 


 
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for all enrolled patients from the index hospitalization at Day 5, at discharge, and then at Day 
14, and through phone contact at Day 30 post randomization. 
 
 
 
 
 
 
 
 
 
 
4.2. SAFETY PARAMETERS 
Adverse Events (AEs) / Serious Adverse events (SAEs) 
All adverse events are collected through Day 5, and all serious adverse events are collected 
through Day 14, regardless of suspected causality. After Day 14, only suspected related serious 
adverse events are collected and entered in the eCRF. 
Adverse events are recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: the severity grade 
(mild/moderate/severe); its relationship to the study treatment (no; yes; yes, investigational 
treatment; 
yes, 
other 
study 
treatment 
(not 
investigational); 
yes, 
both 
and/or 
indistinguishable); its duration (start and end dates and times); whether it constitutes a serious 
adverse event (SAE); action taken regarding investigational treatment; whether other 
medication or therapies have been taken (concomitant medication or non-drug therapy); its 
outcome 
(not 
recovered/not 
resolved; 
recovered/resolved; 
recovering/resolving, 
recovered/resolved with sequelae; fatal; unknown). 
Each pregnancy occurring to a subject involved in the trial is reported as an Adverse Event on 
the eCRF. 
Vital signs 
Height in centimeters (cm) or inches (inch) is measured at screening only. 
Body weight (to the nearest 0.1 kilogram [kg] or 0.1 pound [lb] in indoor clothing, but without 
shoes) is measured at Screening and at 24 and 48 hours after study drug infusion in the 


 
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serelaxin arm / at 24 and 48 hours after randomization in SOC arm, and daily through index 
hospitalization, at Day 5, at discharge, and then at Day 14. These measurements during 
hospitalization can be performed at any time of the day. 
If patient’s body height/weight cannot be measured at screening because of the patient’s 
physical condition, verbal height/weight is acceptable. Height/weight measurements shall be 
obtained as soon as the patient is physically able. 
Body temperature and respiratory rate are measured at Screening, at 6, 12, 24 and 48 hours 
after the start of study drug infusion in the serelaxin arm, and daily through index 
hospitalization, at Day 5, at discharge, and then at Day 14. For the SOC patients, body 
temperature and respiratory rate are measured at Screening, at 6, 12, 24 and 48 hours after 
randomization, and daily through index hospitalization, at Day 5, at discharge, and then at Day 
14, according to the scheduled visits. Patients discharged prior to Day 5 will be required to 
return to the hospital/clinic for Day 5 procedures. 
Daily measurements may be made and recorded by trained study personnel as well as trained 
healthcare personnel as part of their routine clinical duties. 
BP and pulse measurements are performed for all patients at the beginning of the screening 
period (after ICF signature) and at the end of the screening period (prior to randomization). 
For serelaxin patients, BP and heart rate (HR) measurements are also performed before the 
immediate start of study drug administration (0 hours pre infusion start), throughout study 
drug infusion at 30 and 60 minutes, then every hour for the first 6 hours, and then every 3 
hours, including night time hours. Post-infusion, BP and HR are to be measured every 3 hours 
until 12 hours following end of infusion, then every 6 hours for 48 hours and then every 24 
hours through index hospitalization, at Day 5, at discharge, and then at Day 14. For patients 
randomized to the SOC group, BP and HR measurements should also be performed at 6, 12, 
24, 48 hours post randomization, including night time hours, daily through index 
hospitalization, at Day 5, at discharge, and then at Day 14. 
All measurements should be performed as close as possible to specified time point. 
BP and HR are to be measured with the patient in the same position and with the same 
equipment using the same arm throughout study drug infusion. These measurements may be 
made and recorded by trained healthcare personnel as part of their routine clinical duties, as 
well as trained study personnel. 
If at any time during dosing, the subject’s systolic blood pressure decreases by > 40 mmHg 
from just before the study drug infusion baseline but is ≥ 100 mmHg in 2 consecutive 
measurements 15 minutes apart, serelaxin infusion rate should be decreased by 50% for the 
remainder of the 48 hour study drug administration. Serelaxin administration should be 
permanently discontinued at any time if in 2 consecutive measurements 15 minutes apart, 
systolic blood pressure reduces to < 100 mmHg. 
Should the study drug dose be decreased or the study drug be discontinued prematurely due 
to blood pressure decrease, measurements should be taken every half hour through 2 hours 


 
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following the blood pressure decrease event, and then hourly through 5 hours after event 
onset. Upon completion of the 5 hour post event onset time point, heart rate and blood 
pressure measurements should be resumed as outlined above. 
Physical examination findings 
An overall physical examination is performed by the investigational staff at screening and 
includes the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and vascular and 
neurological examinations. An abbreviated physical examination is performed at 6, 12, 24 and 
48 hours after start of study drug infusion in the serelaxin arm (from randomization for 
patients in the SOC arm), and daily through index hospitalization, at Day 5, at discharge, and 
then at Day 14, and includes the examination of general appearance and vital signs (SBP/DBP 
and pulse). 
Following randomization, all physical examination should be performed at approximately the 
same time of day. Information for all physical examinations must be included in the source 
documentation at the study site. Significant findings that are present prior to signing informed 
consent must be included in the Medical History part of the eCRF. Significant findings after 
signing the informed consent, up to and including Day 5, which meet the definition of an AE 
must be recorded on the Adverse Event section of the eCRF. Significant findings after signing 
the informed consent, up to and including Day 14, which meet the definition of an SAE must be 
recorded on the Serious Adverse Event section of the eCRF (Section 7.2 of the study protocol), 
and a completed signed Serious Adverse Event form must be faxed to the local Novartis Drug 
Safety and Epidemiology Department (DS&E) within 24 hours after awareness of the SAE. 
Subjects discharged after 48 hours from the start of drug infusion for serelaxin arm/from 
randomization for SOC arm, but prior to Day 5, will be required to return for a physical 
examination as an outpatient at Days 5 and 14. 
Clinical laboratory test results 
All screening, baseline and post-baseline specimens
 
 collected are analyzed by the local 
laboratory. 
Clinical laboratory tests including hematology and chemistry are performed locally at 
screening, at 24 and 48 hours, at Day 5, at discharge, and then at Day 14 (in both arms). 
Urinalysis is conducted at baseline, 24 and 48 hours only and analyzed locally. 
Clinical hematology evaluations include measurement of hemoglobin, hematocrit, white blood 
cell count, red blood cell count, differential cell count (monocytes, neutrophils, eosinophils, 
lymphocytes, basophils), and platelet count. 
Serum chemistry evaluations include measurement of blood urea nitrogen (BUN) or urea, 
serum creatinine, total bilirubin, phosphate, ALT, AST, alkaline phosphatase, sodium, 
potassium, calcium, total cholesterol, triglycerides, LDL, HDL, glucose, uric acid, albumin, total 


 
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protein and eGFR. In addition, glycated hemoglobin (HBA1c) is measured at screening only, 
and eGFR is measured at screening, at 48 hours, at Day 5, and at discharge. 
Urinalysis includes measurement of glucose, ketones, pH, protein and specific gravity. 
Electrocardiogram (ECG) 
12-Lead ECG evaluation is performed and interpreted locally at screening, at Day 5, and at 
discharge. ECGs must be recorded after 10 minutes rest in the supine position to ensure a 
stable baseline. 
Echocardiography 
Echocardiography evaluation is not a mandatory requirement of the protocol; in case the 
evaluation is performed and the values obtained are available in the source documents, they 
need to be entered into eCRF. Most recent data up to the last 12 months can be entered. 
Liver event 
Details of liver events are collected throughout the study in dedicated eCRF sections, collecting 
an overview of the liver event and also medical history possibly contributing to liver 
dysfunction, history of alcohol use, history of drug abuse, imaging examination, pathology 
results, 
autoimmune 
details, 
viral 
serology, 
liver 
function 
test 
and 
acetaminophen/paracetamol administration. 
Causes that lead to a re-hospitalization or emergency/urgent care >24 hours not resulting in 
admission 
In case reason for re-hospitalization or emergency/urgent care >24 hours not resulting in 
admission is HF, renal impairment, cardiac (chest pain, ACS, MI), other cardiac, vascular, or 
non-cardiovascular, further details are collected in dedicated eCRF sections. 
Survival and Death information 
Details of vital status and death are collected throughout the study in the dedicated eCRF 
sections. 
5. STATISTICAL METHODOLOGY 
5.1. GENERAL METHODOLOGY 
Data will be analysed according to the data analysis Section 9 of the study protocol. 
All statistical tables, listings, figures and analyses will be produced using SAS® release 9.4 (64-
bit) or later (SAS Institute Inc., Cary NC, USA). 
The data from all countries and all sites will be pooled and summarized. Continuous data will 
be summarized by the mean, standard deviation (SD), median, first and third quartiles, 


 
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minimum and maximum. Categorical data will be presented by absolute and relative 
frequencies (n and %) or contingency tables. 
All nominal time points will be used for analysis; actual assessment times will not be used to 
reclassify the time point at which a measure was taken. Time-to-event analyses will be based 
on actual dates (times) reported. 
Subjects will be included in each efficacy analysis based on available assessments, after the 
data handling conventions have been applied. The prevalence approach (i.e., no imputation of 
missing data), if not differently indicated, will be applied. 
Unless stated otherwise, two-sided p-values < 0.05 will be considered statistically significant. 
No formal interim efficacy analysis will be performed and therefore no statistical adjustment of 
alpha level will be required. 
Visit, baseline and post baseline definitions 
Screening phase: The screening phase is defined as the period prior to randomization. After 
obtaining written informed consent, the subject will be evaluated for eligibility to participate in 
the study. 
Baseline definition for efficacy and safety measurements: Baseline date and time is defined as 
the date and time of initiation of study drug for the serelaxin group, or date and time of 
randomization for the SOC group. Of note, the randomization date and time will be used as the 
reference date and time for all time to event analysis. 
Post-baseline phase for efficacy and safety measurements: The post-baseline phase begins at 
the date and time of initiation of study drug administration for the serelaxin group, or the date 
and time of randomization for the SOC group, and ends with the last study assessment/last 
follow-up or the death of subject. For subjects who did not receive study drug, the phase 
begins at the time of randomization. 
Patient disposition and analysis population 
A summary of participating countries and sites will be presented for the Screened Set, showing 
the total number of screened and randomized subjects. Sites which do not enrol any subject 
will be presented as well. The number of patients by region, country and treatment group will 
be presented for the FAS. 
A complete description of patient disposition will be provided for SCR and FAS, overall and by 
treatment group, specifying the number of randomized patients, number of patients at each 
time point based on their latest available data, completed and discontinued patients at each 
study phase (screening, randomized treatment period, follow-up period), and the reason for 
the discontinuation. Relative frequencies will be also reported. 
The number of patients in each of the analysis populations will be summarized and the reasons 
for excluding a patient from any particular population will be provided with the number of 
protocol deviations per each criterion. The number of mis-randomized patients will be 
provided as well. Percentages will be computed using the number of patients in the 


