Conditions: Acute Heart Failure
Keywords: Serelaxin, WHF, Likert Scale, RELAX-AHF-ASIA, RLX030, AHF, acute heart failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 876
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate the efficacy, safety and tolerability of intravenous infusion of serelaxin, when added to standard therapy, in acute heart failure (AHF) patients.

Detailed description:

Arms:
arm 1: Patients will receive continuous intravenous infusion of matching placebo serelaxin for 48 hours. arm 2: Patients will receive continuous intravenous infusion of serelaxin(30 µg/kg/day) for 48 hours.

Interventions: intervention 1: Serelaxin intervention 2: Placebo intervention 3: Standard of CareTherapy
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Intravenous infusion intervention 3: This treatment can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor antagonists, etc.

Protocol document:
Prot_000.pdf: 
Clinical Development
RLX030A
Clinical Trial Protocol CRLX030A2302 / NCT02007720
A multicenter, randomized, double-blind, placebo 
controlled phase III study to evaluate the efficacy, safety 
and tolerability of serelaxin when added to standard 
therapy in acute heart failure patients
Authors:
 
Principal or coordinating 
investigator
for the RLX030A2302 Executive 
Committee
Document type
Amended Protocol Version
Version number
v04 Clean Version
Clinical trial phase:
III
Release date:
10-May-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 4 ...........................................................................................................................10
Amendment 3 ...........................................................................................................................11
Amendment 2 ...........................................................................................................................12
Protocol synopsis...............................................................................................................14
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose ..................................................................................................................24
2
Study objectives.................................................................................................................24
2.1
Primary objective(s)...............................................................................................24
2.2
Secondary and other efficacy objectives ...............................................................25
3
Investigational plan ...........................................................................................................26
3.1
Study design...........................................................................................................26
3.2
Rationale of study design.......................................................................................27
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....29
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................29
3.6
Risks and benefits..................................................................................................29
4
Population..........................................................................................................................30
4.1
Inclusion criteria ....................................................................................................30
4.2
Exclusion criteria...................................................................................................31
5
Treatment...........................................................................................................................33
5.1
Protocol requested treatment .................................................................................33
5.1.1
Study and control drugs ........................................................................33
5.1.2
Additional  treatment.............................................................................33
5.2
Treatment groups...................................................................................................34
5.3
Treatment assignment, randomization...................................................................34
5.4
Treatment blinding.................................................................................................34
5.5
Treating the patient................................................................................................35
5.5.1
Patient numbering .................................................................................35
5.5.2
Dispensing the study drug.....................................................................36
 


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5.5.3
Handling of study drug..........................................................................36
5.5.4
Instructions for prescribing and taking study drug ...............................37
5.5.5
Permitted dose adjustments and interruptions of study drug ................37
5.5.6
Rescue medication ................................................................................38
5.5.7
Concomitant treatment..........................................................................38
5.5.8
Prohibited Treatment.............................................................................39
5.5.9
Discontinuation of study treatment .......................................................39
5.5.10
Withdrawal of informed consent...........................................................40
5.5.11
Loss to follow-up ..................................................................................40
5.5.12
Emergency breaking of assigned treatment code..................................40
5.5.13
Study completion and post-study treatment..........................................41
5.5.14
Early study termination.........................................................................41
6
Visit schedule and assessments .........................................................................................41
6.1
Information to be collected on screening failures..................................................49
6.2
Patient demographics/other baseline characteristics .............................................49
6.3
Treatment exposure and compliance .....................................................................49
6.4
Efficacy..................................................................................................................49
6.4.1
Efficacy assessment 1 ...........................................................................49
6.4.2
Efficacy assessment 2 ...........................................................................50
6.4.3
Appropriateness of efficacy assessments..............................................50
6.4.4
Other efficacy assessments ...................................................................51
6.5
Safety.....................................................................................................................52
6.5.1
Physical examination ............................................................................52
6.5.2
Vital signs..............................................................................................53
6.5.3
Laboratory evaluations..........................................................................54
6.5.4
Electrocardiogram (ECG) .....................................................................54
6.5.5
Pregnancy and assessments of fertility .................................................55
6.5.6
Appropriateness of safety measurements..............................................55
6.6
Other assessments..................................................................................................55
6.6.1
Resource utilization...............................................................................55
6.6.2
Pharmacokinetics ..................................................................................55
6.6.3
Immunogenicity...................................................................................56
6.6.4
Pharmacogenetics/pharmacogenomics .................................................57
7
Safety monitoring ..............................................................................................................57
7.1
Adverse events.......................................................................................................57
7.2
Serious adverse events...........................................................................................59
 