 
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randomized set as denominators. Moreover, any non randomized patient included in the 
Safety set will be reported. 
The difference between treatment groups with respect to protocol deviations and reasons for 
drop-out will be examined. Descriptive statistics will be presented by treatment group for the 
length of follow-up (days), computed as the difference from the randomization date to the end 
of study date + 1 day (i.e., the last known vital status date, even through phone contact). 
Categorical summaries will also be presented for the number and percentage of subjects 
within predefined follow-up intervals as: >0-5 days; 6-14 days; 15-30 days; >30 days. 
Patient demographics and other baseline characteristics 
Demographic and baseline characteristics of patients, including derived variables, will be 
summarized in the FAS and Safety set, overall and by treatment group, with summary 
descriptive statistics. Continuous data will be summarized by means of standard summary 
statistics (i.e., number of observations, mean, standard deviation, median, first and third 
quartiles, minimum and maximum). Categorical data will be presented by absolute and relative 
frequencies (n and %); percentages will be computed considering non-missing information, if 
not differently specified. 
Demographic and baseline characteristics will include sex, age (years), age category (<65 years, 
≥65 years; <75 years, ≥75 years; 18-<65 years, ≥65-<85 years, ≥85 years), race, ethnicity, height 
(Centimeter), body weight (continuous and < 115 kg, ≥ 115 kg) at screening, body mass index 
(kg/m2) at screening, body temperature (Celsius) at screening, respiratory rate (Breath/min) at 
screening, pulse (Beats/min) at start and end of screening and systolic and diastolic blood 
pressure (mmHg) at start and end of screening. 
The above mentioned demographic and baseline characteristics will also be described by 
region (Western EU: Austria-Belgium-Denmark-Finland-France-Germany-Greece-Iceland-Italy-
Portugal-Principality of Monaco-Spain-Switzerland-United Kingdom / Eastern EU: Bulgaria-
Croatia-Czech 
Republic-Estonia-Hungary-Latvia-Lithuania-Poland-Romania-Russia-Serbia-
Slovakia-Slovenia). If applicable, further possible country subgroups may be defined. 
Patients’ age will be computed in years elapsed from birth to the date of the informed consent 
signature. For patients with only year of birth reported (i.e., German sites), age entered by the 
investigator will be used without any computation. 
Patients’ height will be presented in centimetres; estimated and measured assessments will be 
analysed together. 
Patients’ body weight will be presented in kilograms; estimated and measured assessments 
will be analysed together. 
Patients’ body temperature will be presented in degrees Celsius. 
Body mass index will be calculated as body weight (in kg) divided by the square of height (in 
m). 
Background information will be summarized in the FAS and will include the following variables: 


 
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• Subject lifestyle history: highest level of education, subject’s living arrangements and 
home health care arrangements. 
• Prior history of heart failure (yes, no). Time from HF diagnosis to informed consent. It 
will be calculated in months elapsed between diagnosis date and informed consent 
date.  
• Disease NYHA (New York Heart Association) class at approximately 1 month prior to 
admission for index heart failure event (class I - class IV). 
• Primary heart failure etiology (ischemic, non-ischemic and details if non-ischemic). 
Percentages will be computed using the number of patients with a prior heart failure 
event as a denominator. 
• Prior hospitalization due to heart failure (yes/no) and number of prior hospitalization 
due to heart failure in the last 12 months (0, 1, 2, 3, >3 and continuous). Moreover, the 
variable “Prior hospitalization due to heart failure in the last 12 months” will be derived 
as follows: “No” if there is no hospitalization in the past, or there is a hospitalization 
but the number of heart failure hospitalizations in the last 12 months is 0; “Yes” if the 
number of heart failure hospitalizations in the last 12 months is greater than 0. 
• Ejection fraction (EF, %). Summary statistics will be presented for % values. Moreover, 
absolute and relative percentages of patients with EF levels <40% and ≥40%, and <50% 
and ≥50% will be presented. Methods used to determine EF levels will also be 
summarized. 
• Presence of subject on heart transplant list (yes/no). 
• Prior history of diabetes mellitus (yes/no, and if yes with details for control). Details of 
control will be presented with percentages computed using the number of patients 
with a prior history of diabetes mellitus as denominators. 
• The medical history of protocol solicited events with “Occurrence” equal to “Yes” will 
be considered and will be presented by the code list reported in the eCRF. The 
description will be provided by status (ongoing or not), disease classification or severity 
as applicable. Percentages will be computed using the total number of patients in the 
analysis population as denominators. 
• Alcohol history (amount of alcohol consumed in drinks per day). 
• Drug abuse history (patient’s usage status). 
• Smoking history (patient’s usage status). 


 
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• Medical history data not recorded as protocol solicited events or HF will be coded using 
the latest version of MedDRA, and will be presented by System Organ Class and 
Preferred Term, showing absolute and relative frequencies of patients having 
experienced each pathology. Description will be provided by status (ongoing or not). 
Percentages will be computed using the total number of patients in the analysis 
population as denominators. 
• Summary statistics for eGFR at screening will be provided. Moreover, absolute and 
relative percentages of patients with eGFR levels, <25, ≥25 and <30, ≥30 and <60, ≥60 
and <75, and ≥75 mL/min/1.73m2 will be presented. 
• Summary statistics for BNP, NT proBNP, serum cTnI and serum cTnT at screening will be 
provided. In addition to the conventional statistics, geometric mean and 95% CI will be 
reported. 
• Summary statistics for clinical hematology, serum chemistry evaluations at screening 
and urinalysis evaluation at baseline will be provided. 
• 12-lead ECGs overall interpretation at screening will be described (Normal/Clinically 
Insignificant Abnormality/Clinically Significant Abnormality). Moreover, heart rate 
(beats/min), mean PR duration (msec), mean QT duration (msec), corrected QT 
Fridericia interval and mean QRS duration (msec) will be described by means of 
standard summary statistics. 
• Chest X-Ray at screening: procedure performed (yes/no) and overall interpretation will 
be summarized. Chest X-Ray is not considered as study related procedures and is 
performed according to local diagnostic practice. 
• Echocardiography at screening: procedure performed (yes/no) and in which period, 
overall interpretation and LV Ejection Fraction (%). Echocardiography is not considered 
as study related procedures and is performed according to local diagnostic practice. 
• EQ-5D-5L Health Questionnaire at baseline: summary statistics for each dimension 
score, including the subject overall self-rated health status measure (EQ VAS value), 
and index score, will be provided; further details are reported in section “5.2 Efficacy 
data”. 
• Physician assessment of signs and symptoms of HF at baseline: absolute and relative 
frequencies of subjects reporting each sign/symptom will be provided. 
 
In order to account for adequate interpretation of results, the homogeneity of patients’ 
distribution between treatment groups will be tested on demographic and anamnestic 
variables: gender, age, race, prior history of heart failure, NYHA disease classification, atrial 


 
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fibrillation in medical history (“Occurrence” is marked “Yes” on the “Medical History – Protocol 
Solicited Events” eCRF page), and atrial fibrillation at baseline (“Ongoing” is marked “Yes”). P-
values will have a descriptive meaning and any warnings of heterogeneity will be evaluated 
considering the clinical relevance of the involved variables. The p-values will not be considered 
to define any formal basis for determining factors to be included in statistical models. If an 
imbalance of treatment groups with respect to some variables does occur, supplemental 
analyses with addition of these variables in model may be performed to assess the potential 
impact on efficacy as appropriate. 
For continuous variables, homogeneity of data will be tested by means of t-test. 
For categorical variables, Chi-square test will be used. Fisher’s exact test will be used in cases 
where cell frequencies are less than 5. 
Investigational treatment 
Study treatment administration will be summarized for the FAS and the Safety set, for patients 
in the serelaxin arm only. Continuous variables (e.g., dose prescribed in mg, total volume 
administered in mL, rate of infusion in mL/hr, and duration of infusion in hours/days) will be 
summarized with standard summary statistics. Categorical variables (e.g., reason for dose 
change) will be summarized with the number and percentage of patients. Percentages will be 
computed using the number of patients with non-missing information as denominators, unless 
otherwise specified. 
The analysis of study treatment will be performed for the FAS and Safety set, and will include 
the following variables: 
• Time from presentation to randomization (hours) for both treatment groups. The date 
of presentation at screening is obtained from the “Index heart failure hospitalization” 
eCRF page. Time will be presented as elapsed hours and minutes and will be derived as 
difference + 1 minute. Analysis will be presented also by setting of presentation 
(Outpatient clinic or office/ Ambulance or Emergency Medical Service/ Emergency 
Department/ Intensive Care Unit/ Coronary or Cardiac Care Unit/ Cardiology ward/ 
General ward/ Other). 
• Time from first IV loop diuretic administered for the treatment of the Index Heart 
Failure event to randomization (hours) for both treatment groups. The first IV loop 
diuretic administered for index heart failure is obtained from the start date and time 
of the IV loop diuretic recorded at screening on the “Index heart failure 
hospitalization” eCRF page. Time will be presented as elapsed hours and minutes and 
will be derived as difference + 1 minute. 
• Study treatment administered (yes/no) for the serelaxin arm only: variable “Any 
dosage to report?” in the eCRF page “Dosage administration record” and reason why 
study treatment was not administered: variable “Subject Status” in the eCRF page 
“Treatment Completion” for patients with no dosage reported. 


 
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• Time from presentation to study treatment administration for patients with at least 
one reported dosage (hours) in the serelaxin arm only. Date of presentation recorded 
is the earliest of (1) time of presentation either at the ER, ICU/CCU or ward (excludes 
EMS or other pre-hospital care); or (2) time of first IV loop diuretic prior to arrival at 
the hospital (this includes in the clinic, ambulance, or any other setting) for the 
treatment of the current acute heart failure episode. The date of presentation at 
screening is obtained from the “Index heart failure hospitalization” eCRF page. The 
date of study treatment administration for patients with at least one reported dosage 
is obtained from the start date and time of study treatment with a non-missing 
prescribed dose recorded on the “Dosage administration record” eCRF page. Time will 
be presented as elapsed hours and minutes and will be derived as difference + 1 
minute. Analysis will be presented also by setting of presentation (Outpatient clinic or 
office/ Ambulance or Emergency Medical Service/ Emergency Department/ Intensive 
Care Unit/ Coronary or Cardiac Care Unit/ Cardiology ward/ General ward/ Other). 
• Time from randomization to study treatment administration (hours) for patients in the 
serelaxin arm only. The date of study treatment administration is obtained from the 
start date and time of study treatment with a non-missing prescribed dose recorded 
on the “Dosage administration record” eCRF page. Time will be presented as elapsed 
hours and minutes and will be derived as difference + 1 minute.  
• Total volume of study treatment administered (mL) for patients in the serelaxin arm 
only is estimated from the duration of infusion in hours and the corresponding rate of 
infusion in mL/hr. It will be computed as the sum of the reported total volumes of 
study treatment throughout the study. 
• Duration of study treatment administration (hours) for patients in the serelaxin arm 
only. It will be presented as elapsed hours and minutes +1 minute from the start to the 
end of infusion; any temporary treatment interruptions will not be detracted. Number 
of days study treatment infused: the following discrete categories will be computed 
and described, <1 day (i.e., <1440 minutes), between 1 and 2 days (i.e., >=1440 and 
<=2880 minutes) and >2 days (i.e., >2880 minutes). The continuous variable duration 
of study treatment infusion in days and in hours will be summarized as well. 
• Any dose reduction (yes/no) and reason for dose reduction for patients in the serelaxin 
arm only. A dose reduction is defined as a rate of infusion lower than the rate of 
infusion reported in the previous infusion record. Reason for dose reduction will be 
summarized and percentages will be computed on total number of dose reduction. 
Number and percentages of patients who reported any dose reduction by reason for 
dose reduction will be provided. 
• Number of patients for whom study medication dose was discontinued prematurely, 
and the reason for discontinuation for patients in the serelaxin arm only. Patients who 


 
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discontinued prematurely the study drug are defined as patients with at least one dose 
infusion and “Subject Status” on the eCRF page “Treatment Completion” different 
from ‘Completed’. The “Subject Status” will be summarized as well. 
• A listing of patients with actual treatment received different from randomized 
treatment will be provided for the Safety set only for both arms. 
 
Logistic regression models will be fitted considering demographics and anamnestic factors in 
order to identify main predictors for study drug discontinuation. Odds ratio and 95% 
confidence intervals will be provided. 
Univariate regression models will be fitted considering as factors the following variables: age, 
gender, BMI at screening. Moreover, a multivariate regression model will be fitted considering 
all the factors above mentioned and selected with a stepwise method. 
Patients who discontinued prematurely the study drug are defined as subjects with at least 
one dose infusion recorded on the “Dosage administration record” eCRF page and “Subject 
Status” on the eCRF page “Treatment Completion” different from ‘Completed’. 
Concomitant treatments 
Concomitant medications are collected in dedicated eCRF sections at screening, baseline, 24h, 
48h, Day 3, Day 4, Day 5, Day 14, Day 30 and discharge visit; in general, medications taken 
within the screening period are collected at Screening; medications taken since the initial 
presentation of the Index Heart Failure event are reported at baseline; medications taken 
within the 24 hours preceding the visit are entered in eCRF at each post baseline assessment. 
Concomitant medications usage will be described by treatment group according to the 
following details. Medications will be coded using the WHO NOVDD_14_3 dictionary and 
subsequent versions. As a patient may have taken more than one medication, the total 
number of medications could be greater than the total number of patients. Continuous 
variables will be summarized with standard summary statistics, categorical variables with the 
number and percentage of patients. Percentages will be computed using patients included in 
the analysis population as denominators. 
All medications reported in the eCRF pages corresponding to the day of discharge will be 
considered as administered during the index hospitalization. 
Concomitant treatment administration details will be summarized by treatment group for the 
FAS and the Safety set. 
The analysis will include the following variables: 
• Any IV nitrates at the time of randomization (yes/no). A complete description will be 
provided also by medication, with number and percentage of patients taking at least 
one dose of medication (obtained from start date and time and non-missing dose 
recorded at screening on the “Index heart failure hospitalization” eCRF page). 


 
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• Any IV loop diuretic medication taken since the initial presentation of heart failure 
(recorded as “Any medication to report?” in the “IV loop diuretic medication for heart 
failure” dedicated eCRF page from baseline visit) (yes/no). A complete description will 
be provided also by Preferred Term for other medication names not listed in the eCRF, 
with number and percentage of patients taking at least one dose of medication. 
Moreover, the total dose of IV loop diuretic administered during the index 
hospitalization (at most for 5 days of hospitalization) will be described. Doses will be 
converted to Furosemide equivalents for the analysis (Furosemide 40 mg is equivalent 
to Torasemide/Torsemide 20 mg, or Bumetanide 2 mg, or Etacrynic acid/Ethacrynic 
acid 50 mg, see Table 5.1-2 below for the conversion factors). The total dose of IV loop 
diuretic administered during the index hospitalization will be compared between 
treatment groups using a t-test. For subjects who die before Day 5, the minimum of 2 
times of the last recorded dose and 160 mg will be assumed for every day from the 
date of death up to and including Day 5. Data will be presented overall and by day from 
randomization. Data after the index hospitalization will be presented separately. 
Table 5.1-2: Conversion factor for diuretic medications 
Original Unit 
Preferred Unit 
Multiplication Factor 
Furosemide (mg) 
Furosemide (mg) 
1 
Torasemide (mg) 
Furosemide (mg) 
2 
Bumetanide (mg) 
Furosemide (mg) 
20 
Etacrynic acid (mg) Furosemide (mg) 
0.8 
• Any oral (PO) loop diuretic medication taken since the initial presentation (recorded 
with “PO loop diuretics” ticked on the “Other non-IV medications” dedicated eCRF page 
from baseline visit) (yes/no). A complete description will be provided also by preferred 
term for the other name of medication, with number and percentage of patients taking 
at least one dose of medication. Moreover, the total dose of oral loop diuretic 
administered during the index hospitalization (at most for 5 days of hospitalization) will 
be described. Doses will be converted to Furosemide equivalents for the analysis (see 
Table 5.1-2). The total dose of PO loop diuretic administered during the index 
hospitalization will be compared between treatment groups using a t-test. For subjects 
who die before Day 5, the minimum of 2 times of the last recorded dose and 160 mg 
will be assumed for every day from the date of death up to and including Day 5. Data 
will be presented overall and by day from randomization. Data after the index 
hospitalization will be presented separately. 
• All non-IV medications taken since the initial presentation (recorded on the “Other 
non-IV medications” dedicated eCRF page from baseline visit), excluding Per Oral (PO) 
loop diuretics, will be summarized by medication classification and name of 
medication, presenting number and percentage of patients taking at least one dose of 
medication. Data will be presented overall during index hospitalization and by day from 
randomization. Data after the index hospitalization will be presented separately. 


 
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• All IV medications other than loop diuretics taken since the initial presentation 
(recorded in the dedicated eCRF page from baseline visit) and by day from 
randomization will be summarized by medication classification and name of 
medication, presenting number and percentage of patients taking at least one dose of 
medication. Data will be presented overall during index hospitalization. Data after the 
index hospitalization will be presented separately. 
• All other non-IV prior medication taken 30 days before screening (recorded in the 
“Other non-IV prior medication” dedicated eCRF page at screening visit) will be 
summarized by name of medication, presenting number and percentage of patients 
taking at least one dose of medication. 
• All procedures/tests/treatments performed overall during the index hospitalization 
(recorded in the “Index heart failure hospitalization – procedures/tests/treatments 
performed” dedicated eCRF page from Day 5) will be summarized presenting the 
number and percentage of patients reporting the procedure, test or treatment. 
Tabulation will follow the code list reported in the eCRF. 
5.2. EFFICACY DATA 
The primary analysis and the analyses of all secondary and exploratory efficacy variables will 
be based on the FAS. In addition to the primary analysis, the primary efficacy variable will also 
be analysed using the same primary analysis model on the PP set as supportive information. 
Primary efficacy parameter 
Worsening Heart Failure/all cause death through Day 5 
The primary efficacy variable of the study is the time to in-hospital Worsening of Heart Failure 
(WHF) requiring rescue therapy or all cause death through Day 5 post randomization. 
In-hospital worsening of heart failure (WHF) through Day 5 post randomization includes 
worsening signs and/or symptoms of heart failure that require an intensification of 
intravenous therapy for heart failure or mechanical ventilation, renal or circulatory support. 
Such treatment can include the institution or up-titration of IV furosemide, IV nitrates or any 
other IV medication for heart failure, or institution of mechanical support such as assisted 
(invasive or non-invasive) ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or 
ventricular assist device, etc. This endpoint also includes patients who die in this 5-day period 
of any cause before experiencing episode(s) of WHF. 
Time to in-hospital WHF/all cause death through Day 5 post randomization will be analysed 
using survival analysis. 
The time to in-hospital WHF/all cause death will be computed as the number of hours from 
randomization to the earlier of the onset of in-hospital WHF or death plus 1 minute. The onset 
of in-hospital worsening heart failure through Day 5 will be the start date/time of event 


 
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reported at the first assessment point at which the investigator reported worsening heart 
failure; if death occurred, date and time are reported in the dedicated eCRF section. Subjects 
without an event will be censored at the earlier of the last post-baseline assessment date or 
120 hours after randomization. Subjects without any information after baseline (i.e., 
randomization) will be considered censored at 1 minute. 
In case of missing time of in-hospital WHF or death then 00:00 will be imputed. 
Only adjudicated endpoints will be counted in the primary analysis. The “adjudicated 
endpoint” refers to an endpoint and date of the endpoint that has been confirmed by an 
independent adjudication committee who has no access to the treatment code. According to 
the information from the endpoint adjudication committee, the following rules will be applied 
to determine if an event reported in eCRF should be considered valid for the analysis or not: 
Table 5.2-1: Rule for inclusion of events into the analysis 
 
Included in the analysis 
WHF/death reported in the dedicated page of the eCRF and  
confirmed by adjudication committee 
YES 
WHF/death reported in the dedicated page of the eCRF and NOT 
confirmed by adjudication committee 
NO 
If more than one in-hospital WHF occurred, the first one will be used as the event. Censoring 
and time will be defined according to the following rule: 
Table 5.2-2: Censoring and time rules 
 
Status 
Time 
At least one in hospital WHF and/or death occurred and: 
 