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7.2.1
Definition of serious adverse event.......................................................59
7.2.2
Serious adverse event reporting ............................................................59
7.3
Liver safety monitoring .........................................................................................62
7.4
Pregnancy reporting...............................................................................................63
8
Data review and database management.............................................................................63
8.1
Site monitoring ......................................................................................................63
8.2
Data collection.......................................................................................................64
8.3
Database management and quality control............................................................64
8.4
Data Monitoring Committee..................................................................................65
8.5
Adjudication Committee........................................................................................65
9
Data analysis......................................................................................................................65
9.1
Analysis sets ..........................................................................................................65
9.2
Patient demographics and other baseline characteristics.......................................66
9.3
Treatments .............................................................................................................67
9.4
Analysis of the primary variable(s) .......................................................................67
9.4.1
Variable(s).............................................................................................67
9.4.2
Statistical model, hypothesis, and method of analysis..........................67
9.4.3
Handling of missing values/censoring/discontinuations.......................68
9.4.4
Supportive analyses...............................................................................68
9.5
Analysis of secondary variables ............................................................................68
9.5.1
Efficacy variables..................................................................................68
9.5.2
Safety variables .....................................................................................70
9.5.3
Resource utilization...............................................................................71
9.5.4
Health-related Quality of Life...............................................................71
9.5.5
Pharmacokinetics ..................................................................................71
9.5.6
Immunogenicity ....................................................................................71
9.5.7
Pharmacogenetics/pharmacogenomics .................................................72
9.5.8
Biomarkers ............................................................................................72
9.5.9
PK/PD ...................................................................................................72
9.6
Interim analyses .....................................................................................................72
9.7
Sample size calculation..........................................................................................72
10 Ethical considerations........................................................................................................73
10.1
Regulatory and ethical compliance........................................................................73
10.2
Informed consent procedures.................................................................................73
10.3
Responsibility of the investigator and IRB/IEC ....................................................73
10.4
Publication of study protocol and results...............................................................74
 


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10.5
Quality Control and Quality Assurance.................................................................74
11 Protocol adherence ............................................................................................................74
11.1
Protocol amendments.............................................................................................74
12 References .........................................................................................................................76
13 Appendix 1: Clinically notable laboratory values and vital   signs...................................80
14 Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ......................................................................................................................81
15 Appendix 3: Physician assessment of signs and symptoms ..............................................84
16 Appendix 4: Dyspnea Measurement by Likert Scale ........................................................86
17 Appendix 5: Dyspnea Measured by Visual Analog Scale (VAS).....................................87
18 Appendix 6: Blood collection log for PK and immunogenicity samples..........................88
 


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List of tables
Table 5-1
Weight-range adjusted dosing regimen of serelaxin (or placebo) ........37
Table 5-2
Dosing adjustment of study drug administration in the event of 
treatment-emergent systolic BP decrease..............................................37
Table 6-1
Visit assessment ....................................................................................43
Table 9-1
Sample sizes (a= 0.05, Power = 80%, and common odds ratio = 
0.75) ......................................................................................................72
Table 14-1
Liver event and laboratory trigger definitions ......................................81
Table 14-2
Follow up requirements for liver events and laboratory triggers..........82
List of figures
Figure 3-1
Study design..........................................................................................26
 


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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
AHF
Acute heart failure
Alb
Albumin
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
b.i.d.
twice a day
BP
Blood pressure
CCU
Coronary care unit
CEC
Clinical Event Committee 
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
Css
Steady state concentration 
CTRD
Clinical Trial Results Database
CV
Cardiovascular
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ER
Emergency Room
ED
Emergency Department
GCP
Good Clinical Practice
HA
Health authority
HF
Heart failure
HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed consent form
 


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ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IN
Investigator Notification
IV
Intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWRS
Interactive Web Response System
JVP
Jugular venous pulse
LFT
Liver function test
LOS
Length of stay
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA Medical dictionary for regulatory activities
PK
Pharmacokinetics
PT
Preferred Term 
RF
Renal failure
SAE
Serious adverse event
SBP
Systolic blood pressure
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reaction
TD
Study Treatment Discontinuation
ULN
Upper limit of normal
VAS
Visual analog scale
WHF
Worsening heart failure
WoC
Withdrawal of Consent
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the drug being tested in the trial
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Epoch 
A portion of the study which serves a specific purpose. Typical epochs are: 
screening/recruitment, wash-out, treatment, and follow-up
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 protocol-specified 
concomitant background therapies  when these are standard treatments in 
that indication
Medication number
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT/IWRS
Protocol
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial.
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/Patient Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study
Withdrawal of consent (WoC)
Withdrawal of consent from the study is defined as when a patient 
does not want to participate in the study any longer, and does not 
want any further visits or assessments, and does not want any 
further study related contact, and does not allow analysis of already 
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Amendment 4
Amendment rationale
The purpose of this amendment is to implement the following changes as recommended by 
the study Executive Committee:
1. 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, to improve the overall clarity of the study 
inclusion criterion, the study Executive Committee recommended the following changes:

The BNP and NTproBNP inclusion criteria will be increased: BNP ≥500 pg/mL and 
NT proBNP ≥2000 pg/mL 
2. Exclusion criteria for the upper limit of blood pressure at study entry will be added as 
recommended by the Data Monitoring Committee and endorsed by the study Executive 
Committee: patients with systolic blood pressure > 180 mmHg at end of screening will be 
excluded.
Changes to the protocol

Inclusion criterion #3 has been updated with BNP ≥500 pg/mL and NT proBNP ≥2000 
pg/mL

Exclusion criterion added: Patients with systolic blood pressure > 180 mmHg at the end of 
screening will be excluded 

Table 6.1 was updated to include:

Urine pregnancy test for females at Discharge

Assessments of  “blood pressure and heart rate” and “body temp and respiratory rate” 
on Days 60 and 180 to align with section 6.5.2

Contact IRT/IWRS at screening

Section 9.7: To preserve the target study power, the sample size may have to be increased. 
The Section 9.7 'Sample size calculation' has been updated accordingly.

Changes have been made to comply with the updated protocol template:

Updates/changes to cover page

List of abbreviations: additional abbreviations have been added

Glossary of terms: additional term has been added

Sections 5.4, 5.5. 7.1 7.2, 7.4, and 8.1 have been updated

Section 10.3 “Responsibilities of the investigator and IRB/IEC” has been added

Section 10.4 “publication of study protocol and results” has been added

Section 10.5 “Quality Control and Quality Assurance” has been added

Other minor clarifications, administrative, and typographical changes have been 
implemented throughout the protocol.
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. 
 


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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.
Summary of previous amendments
Amendment 3
Amendment rationale
The purpose of this amendment is to implement the following changes as requested by the 
Health Authority in Japan:
1. Add Japanese approved contraceptive methods to the eligibility criterion (exclusion 
criterion #14). This applies only to patients that are recruited for the trial in Japan.
2.
Add the wording to the “History of hypersensitivity to serelaxin or its any ingredients” to 
the eligibility criterion as it was done in the Japanese local phase II trial CRLX030A1201
(exclusion criterion #16). This applies to any patients that are recruited for the trial in all 
the participating countries.
Changes to the protocol

Inclusion criteria #7 has been updated to include the permission for using modified 
sMDRD formula for eGFR estimation in specific ethnic groups where appropriate.

There is an overlapping redundancy in the Exclusion criteria #2 and # 9. The two 
exclusion criteria were combined into a single one.

Exclusion criterion #10 was removed due to the redundancy, as organ transplant is already 
included in exclusion criterion #12.

Exclusion criterion #13 has been updated to include Japanese approved contraceptives as 
requested by Japanese HA.  This is applicable only to patients that are recruited to the 
study in Japan.

Exclusion criterion #15 has been clarified to include: serelaxin “or its any ingredients” per
comment from the Japanese HA.

Exclusion criterion #11 was added to comply with the protocol template: History of 
malignancy of any organ system (other than localized basal cell carcinoma of the skin), 
treated or untreated, within the past year with a life expectancy less than 1 years

Table 6.1: Patient reported dyspnea (LIKERT): assessment at 0 hour was removed as it 
was inadvertently checked

Table 6.1: Vital signs assessments were clarified to align with section 6.5.2 

Section 9.4.4 Supportive analyses: the number of sensitivity analyses “two” was removed

Section 12: Four references have been added
 


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Other minor clarifications, administrative, and typographical changes have been implemented
throughout the protocol. 
The changes herein do not affect the global Informed Consent.  The local ICF in Japan need to 
be updated to reflect the change made to exclusion criteria #13.  
Summary of previous amendments 
Amendment 2
Amendment rationale 
The purpose of amendment 2 is to implement the following changes:  
1. An independent pharmacist or qualified site personnel will prepare the study drug to 
further enhance the blind in the trial. An independent field monitor model will also be 
implemented. Further information can be found in the Pharmacy Manual.  
2. To ensure consistency in the diagnosis and data collection of the index in-hospital 
worsening heart failure, the index in-hospital WHF events will be adjudicated by the 
Clinical Events Committee (CEC).
Changes to the protocol

The independent pharmacist or qualified site personnel and field monitor model has been 
incorporated in sections: 5.1.1, 5.4, 5.5.2, 5.5.3, 5.5.4, and 6.3.  

Requirement for CEC to adjudicate index in-hospital worsening heart failure events has 
been added to sections 6.4.4.2 and 8.5

Inclusion criterion #3 (first bullet) has been amended to emphasize the dyspnea status at 
the time of randomization: Persistent dyspnea at rest or with minimal exertion at screening 
and at the time of randomization

Exclusion criterion #1 has been clarified as: Description of non-cardiac causes was added: 
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. 

Exclusion criterion #6: “uncorrected” was added to further clarify the left ventricular 
outflow obstruction: Significant, uncorrected, left ventricular outflow obstruction, 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), and severe 
mitral stenosis

Exclusion criterion #14 – has been updated for clarification to include the use of methods 
of contraception during dosing of study treatment and for 5 days following the cessation 
of study treatment and to emphasize highly effective contraceptive methods.