 
 
Difference between date and time of first occurrence of WHF/death 
and date and time of randomization +1 minute >120 hours 
Censored 120h 
 
Difference between date and time of first occurrence of WHF/death 
and date and time of randomization +1 minute ≤120 hours 
Event 
Calculated 
difference 
No in hospital WHF and death occurred and: 
 
 
 
Difference between date and time of last assessment* and date and 
time of randomization +1 minute >120 hours 
Censored 120h 
 
Difference between date and time of last assessment* and date and 
time of randomization +1 minute ≤120 hours 
Censored Calculated 
difference 
 
 
 
* Last assessment is the date and time of last available post-baseline 
physician assessment of in-hospital WHF 
 
 
In case a patient is lost to follow-up, events occurring prior to the time of lost to follow-up will 
be counted. If no event occurred, then the patient will be censored at the time of last post-
baseline in-hospital WHF assessment available. 
The primary statistical hypothesis is: 


 
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H0: λ2/λ1 ≥ 1, i.e., the rate of primary event of in-hospital WHF or all cause death is greater or 
equal in the serelaxin group relative to the standard of care group versus the one-sided 
alternative HA: λ2/λ1 < 1, i.e., the rate of in-hospital WHF or all cause death is smaller in the 
serelaxin group relative to the standard of care group, where λ1 and λ2 are the hazard rates for 
in-hospital WHF or all cause death in the standard of care group and serelaxin group, 
respectively. The ratio λ2/λ1 is the hazard ratio of serelaxin to standard of care. 
The hypothesis will be tested based on the FAS with a Gehan’s generalized Wilcoxon test at a 
significance level of 0.025 (one-sided). 
The Kaplan-Meier estimates of the survival functions for each treatment group will be plotted 
and Kaplan-Meier estimates for selected time points with 95% confidence intervals will be 
tabulated.   
The hazard ratio (relative risk) and its associated two-sided 95% confidence interval will be 
estimated based on a Cox proportional hazards model with treatment assignment as a factor. 
 
 
 
 
In addition, a description of all in-hospital WHF that occurred through Day 5 will be provided: 
absolute frequencies and proportions of patients with in-hospital WHF at each assessment 
time point will be presented overall and by concomitant medication (IV therapy with 
vasoactives, IV therapy with loop diuretics, oral therapy with loop diuretics, IV therapy with 
inotropes vasoactives) given (new, restarted or increased dose of medication), and/or by the 
need of mechanical/surgical intervention (yes/no) for the in-hospital WHF. 
In addition to the primary analysis, the primary efficacy variable will also be analysed using the 
same primary analysis model on the PP set as supportive information. 
Subgroup (age [65 and 75 cut off], gender, race [Caucasian and other race], region [Western 
Europe and Eastern Europe], ejection fractions [40% and 50% cut off], prior history of HF [naïve 
vs. prior history of HF]) analyses will be performed for the primary endpoint. 
A Cox proportional hazards model will be fitted considering treatment as a factor and 
covariates the above mentioned subgroup variables. The hazard ratio (relative risk) and its 
associated two-sided 95% confidence interval will be estimated for treatment and 
factors/covariates. 
An additional supportive analysis of the primary efficacy variable will be performed using all 
WHF/all cause deaths through Day 5 post randomisation as reported by the investigators, 
regardless of confirmation from the endpoint adjudication committee. 
The time to WHF/all cause deaths through Day 5 post randomisation will be as described for 
the primary analysis. 


 
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The Kaplan-Meier estimates of the survival functions for each treatment group will be plotted. 
Kaplan-Meier estimates at selected time points and their 95% confidence intervals will be 
provided. 
 
 
 
 
Handling of missing values/censoring/discontinuations 
In the analysis of time to in-hospital WHF/all-cause death through Day 5, patients without any 
event will be censored at the earlier of the last post-baseline physician assessment of in-
hospital WHF or 120 hours post randomization. 
Subjects without any information after baseline (i.e., randomization) will be considered 
censored at 1 minute. 
In case of missing time of in-hospital WHF or death then 00:00 will be imputed. 
Secondary efficacy parameters 
The additional efficacy endpoints will be analysed in the FAS. Standard descriptive statistics will 
be presented for each treatment group at each time point that the endpoint was measured. 
Two-sided p-values <0.05 will be considered statistically significant; no adjustment for multiple 
comparisons will be adopted. 
Time to in-hospital WHF/All cause death/readmission for heart failure through Day 14 post 
randomization 
Time to in-hospital WHF/all cause death/readmission for heart failure through Day 14 post 
randomization will be analyzed using survival analysis. 
The time to in-hospital WHF/all cause death/readmission will be computed as the number of 
hours from randomization to the earlier of the onset of in-hospital WHF or death or 
readmission for heart failure plus 1 minute. The onset of in-hospital WHF through Day 14 will 
be the start date/time of event reported at the first assessment point at which the investigator 
reported worsening heart failure (either during the initial hospitalization or re-hospitalization 
for heart failure); if death occurred, date and time are reported in the dedicated eCRF section 
“Death – (Endpoint to be adjudicated)”; the date and time of admission of first re-
hospitalization with Primary reason for Hospitalization equal to “Heart Failure” will be 
considered as the readmission moment (as reported in the dedicated eCRF section 
“Rehospitalization Information (Endpoint not to be adjudicated)”. Subjects without an event 
will be censored at the earlier of the last post-baseline assessment or 336 hours after 
randomization. Subjects without any information after baseline (i.e., randomization) will be 
considered censored at 1 minute. 


 
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In case of missing time of in-hospital WHF or death or rehospitalisation for heart failure then 
00:00 will be imputed. 
According to the information from the endpoint adjudication committee, the following rules 
will be applied to determine if an endpoint reported in eCRF should be considered valid for the 
analysis or not: 
Table 5.2-3: Rule for inclusion of events into the analysis 
 
Included in the analysis 
WHF/death occurred within Day 5, reported in the dedicated 
page of the eCRF and confirmed by adjudication committee 
YES 
WHF/death occurred within Day 5, reported in the dedicated 
page of the eCRF and NOT confirmed by adjudication 
committee 
NO 
WHF/death occurred after Day 5 through Day 14 and 
reported in the dedicated page of the eCRF 
YES 
Readmission for heart failure reported in the dedicated page 
of the eCRF 
YES 
 
Censoring and time will be defined according to the following rule: 
Table 5.2-4: Censoring and time rules 
 
Status 
Time 
At least one in hospital WHF/death/readmission for HF occurred and: 
 
 
 
Difference between date and time of first occurrence of 
WHF/death/readmission for HF and date and time of randomization +1 
minute >336 hours 
Censored 336h 
 
Difference between date and time of first occurrence of 
WHF/death/readmission for HF and date and time of randomization +1 
minute ≤336 hours 
Event 
Calculated 
difference 
No in hospital WHF/death/readmission for HF occurred and: 
 
 
 
Difference between date and time of last assessment* and date and 
time of randomization +1 minute >336 hours 
Censored 336h 
 
Difference between date and time of last assessment* and date and 
time of randomization +1 minute ≤336 hours 
Censored Calculated 
difference 
 
 
 
* Last assessment is the date and time of last available post-baseline 
physician assessment of in-hospital WHF 
 
 
 
In case a patient is lost to follow-up, only the data until the last post-baseline in-hospital WHF 
assessment available will be considered in the analysis. 
Treatment groups will be compared with a Gehan’s generalized Wilcoxon test. The Kaplan-
Meier estimates of the survival functions for each treatment group will be plotted. The Kaplan-


 
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Meier estimates of the cumulative event rate will also be presented in tables by treatment 
group for each day and also by time interval (>0-5 days, >5-14 days). 
Absolute frequencies and proportions of patients with event (as defined in the time to event 
analysis), overall (in-hospital WHF/all cause death/readmission) and by type of event (in-
hospital WHF; all cause death; readmission), through Day 14 in each treatment group will also 
be provided (percentages based on population of analysis). 
In addition, a description of all in-hospital WHF that occurred through Day 14 will be provided: 
absolute frequencies and proportions of patients with in-hospital WHF at each assessment 
time point will be presented overall and by the concomitant medication given (new, restarted 
or increased dose of medication), and/or by the need of mechanical/surgical intervention 
(yes/no) for the in-hospital WHF. 
A summary of number and percentage of patients with or without WHF events through Day 5 
(recorded on “Clinical worsening of heart failure” eCRF page for adjudicated events), and from 
Day 6 through Day 14 (recorded on “Heart failure details” eCRF page for events not to be 
adjudicated), will be provided by treatment. 
Persistent signs or symptoms of HF/ non-improvement 
Absolute frequencies and proportions of patients with persistent symptoms or signs of HF / 
not showing an improvement at any visit vs. baseline (persisting need of IV therapy for HF) in 
each treatment group will be provided, and also at each assessment time point (24 hours, 48 
hours, Day 3, Day 4) through Day 5 and at discharge, together with standard errors, asymptotic 
(Wald) and exact (Clopper-Pearson) confidence limits. The rates in the two groups will be 
compared by means of Chi square test at each time point. In case of cell frequencies less than 
5, Fisher’s Exact test will be used. 
Patients with persistent symptoms or signs of HF / not showing an improvement versus 
baseline conditions at each assessment time point are those patients who take any IV therapy 
for HF at the assessment time point as reported in the eCRF sections “IV Loop Diuretic 
Medication for Heart Failure” and “IV Medications Other than Loop Diuretics”. 
Improvement in signs or symptoms of HF 
A time-to-event analysis through Day 14 will be performed. Hazard ratios of being a responder 
for each of the signs and symptoms variables (response is defined as ≥1 point improvement 
from baseline) will be estimated using a Cox regression model with treatment as a factor. 
Treatment groups will be compared with a Gehan’s generalized Wilcoxon test. The Kaplan-
Meier estimates of the cumulative event rate will also be presented by treatment group. 
One or more point improvement will be defined as a reduction from baseline of at least one 
point in the specific sign/symptom according to the score defined in the table below. 


 
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Table 5.2-5: Scores for the definition of improvement 
 
Categorical 
value 
Numerical 
value 
Dyspnea on exertion 
None 
0 
Mild 
1 
Moderate 
2 
Severe (including dyspnea at rest) 3 
Orthopnea 
None 
0 
1 pillow (10cm) 
1 
2 pillows (20cm) 
2 
>30 degrees 
3 
Edema 
0 
0 
1+ 
1 
2+ 
2 
3+ 
3 
Rales 
No rales 
0 
Rales <1/3 
1 
Rales 1/3-2/3 
2 
Rales >2/3 
3 
Jugular venous pulse (JVP) 
<6cm 
0 
6-10cm 
1 
>10cm 
2 
Body weight increase 
No 
0 
Yes 
1 
The scores will be presented as both categorical and continuous (i.e., numerical values in Table 
5.2-5) statistics. Change from baseline will be computed as the baseline value subtracted from 
the post baseline values. Cross tabulation of categorical values at baseline and at each 
assessment time point will be presented by treatment group. 
Each sign or symptom of HF, collected in “Physician Assessment of Signs and Symptoms of 
Heart Failure” eCRF page, will be analysed separately. The event is defined as ≥1 point 
improvement from baseline. The time to being a responder will be computed as the number of 
hours from randomization to the date and time of the first assessment at which a ≥1 point 
improvement from baseline is detected plus 1 minute. Subjects without an event will be 
censored at the earlier of the last post-baseline assessment of signs and symptoms of HF or 
336 hours (i.e., 14 days) after randomization. Subjects without any information after baseline 
(i.e., randomization) will be considered censored at 1 minute. In case of missing time of 
assessment of signs and symptoms of heart failure then 00:00 will be imputed. The analysis 
will be performed excluding subjects with the following signs and symptoms at baseline: 
‘None’ for Dyspnea on exertion and Orthopnea; ‘0’ for Edema; ‘No rales’ for Rales; ‘<6 cm’ or 
‘Not evaluable’ for Jugular venous pulse, ‘No’ for Body weight increase. 
Table 5.2-6: Censoring and time rules 


 
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Status 
Time 
At least one (≥1) point improvement occurred and: 
 
 
 
Difference between date and time of first occurrence improvement 
(i.e., date and time of physician assessment where improvement was 
assessed) and date and time of randomization +1 minute >336 hours 
Censored 336h 
 
Difference between date and time of first occurrence improvement 
(i.e., date and time of physician assessment where improvement was 
assessed) and date and time of randomization +1 minute ≤336 hours 
Event 
Calculated 
difference 
No improvement occurred and 
 
 
 
Difference between date and time of last available physician 
assessment and date and time of randomization +1 minute >336 hours 
Censored 336h 
 
Difference between date and time of last available physician 
assessment and date and time of randomization +1 minute ≤336 hours 
Censored Calculated 
difference 
Moreover, summary statistics for data about physician assessment of signs and symptoms of 
HF will be provided at each assessment time point by treatment group. Absolute and relative 
frequencies of patients reporting each sign/symptom will be provided. Percentages will be 
computed considering patients with non-missing information at each assessment time point 
and by each type of sign and symptom. 
Renal deterioration 
Renal deterioration will be assessed as the proportion of patients with an increase of ≥0.3 
mg/dL from screening in serum creatinine levels. Absolute frequencies and proportions of 
patients with renal deterioration at each assessment time point in each treatment group will 
be provided, together with standard errors, asymptotic (Wald) and exact (Clopper-Pearson) 
confidence limits. Rate of renal deterioration in the two groups will be compared by means of 
Chi square test at each assessment time point. In case of cell frequencies less than 5, Fisher’s 
Exact test will be used. 
Index length of hospital stay 
Index length of hospital stay (in hours) will be defined as the index hospitalization discharge 
date and time (obtained from the “Index hospitalization summary” eCRF page) minus the index 
hospitalization admission date and time plus 1 minute (obtained from the “hospitalization” 
eCRF page); it will be presented as elapsed hours. 
Subjects still in the hospital at Day 30 will be censored at Day 30. Subjects who die during the 
initial hospitalization will be assigned the maximum length of stay (including those censored at 
Day 30) plus 24 hours. 
Treatment groups will be compared using a Wilcoxon rank-sum test. Descriptive statistics by 
treatment group will be presented. Analysis will be done overall and by location for patients 
presented to Outpatient clinic or office / Ambulance or Emergency Medical Service / 
Emergency Department / Intensive Care Unit / Coronary or Cardiac Care Unit / Cardiology 
Ward / General Ward / Other, as recorded on the “Index heart failure hospitalization” eCRF 
page. 


 
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Estimated duration (days) of stay in acute care unit (Coronary or cardiac critical care unit / 
General intensive care unit / Step down unit or telemetry unit / Cardiology department or 
cardiac ward / General ward), as recorded on the “Index hospitalization summary” eCRF page, 
will be summarized by treatment group. 
Death through Day 30 
The time (in days) from randomization to the event plus 1 day will be used for analysis. If death 
occurred, date is reported in the dedicated eCRF sections “Death – (Endpoint to be 
adjudicated)” or “Death – (NOT to be adjudicated)”. Subjects without an event will be 
censored at the earlier of the last contact date (Last known date patient alive in “Survival 
Information” section) or Day 30. Subjects without any information after baseline will be 
considered censored at 1 day. 
Table 5.2-7: Censoring and time rules 
 
Status 
Time 
Death occurred: 
 
 
 
Difference between date of death and date of randomization +1 day 
>30 days 
Censored 30 days 
 
Difference between date of death and date of randomization +1 day 
≤30 days 
Event 
Calculated 
difference 
No death occurred: 
 
 
 
Difference between date of last survival status* and date of 
randomization +1 day >30 days 
Censored 30 days 
Difference between date of last survival status* and date of 
randomization+1 day ≤30 days 
Censored Calculated 
difference 
 
 
 
* Last survival status is the last known date patient was alive 
 
 
 
Treatment groups will be compared using a generalized Wilcoxon test. The Kaplan-Meier 
estimates of the survival functions for each treatment group will be plotted and summarized. 
Re-hospitalization post-discharge 
Patients not discharged from the index hospitalization will not be included in the summary of 
number of re-hospitalizations. 
The number of re-hospitalizations per patient by treatment group will be described. Treatment 
groups will be compared using a Wilcoxon rank-sum test. 
The number of patients with re-hospitalization will be summarized. Categories of patients’ 
number of re-hospitalizations will be 0, 1, 2, >2, and will be compared between treatment 
groups with a Chi-Square test. In case of cell frequencies less than 5, Fisher’s Exact test will be 
used. Cochran-Armitage Test for trend will also be performed. 


 
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Patients not discharged from the index hospitalization will be included in the analysis of time 
to first re-hospitalization. 
Time to first re-hospitalization (in days) will be defined as the first re-hospitalization date (Date 
of admission in “Rehospitalization Information”) minus the randomization date plus 1 day. 
Subjects still in hospital at Day 30 will be censored at Day 30, calculated as randomization date 
+ 30 days. Subjects who die after index hospitalization discharge or when not hospitalized will 
be assigned the date of death as their time to re-hospitalization. Similarly, subjects who died 
during index hospitalization without being discharged will have their date of death as their 
time to re-hospitalization. 
Table 5.2-8: Censoring and time rules 
 
Status 
Time 
Patient not discharged from index hospitalization at Day 30 
Censored 30 days 
Patient not discharged but who died during index hospitalization: 
 
 
 
Difference between date of death and date of randomization +1 day 
>30 days 
Censored 30 days 
 
Difference between date of death and date of randomization +1 day 
≤30 days 
Event 
Calculated 
difference 
Patient discharged from index hospitalization and with at least one re-
hospitalization: 
 
 
 
Difference between date of first re-hospitalization and date of 
randomization +1 day >30 days 
Censored 30 days 
 
Difference between date of first re-hospitalization and date of 
randomization +1 day ≤30 days 
Event 
Calculated 
difference 
Patient discharged from index hospitalization but without re-
hospitalization: 
 
 
 
Difference between date of last visit* and date of randomization +1 
day >30 days 
Censored 30 days 
 
Difference between date of last visit* and date of randomization +1 
day ≤30 days 
Censored Calculated 
difference 
Patient discharged from index hospitalization but who died without re-
hospitalization: 
 
 
 
Difference between date of death and date of randomization +1 day 
>30 days 
Censored 30 days 
 
Difference between date of death and date of randomization +1 day 
≤30 days 
Event 
Calculated 
difference 
 
 
 
* Last visit includes date of last visit (if subject is alive at the study 
termination) 
 
 
 
Treatment groups will be compared using a Gehan’s generalized Wilcoxon test. The Kaplan-
Meier estimates for each treatment group will be plotted. Descriptive statistics by treatment 
group will be presented. 


 
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Re-hospitalisation characteristics, such as type of re-hospitalisation (urgent/emergency or 
elective) and reason (both primary and detailed), will be described presenting absolute 
frequencies and percentages calculated on the total of re-hospitalizations occurred with non-
missing information. Estimated duration (days) for specific acute care units (recorded on the 
“Rehospitalization information” eCRF page) will be summarized by treatment group providing 
number of observations, mean, standard deviation, median, first and third quartiles, minimum 
and maximum. Absolute and relative frequencies of patients presenting at least one re-
hospitalisation by type (urgent or elective) and by primary reason will be provided; 
percentages will be computed using the total number of patients discharged from index 
hospitalization as denominators. 
All procedures/tests/treatments performed (recorded on the “Rehospitalization – 
procedures/tests/treatments performed” eCRF page) will be summarized presenting number 
and percentage of subjects reporting the procedure/test/treatment; the data will be 
summarized overall and percentages will be calculated using subjects with at least one re-
hospitalization as denominators. Tabulation will follow the code list reported in the eCRF. 
Resource utilization 
Summary statistics on data about healthcare resource utilization collected throughout the 
index hospitalization, at discharge and at Day 5, and then at Day 14 post randomization, and 
through phone contact at Day 30 post randomization will be provided by treatment group. 
Index hospitalization length of stay (days) for specific acute care units will be summarized by 
treatment group providing number of observations, mean, standard deviation, median, first 
and third quartiles, minimum and maximum. Total length of stay for each specific acute care 
unit will be calculated by summing the estimated duration (days) at each assessment point. 
Absolute frequencies and percentages of subjects discharged and location of discharge (home 
/ long term care facility) will be provided by treatment group. 
In addition, description of emergency/urgent care > 24 hours not resulting in admission will be 
provided by treatment. Number of subjects with 0, 1, 2, >2 events will be summarized and 
compared between treatment groups with a Chi-Square test. In case of cell frequencies less 
than 5, Fisher’s Exact test will be used. Cochran-Armitage Test for trend will also be performed. 
Reason for emergency/urgent care visit > 24 hours not resulting in admission (both primary 
and detailed) will be described presenting absolute frequencies and percentages calculated on 
the total of emergency/urgent care visits with non-missing information. Absolute and relative 
frequencies of patients presenting at least one emergency/urgent care visit by primary reason 
will be provided; percentages will be computed using the total number of patients discharged 
from index hospitalization as denominators. 
All tests performed at the emergency/urgent care visit will be summarized presenting number 
and percentage of subjects reporting the test; the data will be summarized overall and 
percentages will be calculated using subjects with at least one emergency/urgent care visit as 
denominators. Tabulation will follow the code list reported in the eCRF. 