Exclusion criterion #19 was updated to include additional other medical conditions: Any 
other medical condition(s) 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 
 


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drug or alcohol abuse or psychiatric disorders, sufficient to interfere with the patient’s 
ability to comply with the protocol instructions or follow-up procedures.

The following additional objective was added to the “other objectives” and incorporated 
in sections 2.2, 6.4.2, and 9.4.2 in order to evaluate possible variations in the definition of 
in-hospital worsening heart failure: time to worsening heart failure through Day 5 where 
the worsening heart failure is defined by symptoms only, signs only, and by both 
symptoms and signs

Table 6-1 Visit assessment – In hospital worsening heart failure assessments at discharge 
visit was added. 

Section 7 was updated for clarity and according to the updated protocol template

Section 9.4.2 was amended to clarify the analysis method

Liver event laboratory requirements have been updated in Appendix 2 Table 14-1 and 
Table 14-2.
Amendment 1
Short summary of the amendment rationale and changes
The purpose of this amendment is to update the exclusion criteria to be consistent with the 
amended protocol for the ongoing RELAX-AHF 2 (CRLX030A2301) study as endorsed by 
the study Executive Committee. The exclusion criterion for the use of inotropes 2 hours prior 
to screening has been changed to 2 hours prior to randomization to improve recruitment 
(exclusion criterion #7).
In addition updates to the following sections have been updated to be consistent with the 
RELAX-AHF 2 amended protocol:  

The definition of worsening heart failure (WHF) has been revised (sections 2.1, 6.4.1, 
6.4.4.2, 7.2.2).  The time for assessing worsening heart failure “24 hours or more after 
initiation of study drug” was removed.  

Section 4.1 Inclusion criteria: A footnote related to inclusion criteria #1 was added to 
clarify assessments that can be used to support patient screening.

Section 5.5.4 Instructions for prescribing and taking study treatment:  A 4 hour window 
for initiating treatment after randomization was added.

Table 6-1 Visit assessment – table was updated to reflect the revised WHF definition 

Worsening heart failure assessments at 6 and 12 hour after initiation of infusion was
added
 


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Protocol synopsis
Protocol number
CRLX030A2302
Title
A multicenter, randomized, double-blind, placebo controlled phase III study 
to evaluate the efficacy, safety and tolerability of serelaxin when added to 
standard therapy in acute heart failure patients
Brief title
Efficacy, safety and tolerability of serelaxin when added to standard 
therapy in Asian patients with acute heart failure (AHF)
Sponsor 
and 
Clinical 
Phase
Novartis/III
Investigation type
Biologic
Study type
Interventional
Purpose and rationale
The purpose of this study is to evaluate the efficacy, safety and tolerability 
of intravenous infusion of 30 μg/kg/day serelaxin for 48 hours within 16 
hours of clinical presentation, when added to standard therapy, in 
approximately 1,520 primarily Asian AHF patients randomized to receive 
serelaxin or placebo to demonstrate superiority in early improvement in 
signs and symptoms of congestion and reduction in worsening heart 
failure (WHF) as evaluated by a clinical composite as the primary 
endpoint.  In addition the study will also assess the effect of serelaxin on 
the cardiovascular (CV) and all-cause deaths as listed as secondary 
endpoint. The results of which will be interpreted along with the results 
from other global studies
Acute heart failure (AHF) is a major public health problem with high 
disease prevalence associated with high mortality, morbidity, and financial 
costs. It is the most common cause of hospitalization in patients 65 years 
and older (Hunt et al 2009). As its prevalence is projected to increase by 
25% over the next 20 years (Heidenreich et al 2011), the burden of HF for 
health care systems will also increase.  Coronary artery disease and 
hypertension are common causes for AHF in Western countries (Yancy et 
al 2013, McMurray  et al 2012); similar etiology was also found in Asian 
countries in recent years (Jiang H and Ge J, 2009, Shiba  and Sjimokawa  
2008, Oh et al 2013, Youn YJ, et al 2012).  Similar to the US and Europe, 
AHF remains an unmet medical need in Asian countries and the leading 
cause for hospital admissions (Goda et al 2009, Park et al 2010).
The study is being conducted primarily in Asian countries for the 
generation of clinical evidence in AHF patients to fulfill the requirements by 
the local health authorities in these countries.  The trial is designed to 
demonstrate the clinical benefits in early relief of signs and symptoms of 
congestion and prevention of worsening heart failure by serelaxin on top of 
standard care.  The study will also collect evidence to evaluate the effect 
of serelaxin on the reduction of CV mortality in Asian AHF patients.
Primary Objective(s)
To demonstrate that serelaxin is superior to placebo in improving the 
clinical composite of “treatment success,” “treatment failure” and 
“ unchanged”
 


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
Treatment success is defined as moderate or marked 
improvement in patient reported dyspnea by Likert scale AND at 
least 2 points improvement for at least 2 out of 4 physician 
assessed signs and symptoms including orthopnea, rales, edema 
and jugular venous pulse (JVP) and none of them deteriorating (≥ 
0 point improvement) at Day 2. Refer to the efficacy assessment 
1 Section 6.4.1 and the physician assessment of signs and 
symptoms Section 15 Appendix 3.

Treatment failure is defined as in-hospital worsening heart failure 
or re-hospitalization due to heart failure or renal failure (RF) or 
death through Day 5. 

All remaining patients are classified as having unchanged 
treatment status if they meet neither the criteria for treatment 
success at Day 2 nor the criteria for treatment failure through Day 
5.  
Secondary 
and 
other 
objectives
Secondary objectives

To evaluate the effect of serelaxin as compared to placebo on
reducing time to in-hospital worsening heart failure through Day 5

To evaluate the effect of serelaxin as compared to placebo  on
reducing cardiovascular deaths through a follow up period of 180 days

To evaluate the effect of serelaxin as compared to placebo on
reducing all-cause deaths during a follow-up period of 180 days
Other efficacy objectives

To evaluate the effect of serelaxin as compared to placebo on 
reducing time to moderate or marked improvements in dyspnea 
assessed by Likert scale through Day 5

To evaluate the effect of serelaxin as compared to placebo on 
changes of dyspnea assessed by VAS-AUC through Day 5

To evaluate the effect of serelaxin as compared to placebo on
reducing the time in index ICU/CCU through Day 5

To evaluate the effect of serelaxin as compared to placebo in 
prevention of renal dysfunction or in-hospital worsening of renal 
function through Day 5 

To evaluate the effect of serelaxin as compared to placebo on 
reducing the time to re-hospitalization due to HF and renal failure 
through Day 180

To evaluate the effect of serelaxin as compared to placebo on 
reducing the composite endpoint of CV death or re-hospitalization due 
to HF/renal failure through Day 180

To evaluate the effect of serelaxin as compared to placebo on time to 
in-hospital worsening heart failure through Day 5 where the in-hospital
worsening heart failure is defined by symptoms only, signs only, and 
by both symptoms and signs

To evaluate the effect of serelaxin as compared to placebo on 
reducing the total intravenous loop diuretic dose, vasoactive and 
inotropes drug usage through Day 5 

To evaluate the effect of serelaxin as compared to placebo on the 
changes from baseline in cardio-renal biomarkers on Days 2 and 5   
Safety

To evaluate the safety and tolerability of intravenous serelaxin in AHF 
 


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patients. 
Study design
Multicenter, randomized, double-blind, placebo-controlled study
Population
The study population will consist of AHF Asian patients who typically 
present with normal to elevated BP and decreased renal function and
those who meet the inclusion and exclusion criteria.
Inclusion criteria
1. Written informed consent must be obtained before any study specific 
assessment is performed*
2. Male or female  ≥ 18 years of age, with body weight ≥ 30kg and ≤160 
kg 
3. Hospitalized for AHF; AHF is defined as including all of the following 
measured at any time between presentation (including the emergency 
department and outpatient clinic) and the end of screening:

Persistent dyspnea at rest or with minimal exertion at screening 
and at the time of randomization

Pulmonary congestion on chest radiograph

BNP ≥500 pg/mL or NT-proBNP ≥2,000 pg/mL
4. Systolic BP ≥125 mmHg at the start and at the end of screening
5. Able to be randomized within 16 hours from presentation to the 
hospital, including the emergency department and outpatient clinic
6. Received intravenous furosemide of at least 40 mg total (or equivalent) 
at any time between presentation (this includes outpatient clinic, 
ambulance, or hospital including emergency department) and the start 
of screening for the study for the treatment of the current acute HF 
episode
7. Impaired renal function defined as an eGFR between presentation and 
randomization of ≥ 25 and ≤75mL/min/1.73m2, calculated using the
sMDRD formula (or modified sMDRD formula according to specific 
ethnic groups and local practice guidelines). (Levey et al 2006; Ma et 
al 2006; Matsuo et al 2009; Townamchai et al 2013)
* 
Patient 
assessments 
of 
AHF 
that 
are 
per 
current 
local 
institutional/hospital standard protocol or part of routine clinical care that 
are performed within 16 hours from presentation are allowed before 
signing informed consent, and can be used to support patient screening.
Exclusion criteria
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.
Temperature >38.5°C (oral or equivalent), sepsis, active and clinically 
significant infection requiring IV anti-microbial treatment, or known 
presence or evidence of Human Immunodeficiency Virus (HIV) 
infection (based on history and/or clinical findings, including laboratory 
results obtained during screening period).
3.
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).
 