 
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Health-related Quality of Life 
Health-related quality of life assessments, by means of the EuroQoL EQ-5D-5L questionnaire, 
will be used to derive pre-specified quality of life scores according to the EuroQoL EQ-5D-5L 
questionnaire manual. 
The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression); each dimension has 5 levels of answer: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The patient is asked to indicate 
his/her health state for each of the 5 dimensions; the decision results in a 1-digit number 
expressing the level selected for that dimension. The digits for 5 dimensions can be combined 
in a 5-digit number describing the subject’s health state. It should be noted that the numerals 
1-5 have no arithmetic properties and should not be used as a cardinal score. A total of 3,125 
possible health states are defined; each state is referred to in terms of a 5-digit code. 
Each dimension will be summarized at baseline and at each assessment time point by 
treatment group providing absolute and relative frequencies of each level answer (percentages 
will be calculated on non-missing data for each dimension). Results will be provided also for 
subgroup variables such as age (i.e., <65 vs. ≥65 years), gender and region (i.e., Eastern Europe 
vs. Western Europe). 
EQ-5D-5L levels will be also dichotomised into 'no problems' (i.e., level 1) and 'problems' (i.e., 
levels 2 to 5), therefore changing the profile into frequencies of reported problems. 
Dichotomised variable in the two groups will be compared by means of Chi square test at each 
assessment time point. In case of cell frequencies less than 5, Fisher’s Exact test will be used. 
Each dimension will be summarized at Day 2, Day 5 and Day 14 assessment time points post 
randomization by treatment group, also providing absolute and relative frequencies of each 
level answer (percentages will be calculated on non-missing data for each dimension) by 
baseline level answer and by hospitalization status (hospitalized/not hospitalized) at study 
visit. 
Summary statistics (number of observations, mean, standard deviation, median, first and third 
quartiles, minimum and maximum) of raw data and change (absolute and %) from baseline will 
be provided at each assessment time point for the subject’s overall self-rated health status 
measure (EQ VAS values) by treatment group and by hospitalization status (hospitalized/not 
hospitalized) at study visit. The value of 100 is the best health the subject can imagine; 0 is the 
worst health the subject can imagine. Treatment groups will be compared for changes 
(absolute) from baseline using t-tests. 
Summary statistics of raw data and change (absolute and %) from baseline will also be 
provided at each assessment time point for subgroup variables such as age (i.e., <65 vs. ≥65 
years), gender, region (i.e., Eastern Europe vs. Western Europe), and occurrence of at least one 
WHF through Day 14. 
If data do not respect normality assumption, a Wilcoxon rank sum test will be applied. 


 
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EQ-5D-5L health states will be converted into a single index value using UK as the reference 
country for all countries. Studies that derive values sets and procedure for the index 
computation are under development in a number of countries; the most updated SAS code 
from the EQ Executive Office will be applied (i.e. reference set for UK updated on January 2016 
obtained from “Devlin, N., Shah, K., Feng, Y., Mulhern, B. and van Hout, B., 2016. Valuing 
Health-Related Quality of Life: An EQ-5D-5L Value Set for England. OHE Research Paper 16/01. 
London: Office of Health Economics”). Summary statistics will be provided for the index value 
at each visit by treatment group. 
To compare treatment groups in quality of life change from baseline (i.e., randomization), a 
mixed model for repeated measures will be fitted to overall health index score absolute 
changes from baseline (score at time of assessment - score at baseline), and considering 
treatment, visit and treatment by visit as factors, and value at baseline as covariate. 
If data do not respect normality assumption, a rank transformation will be applied. 
The questionnaire/scale completion status will be summarised descriptively by treatment 
group at each visit. 
5.3. SAFETY DATA 
All the safety analyses will be done on the Safety set. 
Adverse events 
The incidence of Adverse Events (AEs) recorded through Day 5 and Serious Adverse Events 
(SAEs) recorded through Day 14 will be presented for the Safety set. Treatment emergent 
AEs/SAEs will be considered as those AEs/SAEs with an onset date and time after treatment 
initiation for the serelaxin group. For the Standard of Care Only group, date and time of 
randomization will be considered as treatment initiation. In case of missing time of onset of 
the event, only the onset date will be used for the evaluation of the incidence of the AE. 
Adverse events with an onset between informed consent and treatment initiation will be listed 
separately. 
Tables reporting general summary of AEs will be produced by treatment group specifying the 
number of total events and absolute and relative frequency of patients with AEs. As a patient 
may have more than one AE, the total number of AEs could be greater than the total number 
of patients. Further summaries by treatment group will be produced for non-serious AE and 
serious AE by time period, e.g., through Day 5 and through Day 14. 
Absolute and relative frequency of patients with drug-related AEs, severe AEs, SAEs, AEs with 
an outcome of death, AEs leading to permanent discontinuation of treatment, AEs indicative of 
safety risk and events of interest (please refer to the section below for the definition of safety 
risk events and events of interest) will also be reported for treatment emergent AEs. The 
number of distinct adverse events by low level term will be provided. Drug-related AEs will be 
the AEs with relationship to study treatment equal to “Yes”, ”Yes, investigational treatment”, 
“Yes, other study treatment (not-investigational)”, “Yes, both and/or indistinguishable”; if the 


 
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relationship to study drug is unknown or missing, the AE will be considered to be drug-related 
as well. eCRF severe events will be considered as severe events in the analysis. These 
summaries will be repeated for treatment emergent SAEs. 
Treatment emergent AEs will be tabulated by System Organ Class (SOC) and Preferred Term 
(sorted in alphabetical order within each SOC) using the latest MedDRA dictionary, and by 
System Organ Class, Preferred Term and severity. Absolute and relative frequency of patients 
who have experienced each type of event will be presented; if the same patient reported more 
than one occurrence of the same AE with different intensity, the worst reported severity grade 
for each event for the patient will be used for the analysis. The most frequent treatment 
emergent AEs will also be tabulated by Preferred Term sorted by descending frequency for AEs 
with an incidence rate of at least 5% in the serelaxin group. 
In addition, treatment emergent adverse events associated with 
• worsening heart failure (WHF)/all cause death through Day 5 
• confirmed systolic blood pressure decrease event (CBPDE) 
will be summarized by system organ class and preferred term. These AEs are determined by 
taking the answer “Yes” to the questions “Does AE meet the definition of Endpoint?” and 
“Does AE meet the definition of Systolic Blood Pressure Decrease Event?”, respectively. 
Treatment emergent SAEs will be summarized similarly. Treatment emergent SAEs will be 
summarized by time period of onset, i.e., through Day 5 and through Day 14. Treatment 
emergent SAEs are defined as those which start after treatment start for serelaxin group, or 
after randomization for Standard of Care group. 
All study-drug-related AEs, AEs with an outcome of death, AEs leading to permanent 
discontinuation of treatment will be listed with all their details. Time from the treatment start 
for serelaxin group or from randomization for Standard of Care group, to the AE start/end 
date, will be also computed. Elapsed days, hours and minutes plus 1 minute will be reported 
on the listing. 
In case of an ongoing event, no days relative to the end of the event will be computed. 
In case of missing time of start or end of an event, no relative days will be computed. 
Safety risks and events of interest 
Adverse events will be also presented according to the search strategies using the latest 
MedDRA dictionary version available before database lock, as specified in the Case Retrieval 
Strategy (CRS) defined by Novartis. Adverse events will be characterized as safety risks and as 
events of interest according to the rules specified in Table 5.3-1 and Table 5.3-2, respectively. 
Safety risks and events of interest through Day 5 and Day 14 will be summarized by treatment 
group and tabulated by safety risk / events of interest, NMQ, HLGT, SMQ or SOC, and 
Preferred Term of MedDRA dictionary. Absolute and relative frequency of patients who have 
experienced each type of event will be presented. 


 
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Table 5.3-1: MedDRA* search specifications to evaluate safety risks 
Safety Risk 
Specification 
Hypotension (identified) 
NMQ ‘Hypotension’ (Broad) 
Hemoglobin/ hematocrit transient 
decrease 
(potential) 
CMQ 'Hemoglobin/ hematocrit transient decrease' 
• 
SMQ ‘Haemorrhages’ (Broad) 
• 
HLGT ‘Anaemias nonhaemolytic and marrow 
depression’ 
• 
SMQ ‘Haematopoietic erythropenia’ (Broad) 
Fetotoxicity and teratogenicity (potential) 
SMQ ‘Pregnancy and neonatal topics’ (Broad) 
CMQ: Customized MedDRA query; HLGT: High level group term; NMQ: Novartis MedDRA query; SMQ: 
Standardized MedDRA query. 
* According to MedDRA v19.1. Specifications could possibly change before database lock. 
 


 
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Table 5.3-2: MedDRA* search specifications to evaluate events of interest 
Event of Interest 
Specification 
Menorrhagia/Metrorrhagia 
HLGT ‘Menstrual cycle and uterine bleeding disorders’ 
Hypokalemia 
NMQ ‘Hypokalemia’ (Broad) 
Hypersensitivity/Immunogenicity 
CMQ 'Hypersensitivity, Immunogenicity, Cutaneous reactions': 
• 
SMQ ‘Hypersensitivity’ (Broad) 
• 
SMQ ‘Angioedema’ (Broad) 
• 
SMQ ‘Anaphylactic reaction’ (Broad) 
• 
SOC ‘Immune system disorders’ 
• 
HLGT ‘Immunology and allergy investigations’ 
• 
HLGT ‘Administration site reactions’ 
• 
SMQ ‘Severe cutaneous adverse reactions’ (Broad) 
Cardiac failure 
SMQ ’Cardiac failure’ (Broad) 
QT prolongation 
CMQ 'Cardiac arrhythmias/QT prolongation': 
• 
SMQ ‘Torsade de pointes/QT prolongation’ (Broad) 
• 
SMQ ‘Cardiac arrhythmias’ (Broad) 
Thromboembolic events 
SMQ ‘Embolic and thrombotic events’ (Broad) 
Renal impairment 
CMQ 'Renal impairment': 
• SMQ ‘Acute renal failure’ (Broad) 
• PT 'Chronic kidney disease' 
Respiratory failure 
SMQ ‘Respiratory failure’ (Broad) 
Hepatotoxicity 
SMQ ‘Drug related hepatic disorders – comprehensive search’ 
(Broad) 
Potential promotion of cancers 
SMQ ‘Malignancies’ (Broad) 
CMQ: Customized MedDRA query; HLGT: High level group term; NMQ: Novartis MedDRA query; SMQ: 
Standardized MedDRA query; SOC: System organ class. 
* According to MedDRA v19.1. Specifications could possibly change before database lock. 
Liver events 
Liver events are a subgroup of Adverse Events. 
As a patient may have more than one liver event the total number of liver events could be 
greater than the total number of patients. The number of subjects with 0, 1, 2, >2 liver events 
will be summarized by treatment. Summary statistics on data about liver events will be 
provided by treatment. 
Liver events details, collected in the “Liver Event - Overview” section and including medical 
history possibly contributing to liver dysfunction, alcohol consumption, drug abuse and 
acetaminophen/paracetamol intake, will be described presenting absolute and relative 
frequencies of liver events in each category of variable (percentages will be calculated on the 
total of liver events with non-missing information). 