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4.
Patients with systolic blood pressure >180 mmHg at the end of 
screening
5.
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
6.
Patients with Hematocrit <25%, or a history of blood transfusion within 
the 14 days prior to screening, or active life-threatening 
gastrointestinal (GI) bleeding
7.
Significant uncorrected left ventricular outflow obstruction, 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), and severe mitral stenosis
8.
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 and carperitide), 
positive inotropic agents and vasopressors, or mechanical support 
(endotracheal intubation, mechanical ventilation; intra-aortic balloon 
pump or any ventricular assist device; hemofiltration, ultrafiltration or 
dialysis), with the exception of IV furosemide (or equivalent), or IV 
nitrates at a dose of ≤ 0.1 mg/kg/hour if the patient has a systolic 
BP >150 mmHg at screening.
9.
Hepatic disease unrelated to HF etiology and as determined by any 
one of the following: AST and/or ALT values exceeding 3 X ULN 
and/or bilirubin > 1.5 X ULN at screening, history of hepatic 
encephalopathy, esophageal varices, or portacaval shunt,  diagnosis 
of cirrhosis, chronic Hepatitis B or chronic Hepatitis C infection by any 
means (e.g. based on history,  clinical findings,  laboratory results or
imaging)
10. Major surgery, including implantable devices (e.g. ICD, CRT), or major 
neurologic event including cerebrovascular events, within 30 days prior 
to screening
11. Any major solid organ transplant recipient or planned/anticipated organ 
transplant within 1 year.  
12. History of malignancy of any organ system (other than localized basal 
cell carcinoma of the skin), treated or untreated, within the past year 
with a life expectancy less than 1 year
13. Pregnant or nursing (lactating) women, where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test
14. 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 following the cessation of study treatment. Highly effective 
contraception methods include: Total abstinence (when this is in line 
with the preferred and usual lifestyle of the subject). Periodic 
abstinence (e.g., calendar, ovulation, symptom thermal, post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception. Refer to Section 4.2 exclusion criteria #13 for complete 
details.
15. Use of other investigational drugs within 30 days prior to screening
16. History of hypersensitivity to serelaxin or its any ingredients
 


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17. History of participating in serelaxin clinical studies 
18. Inability to follow instructions or comply with follow-up procedures
19. 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 disorders, sufficient to interfere with the patient’s 
ability to comply with the protocol instructions or follow-up procedures
Investigational 
and 
reference therapy

Serelaxin (30 µg/kg/day) administered by body weight category 
(Table 5-1) infused over 48 hours

Placebo
Efficacy assessments
Primary efficacy assessment
The primary efficacy variable is defined as the clinical composite endpoint 
based on:

Treatment success defined as

Moderate /marked improvement in dyspnea by the Likert Scale at 
Day 2 AND   ≥ 2 points improvement in ≥2 of 4 physician 
assessed symptoms and signs of congestion (orthopnea, edema, 
rales and JVP) and none of them deteriorating (≥ 0 point 
improvement) at Day 2 Refer to the physician assessment of 
signs and symptoms, Section 15 Appendix 3.  

Treatment failure defined as

In-hospital worsening heart failure through Day 5 or 

All-causes of death through Day 5, or re-hospitalization due to 
heart failure or renal failure through Day 5

Unchanged defined as
All remaining patients are classified as having unchanged 
treatment status if they meet neither the criteria for treatment 
success at Day 2 nor the criteria for treatment failure through Day 
5.
If a patient is determined as treatment failure through Day 5, then he/she 
will be excluded from the assessment of treatment success at Day 2 or 
unchanged even if the patient experience improved signs and symptoms 
at Day 2.
Secondary assessments

Time to WHF through Day 5

Time to cardiovascular death during a follow-up period of 180 days

Time to all-cause death through a follow-up period of 180 days
Other secondary efficacy assessments:

Time to moderate or marked improvements in dyspnea by Likert scale 
through Day 5

Dyspnea by VAS-AUC changes through Day 5

Length of stay in index ICU/CCU

Renal dysfunction & prevention of in-hospital worsening of renal 
function through Day 5

Time to re-hospitalization due to HF and renal impairment through Day 
180

Time to CV death or re-hospitalization due to HF/RF through Day 180
 


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
Time to in-hospital worsening heart failure through Day 5 where the in-
hospital worsening heart failure is defined by symptoms only, signs 
only, and by both symptoms and signs

Use of loop diuretics and vasoactive agents through Day 5

Changes in cardio-renal biomarkers (Days 2 and 5)
Safety assessments

Physical examination

Vital signs

Height and weight

Laboratory evaluations

Electrocardiograph
Other assessments

Healthcare resource utilization (RU parameter)

Pharmacokinetics

Immunogenicity
Data analysis
The primary efficacy variable will be the trichotomous clinical composite 
endpoint based on (i) treatment ‘success’ of congestion improvement of 
dyspnea in Likert (moderately and markedly improvement) AND at least 2 
points improvement for at least 2 out of 4 signs and symptoms variables at
Day 2, (ii) treatment ‘failure’ of in-hospital worsening heart failure, death or 
re-hospitalization due to HF or RF through Day 5 and (iii) neither as ‘no 
change’.
The primary analysis will be the comparison of two trinomial distributions 
of trichotomous clinical composite endpoint between placebo and 
serelaxin groups. 
The primary statistical hypothesis is:
H0: ≥1 vs Ha: < 1
Where is the common value of two odds ratios of clinical composite 
endpoint (‘failure’ versus combined ‘no change’ and ‘success’ or combined 
‘failure’ and ‘no change’ versus ‘success’) between placebo and serelaxin. 
H0 is the null hypothesis and Ha is the alternative hypothesis (Whitehead 
1993). The hypothesis will be tested based on the FAS with an ordered 
logistic-regression (proportional odds) model that includes treatment and 
country as factors (McCullagh, 1980).  Given the classification of (-1 
denoting ‘failure’, 0 for ‘no change’ and 1 for ‘success’, an odds ratio of 
less than 1 would favor serelaxin.  The odds ratio and 95% confidence 
interval for the treatment effect will be calculated and presented.  There 
are three secondary variables: 

WHF through Day 5

CV death through Day 180  

All-cause death through Day 180. 
All of these secondary variables are time-to-event variables.  The
hypothesis will be tested based on the FAS at a significance level of 
0.025 (one-sided).
The three secondary variables will be tested using hierarchical testing 
procedure in controlling overall α of 0.05 (Bretz, et al 2009).  If primary 
endpoint is significant, WHF will be tested first at α of 0.05.  If WHF is 
significant at the same α level then will proceed to test CV death and only 
 


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if CV death is significant then will test all-cause death at α of 0.05.  
Time
to
WHF
through
Day
5
will
be
analyzed
using
Gehan’s 
generalized Wilcoxon test. Patients died in the 5-day period will be 
considered as having WHF event. Patients without an event will be
censored at the earlier of the last contact date or 120 hours after
randomization. 
Kaplan-Meier curves will be presented graphically by
treatment group and Kaplan-Meier estimates for selected time points with
95% confidence intervals will be tabulated.
CV death and all-cause death will be analyzed with a log-rank test. 
Number
and
percentage
of patients
who
died
from
cardiovascular
reasons
based
on the
number
of
patients
in
the
population
as
denominator will be provided by treatment group. 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, for CV death and all-cause death, 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.
For CV death, a patient without an event will be censored at the earlier of:

Date of death for non-CV related causes

The last date at which the vital status was known

Day 180
For all-cause death, a patient without an event will be censored at the last 
date at which the vital status was known or at Day 180.
Safety variables 
The incidence of adverse events (AEs) recorded through Day 5 and the
incidence of serious adverse events (SAEs) recorded through Day 14 will
be presented for the Safety Set. Incident AEs will be considered those
AEs with an onset date and time after the initiation of study drug.  
AEs with an onset between informed consent and study drug initiation
will be listed separately. AEs will be coded using MedDRA. 
All 
reported AEs will be summarized by system organ class (SOC) and
preferred term by treatment groups. SAEs will be summarized similarly.
Interim analysis
There will be no formal efficacy interim analysis.
Key words
Acute Heart Failure (AHF), Congestion, Worsening Heart Failure (WHF), 
Renal Impairment, Serelaxin, Biologic.
 


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1
Introduction
1.1
Background
Acute heart failure (AHF) is a major public health problem with high disease prevalence 
associated with high mortality, morbidity, and financial costs. It is the most common cause of 
hospitalization in patients 65 years and older (Hunt et al 2009). As its prevalence is projected 
to increase by 25% over the next 20 years (Heidenreich et al 2011), the burden of HF for 
health care systems will also increase.  Coronary artery disease and hypertension are common 
causes for AHF in Western countries (Yancy et al 2013, McMurray  et al 2012); similar 
etiology was also found in Asian countries in recent years (Jiang H and Ge J, 2009, Shiba  and 
Sjimokawa  2008, Oh et al 2013, Youn YJ, et al 2012).  Similar to the US and Europe, AHF 
remains an unmet medical need in Asian countries and the leading cause for hospital 
admissions (Goda et al 2009, Park et al 2010).
AHF is defined as the rapid onset of, or changes in, signs and symptoms of heart failure (HF)
requiring urgent therapy, which usually results in hospitalization (McMurray et al 2012). 
Recent HF registries consistently show that more than 80% of AHF patients present with 
dyspnea, 60-80% with renal impairment, and >50-75% with normal to elevated systolic blood 
pressure (BP) (Adams et al 2005, Gheorghiade et al 2006a, Gheorghiade et al 2006b, 
Gheorghiade et al 2009). AHF is triggered by a combination of (1) pulmonary, central and 
peripheral venous congestion and (2) hypoperfusion, both of which induce end organ damage 
and metabolic abnormalities. The pathophysiology of AHF remains complex, which can 
include abnormal ventricular systolic and/or diastolic function, myocardial injury as 
manifested by elevation of circulating cardiac troponin, vascular changes such as endothelial 
dysfunction, increased aortic impedance and left ventricular afterload, renal dysfunction 
precipitating sodium and fluid retention, as well as neurohormonal and inflammatory 
activations (Metra et al 2010a, Metra et al 2012).
AHF is a clinical syndrome with heterogeneous underlying pathophysiological changes. 
Multiple symptoms and signs of hypoperfusion and/or congestion can be presented in 
different AHF patients with varying severities.  Severity and changes in the symptoms and 
signs of congestion are the basis of the clinical management strategy (Yancy et al 2013, 
McMurray et al 2012). 
The importance of congestion in AHF as an essential target of evaluation and treatment has 
gained wide recognition (Gheorghiade et al 2006b).  One of the most important treatment 
targets for AHF patients is to relieve symptoms and signs of congestion as early as possi ble.  
While multiple signs and symptoms can be presented in AHF patients, dyspnea is one of the 
most common presenting symptoms of congestion and the most common physician-assessed 
signs and symptoms of congestion include dyspnea on exertion, orthopnea, rales, edema and 
elevated jugular venous pressure (JVP) (McMurray et al 2012, Gheorghiade et al 2010, 
Harinstein  et al 2011). The overall status and severity of congestion as assessed by various 
signs and symptoms such as orthopnea, rales, and JVP, is prognostic of clinical outcomes 
(Wang et al 2005, Wong et al 2007, Peacock et al 2010, Konstam et al 2011, Kelder et al 
2011, Drazner et al 2001, Drazner et al 2008, Ambrosy et al 2013). Furthermore, not all AHF 
 