 
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Imaging, pathology, autoimmune and viral serology assessments will be presented with the 
total of liver events; results will be presented by each procedure and percentages will be 
calculated on each procedure with non-missing information. 
Vital signs 
Vital signs evaluations will include measurements of body weight (Kilogram), body mass index 
(kg/m2), height (cm) at screening, body temperature (Celsius), respiratory rate (Breath/min), 
pulse (Beats/min) and systolic and diastolic blood pressure (mmHg). Conversions from 
different units will be performed as aforementioned (see Section 5.1). 
Summary statistics (i.e., number of observations, mean, standard deviation, median, first and 
third quartiles, minimum and maximum) of raw data and change (absolute and %) from 
screening (i.e., start of screening for all parameters and end of screening only for pulse and 
blood pressure) will be provided at each assessment time point. Treatment groups will be 
compared for changes (absolute) from screening (i.e., start and end, where applicable) for 
each parameter. The estimated difference between treatment groups and 95% CI will be 
presented. 
For serelaxin group only, descriptive statistics of raw data and change (absolute and %) versus 
the pre-dose value will also be provided for heart rate (Beats/min) and systolic and diastolic 
blood pressure (mmHg) collected for drug infusion and post-drug infusion monitoring. 
Summary statistics for raw data, absolute change and percentage change from screening, and 
absolute change and percentage change from Day 5 will be provided by treatment group for 
heart rate (Beats/min), systolic and diastolic blood pressure (mmHg) collected daily through 
the hospitalization (after Day 5 and up to Day 29). 
Line plots of the mean and standard error of systolic and diastolic blood pressure over time by 
treatment group will be provided. 
Laboratory data: hematology and chemistry 
Summary statistics of raw data and change (absolute and %) from screening at each scheduled 
visit and for each laboratory parameter will be presented by treatment group. Laboratory data 
will be analysed and presented considering the preferred unit of measurement. Treatment 
groups will be compared for changes (absolute) from screening for each parameter. The 
estimated difference between treatment groups and 95% CI will be presented. 
Laboratory data will also be summarized by presenting for each laboratory parameter shift 
tables showing the pattern of change from screening versus each post-screening visit, based 
on the cross-classification of the number and percentage of subjects in each treatment group 
with any post-screening value that is below [low], within [normal], above [high], below&above 
[low&high] the normal ranges.  
Abnormal laboratory values will be presented for each subject in a data listing with an 
indication of whether the value is above (H) or below (L) the normal reference range and if it is 
notable. 


 
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The categorical analysis for laboratory parameters will be presented using the criteria reported 
in Table 5.3-3. The number and percentage of subjects meeting each specified criterion will be 
tabulated by visit and for any post-baseline visit. For those criteria with the specified cut off 
point (e.g., < or > x.x), the summary statistics will be presented for baseline and each post-
baseline visit, with the denominator including those subjects with evaluable measurements at 
the specified visits. For criteria with specification regarding the relative change from baseline, 
the summary statistics will be presented for each post-baseline visit with the denominator 
including those subjects with evaluable measurements at both baseline and the corresponding 
post-baseline visit. 


 
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Table 5.3-3: Categorical analysis for laboratory parameters 
 
Parameter categories 
Criterion 
Hematology 
Red blood cell counts 
(RBC) 
>50% increase 
>20% decrease 
<2.5x10^6/uL 
>8.5x10^6/uL 
Hemoglobin 
>50% increase 
>20% decrease 
>20 g/dL 
<8 g/dL 
Hematocrit 
>50% increase 
>20% decrease 
<20% 
>60% 
RBC, Hemoglobin, & 
Hematocrit 
RBC > 20% decrease AND Hemoglobin > 20% 
decrease AND Hematocrit > 20% decrease 
White blood cell counts 
(WBC) 
>100% increase 
>50% decrease 
<3.5x10^9/L 
>25x10^9/L 
Platelet 
>75% increase 
>50% decrease 
<50x10^9/UL 
>600x10^9/UL 
Neutrophils 
<1.5x10^9/L 
<1.0x10^9/L 
Lymphocytes 
None 
Serum Chemistry 
Blood Urea Nitrogen 
(BUN) 
>100% increase 
>14.28 mmol/L 
Creatinine 
>100% increase 
>50% increase 
Increase of >=0.3 mg/dL 
Increase of >=0.5 mg/dL 
Increase of >=1.0 mg/dL 
>2 mg/dL 
>2.5 mg/dL 
Estimated Glomerular 
Filtration Rate (eGFR) 
Decrease of >25% 
Decrease of >50% 
Decrease of >30mL/min/1.73m2 
Potassium 
>6 mmol/L 
>5.5 mmol/L 
<3.0 mmol/L 
Calcium 
<1.75 mmol/L 
>3.1 mmol/L 
Sodium 
<120 mmol/L 
<130 mmol/L 
>155 mmol/L 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 60 of 66 
 
 
In addition, for the liver function test (LFT), summary table will be provided on the number and 
proportion of patients having the criteria defined in Table 5.3-4. These are evaluated at each post-
baseline visit as well as at any post-baseline visit. The data are summarized using two approaches: 
1. Patients with newly occurring abnormalities, defined as events occurring post baseline 
for patients who did not meet the abnormal criteria at baseline (Table 5.3-4).  
2. Patients with abnormalities post baseline, regardless of the baseline values (Table 5.3-
5). 
Table 5.3-4: LFT categorical analysis (‘newly occurring’) 
Category 
family 
Category - Numerator  
Subjects at risk meeting the criteria at post BL 
Denominator  
Subjects at risk and meeting the 
following criteria at BL 
ALT/AST 
ALT or AST >3x ULN 
Subjects with ALT and AST ≤3x ULN at BL 
ALT or AST >5x ULN 
ALT or AST >8x ULN 
ALT or AST >10x ULN 
Hy’s chemistry 
category 
ALT or AST >3x ULN and TBL >1.5x ULN 
Subjects with ALT and AST ≤3x ULN at BL 
ALT or AST >3x ULN and TBL >2x ULN 
ALT or AST >5x ULN and TBL >2x ULN 
ALT or AST >8x ULN and TBL >2x ULN 
ALT or AST >10x ULN and TBL >2x ULN 
ALT or AST >3xULN and TBL >2x ULN and ALP <2x ULN 
TBL & ALP 
TBL >1.5x ULN and ALP >2x ULN 
Subjects with TBL ≤1.5x ULN and ALP ≤2x 
ULN at BL 
(comment: the intention is that both 
parameters must below threshold) 
TBL >2x ULN and ALP >2x ULN 
Isolated TBL 
TBL >1.5x ULN & ALT and AST ≤3x ULN and ALP ≤2x ULN 
Subjects with TBL ≤1.5x ULN & ALT and AST 
≤3x ULN and ALP ≤2x ULN 
(comment: same denominator as for ‘isolated 
ALP’) 
TBL >2x ULN & ALT and AST ≤3x ULN and ALP ≤2x ULN 
TBL >3x ULN & ALT and AST ≤3x ULN and ALP ≤2x ULN 
Isolated ALP 
ALP >2x ULN &  ALT and AST ≤3x ULN and TBL ≤1.5x ULN 
Subjects with ALP ≤2x ULN & ALT and AST 
≤3x ULN and TBL ≤1.5x ULN 
(comment: same denominator as for ‘isolated 
TBL’) 
ALP >3x ULN & ALT and AST ≤3x ULN and TBL ≤1.5x ULN 
ALP >5x ULN & ALT and AST ≤3x ULN and TBL ≤1.5x ULN 
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total 
bilirubin; ULN: upper limit of normal. 


 
Statistical Analysis Plan 
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Protocol number: CRLX030A3301 
 
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Table 5.3-5: LFT categorical analysis (‘any post-baseline elevation’) 
Category 
family 
Category - Numerator  
Subjects at risk meeting the criteria at post BL 
Denominator  
Subjects at risk  
ALT/AST 
ALT or AST >3x ULN 
Subjects with a post BL value 
ALT or AST >5x ULN 
ALT or AST >8x ULN 
ALT or AST >10x ULN 
Hy’s chemistry 
category 
ALT or AST >3x ULN and TBL >1.5x ULN 
ALT or AST >3x ULN and TBL >2x ULN 
ALT or AST >5x ULN and TBL >2x ULN 
ALT or AST >8x ULN and TBL >2x ULN 
ALT or AST >10x ULN and TBL >2x ULN 
ALT or AST >3xULN and TBL >2x ULN and ALP <2x ULN 
TBL & ALP 
TBL >1.5x ULN and ALP >2x ULN 
TBL >2x ULN and ALP >2x ULN 
Isolated TBL 
TBL >1.5x ULN & ALT and AST ≤3x ULN and ALP≤2x ULN 
TBL >2x ULN & ALT and AST ≤3x ULN and ALP ≤2x ULN 
TBL >3x ULN & ALT and AST ≤3x ULN and ALP ≤2x ULN 
Isolated ALP 
ALP >2x ULN &  ALT and AST ≤3x ULN and TBL ≤1.5x ULN 
ALP >3x ULN & ALT and AST ≤3x ULN and TBL ≤1.5x ULN 
ALP >5x ULN & ALT and AST ≤3x ULN and TBL ≤1.5x ULN 
Plots showing the relationship between maximum TBL and ALT or AST at any visit (eDISH plot 
for the evaluation of drug-induced serious hepatotoxicity) will also be provided. 
Laboratory data: urinalysis 
Summary statistics for data about urinalysis will be provided at each assessment time point by 
treatment group. For each parameter result, absolute and relative frequencies of patients 
reporting it will be provided. Percentages will be computed considering patients with non-
missing information at each assessment time point. 
Electrocardiogram (ECG) 
The number and proportion of patients by procedure performed and overall interpretation will 
be provided at each assessment time point by treatment group. Percentages will be computed 
considering patients with non-missing information at each assessment time point. Summary 
statistics will be provided at each assessment time point by treatment group. 
Heart rate (beats/min), mean PR duration (msec), mean QT duration (msec), corrected QT 
Fridericia interval (QTcF) and mean QRS duration (msec) will be described, providing number 
of observations, mean, standard deviation, median, first and third quartiles, minimum and 
maximum at each assessment time point by treatment group. 
The number and proportion of patients with the following criteria at any post-baseline visit will 
be presented: 


 
Statistical Analysis Plan 
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Table 5.3-6: Criteria for ECG categorical analysis 
Topic 
Parameter categories 
Criterion for denominator  
QT/QTcF 
QT/QTcF >450 msec 
Subjects with QT/QTcF ≤450 msec at BL 
QT/QTcF >480 msec 
Subjects with QT/QTcF ≤480 msec at BL 
QT/QTcF >500 msec 
Subjects with QT/QTcF ≤500 msec at BL 
QT/QTcF >450 msec; males only  
Male subjects with QT/QTcF ≤450 msec 
at BL 
QT/QTcF >460 msec; females only 
Female subjects with QT/QTcF ≤460 
msec at BL 
QT/QTcF increase from BL >30 msec 
Subjects with a non-missing value at BL 
and post BL 
QT/QTcF increase from BL >60 msec 
Subjects with a non-missing value at BL 
and post BL 
PR 
PR >200 msec  
Subjects with PR ≤200 msec at BL  
PR >220 msec 
Subjects with PR ≤220 msec at BL  
PR > 200 msec and change from BL ≥25%  Subjects with PR ≤200 msec at BL  
QRS 
QRS >110 msec and change from BL 
≥25%  
Subjects with QRS ≤110 msec at BL  
QRS >120 msec and change from BL 
≥25% 
Subjects with QRS ≤120 msec at BL  
Heart Rate 
Heart rate >100 bpm and change from BL 
≥25%  
Subjects with heart rate ≤100 bpm at BL 
Heart rate <50 bpm and change from BL 
≥25%  
Subjects with heart rate ≥50 bpm at BL 
In addition, shift tables comparing baseline ECG overall interpretation (normal, clinically 
insignificant abnormality, clinically significant abnormality) with Day 5/discharge ECG overall 
interpretation (normal, clinically insignificant abnormality, clinically significant abnormality) 
will be provided by treatment group. 
A listing of clinically significant abnormalities in ECG evaluations will be provided. 
Echocardiography 
Echocardiography is not considered as study related procedures and is performed according to 
local diagnostic practice. 
Overall interpretation will be described by providing the number and proportion of subjects in 
each category at each assessment time point by treatment group. Percentages will be 
computed considering patients with non-missing information at each assessment time point. 
LV Ejection Fraction (%) will be described by means of summary statistics (i.e., number of 
observations, mean, standard deviation, median, first and third quartiles, minimum and 
maximum) at each assessment time point by treatment group. 
Systolic blood pressure decrease event 


 
Statistical Analysis Plan 
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Protocol number: CRLX030A3301 
 
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Rev.01 
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A confirmed systolic blood pressure decrease event (CBPDE) is defined as systolic blood 
pressure decreases by > 40 mmHg from just before the study drug infusion at baseline but is ≥ 
100 mmHg in 2 consecutive measurements 15 minutes apart, or if in 2 consecutive 
measurements 15 minutes apart, systolic blood pressure reduces to < 100 mmHg, as reported 
in the “Systolic blood pressure decrease event – vital signs” eCRF. 
For the serelaxin arm only, the number and proportion of patients who experienced a 
confirmed systolic blood pressure decrease event during study drug administration will be 
provided. Percentages will be computed considering patients in the analysis population. 
The number and proportion of patients who experienced 0, 1, 2, >2 confirmed systolic blood 
pressure decrease events will be provided together with the number and proportion of 
patients who experienced asymptomatic/symptomatic events (as recorded on the “Systolic 
Blood pressure Decrease Event” eCRF page). 
The total number of events will be further characterized, showing absolute and relative 
frequencies of events for the following characteristics: 
• Outcome: not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown 
• Action taken with study treatment: none, dose adjusted but not discontinued, 
permanently discontinued, dose adjusted then permanently discontinued 
The category of “dose adjusted then permanently discontinued” for action taken is 
derived by combining the categories “dose adjusted but not discontinued” and 
“permanently discontinued” when recorded separately in the eCRF for the same 
CBPDE. 
• Medications or therapies taken: yes or no, if yes type of medication/therapy 
(fluids/crystalloids, 
inotropes, 
vasopressors, 
circulatory 
support, 
mechanical 
ventilation, other) 
Percentages will be computed considering events with non-missing information. 
The number and proportion of patients who experienced at least one confirmed systolic blood 
pressure decrease events will be also presented by outcome, action taken and 
medications/therapies taken. 
The number and proportion of patients who experienced at least one systolic blood pressure 
decrease events will be also presented by type of event in terms of SBP onset value (mmHg): 
• if systolic blood pressure decreased by > 40 mmHg from baseline but was ≥ 100 
mmHg; 
• if systolic blood pressure reduced to < 100 mmHg. 


 
Statistical Analysis Plan 
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Protocol number: CRLX030A3301 
 
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The SBP value (mmHg) at baseline (i.e., at randomization) will be summarized for patients with 
a confirmed SBP decrease event and for those without a confirmed SBP decrease event. 
The following summaries will be presented for patients with a confirmed SBP decrease event: 
• Time (hours) to first CBPDE, defined as time from randomization date and time to the 
first CBPDE date and time + 1 minute 
• SBP (mmHg) decrease from baseline to first CBPDE 
• Trough SBP (mmHg) since CBPDE, defined as the minimum of SBP values recorded 
during the study including the measurements occurred before CBPDE 
• SBP (mmHg) decrease from baseline to trough, where the trough SBP is the minimum 
value recorded for any CBPDE 
Summary statistics will be provided for heart rate (Beats/min) and systolic and diastolic blood 
pressure (mmHg) at each assessment time point following the first event onset. Summaries of 
heart rate, SBP and DBP will be provided separately for those confirmed events (both 
symptomatic and asymptomatic, as recorded on the eCRF) that resulted in study drug dose 
reduction but not discontinuation, those that resulted in study drug discontinuation, and those 
that resulted in study drug dose reduction then permanent discontinuation. 
The possible interaction between the effect of serelaxin and the effect of IV nitrate 
administration within the first 48 hours will be examined by providing the number and 
proportion of patients who experienced at least one confirmed systolic blood pressure 
decrease event split by intake of IV nitrate within 48 hours (i.e., subgroup of patients without 
any intake of IV nitrate within 48 hours vs. subgroup of patients with at least one intake of IV 
nitrate within 48 hours). A subject with at least one intake of IV nitrate within 48 hours is 
defined as a subject who: 
• was on IV nitrates at the time of randomization (eCRF section “Index Heart Failure 
Hospitalization”); 
• started new IV nitrates, restarted IV nitrates, or increased dose of IV nitrates (e.g., 
isosorbide dinitrate, nitroglycerine, sodium nitroprusside) as a consequence of WHF 
while still under serelaxin infusion (eCRF section “Clinical Worsening of Heart Failure 
(Endpoint to be adjudicated)”). 
Category of patients with at least one confirmed systolic blood pressure decrease event 
CBPDE/ no CBPDE will be compared between categories with a Chi-Square test. In case of cell 
frequencies less than 5, Fisher’s Exact test will be used. Category of patients with at least one 
asymptomatic CBPDE / at least one symptomatic CBPDE / no CBPDE will be compared between 
categories with a Chi-Square test. In case of cell frequencies less than 5, Fisher’s Exact test will 
be used. Cochran-Armitage Test for trend will also be performed. 
To further investigate the impact of CBPDE, the following analyses will be performed: 
• baseline characteristics by CBPDE (yes/no); 


 
Statistical Analysis Plan 
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Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
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• concomitant medications by CBPDE (yes/no); 
• worsening heart failure/all cause death through Day 5 by CBPDE (yes/no) and by CBPDE 
impact on study drug administration (dose decreased but not discontinued, or study 
drug discontinued, or both); 
• adverse events through Day 5 and through Day 14 by CBPDE (yes/no) 
Causes that lead to a re-hospitalization or emergency/urgent care >24 hours not resulting in 
admission 
In case the reason for re-hospitalization or emergency/urgent care >24 hours not resulting in 
admission is HF, renal impairment, or cardiac (chest pain, ACS, MI), further details are collected 
in dedicated eCRF sections (“Rehospitalization information”, “Heart failure details”, “Acute 
MI/ACS/chest pain” and “Renal failure”). 
Data will be summarized presenting absolute and relative frequencies (percentages calculated 
on events with non-missing information) for discrete variables; presenting number of 
observations, mean, standard deviation, median, first and third quartiles, minimum and 
maximum for continuous variables. 
Survival and Death information 
Descriptive statistics by treatment group will be presented for death information. 
All deaths occurred will be listed with all their details. 
Pregnancy test results 
Any pregnancies reported will be listed and outcome reported. 
5.4. INTERIM ANALYSIS 
No formal interim analyses are planned. 
An external independent Data Monitoring Committee (DMC) is appointed to monitor the 
safety of study participants and to ensure that the program is conducted with highest scientific 
and ethical standards. This DMC will review the safety data and data relating to the primary 
efficacy endpoint throughout the trial and make safety recommendations on the conduct of 
the trial. The committee will not provide recommendations based on the efficacy analysis. No 
consequent early termination or sample size adjustment will be based on the DMC-related 
efficacy analysis. In case the recommendations are considered to have significant bearing on 
the benefit-risk of the trial, these will be communicated by DMC to Executive Committee 
members and Novartis. The final decisions will be communicated to the investigators within an 
appropriate timeframe. 


 
Statistical Analysis Plan 
Sponsor: NOVARTIS 
Protocol number: CRLX030A3301 
 
FRM-STA003-01 
Rev.01 
Page 66 of 66 
 
6. APPENDIX 
Appendix I: Table of Conversion Factor for Laboratory Parameters.