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patients present with all of the symptoms and signs of AHF. Different types of clinical 
symptoms and signs can be developed in AHF patients with varying severities.  Therefore, it 
is incomplete to evaluate the disease status of AHF by assessing a single clinical symptom. 
Therefore, a clinical composite endpoint that comprises multiple signs and symptoms of 
congestion could reflect more holistically the status of congestion and a more clinically 
reliable indicator for therapeutic efficacy in clinical trials.
Although symptomatic relief does occur in a subset of patients following currently available 
AHF therapy within a few days of admission, such improvement is usually incomplete. 
Persistent or recurrent HF symptoms both during and after hospitalization contribute to the 
downward-spiral of disease progression with poor clinical outcomes. The presence of 
worsening HF symptoms confers a poorer prognosis for AHF patients (Damman et al 2007, 
Metra et al 2008). With currently available therapy, the mortality in AHF patients remains 
very high, e.g. 30 day, 1 year and 5 year mortalities are reportedly 10.4%, 22% and 42.3%
respectively (Lloyd-Jones et al 2010).
Therefore, the main clinical challenges in AHF management are to achieve optimal and 
sustained resolution of congestion, to prevent in-hospital worsening of heart failure and renal 
dysfunction, and most importantly, reduce both short- and intermediate-term mortality. 
However, current standard of care for AHF offers few options available to the practicing 
physicians and remains largely unchanged over the last few decades: oxygen in case of 
hypoxemia, loop diuretics, vasodilators, inotropes and opiates, with diuretics as the 
cornerstone of AHF therapy. These pharmacological treatments are focused on achieving 
short-term symptom relief and decongestion but none of these interventions has definitively 
shown a beneficial impact on either short- or intermediate-term mortality underscoring the 
significant unmet medical need in the AHF patient population (Hunt et al 2009, Yancy et al 
2013, McMurray et al 2012). In terms of standard of care, there are no marked differences 
among the guidelines established for the treatment of AHF in the US, Europe and Asian 
countries (JCS 2013, McMurray et al 2012, Yancy et al 2013, Lindenfeld et al 2010, Chinese 
Society of Cardiology 2011) although there are some variations in drugs approved in different 
countries, e.g. carperitide in Japan (JCS 2013). Based on guidelines listed above, there is
currently no Class 1, Level A guideline recommendations for pharmacological treatments of
AHF.
Relaxin (H2) is a naturally occurring peptide hormone associated with many of the maternal 
hemodynamic and renovascular changes that occur in response to pregnancy, such as systemic 
and renal vasodilation and increases in global arterial compliance (Conrad 2010, Conrad 
2011a, Conrad 2011b, Conrad and Shroff 2011). Relaxin’s activity is initiated by binding to 
its cognate receptor, relaxin family peptide receptor 1 (RXFP1), which is present in the 
systemic and renal vasculature as well as in human heart (Hsu et al 2002). Studies show that 
nitric oxide, endothelin type B receptor, vascular endothelial growth factor (VEGF) and cyclic 
adenosine monophosphate (cAMP) act as mediators for the vasodilatory as well as anti-
fibrotic and anti-inflammatory effects of relaxin (Bani et al 1998, Danielson et al 1999, 
Dschietzig et al 2003, Du et al 2010). With these pleiotropic effects, relaxin may benefit HF 
patients not only through its favorable hemodynamic effects but also via its protective effects 
on the heart and kidney, leading to potential mortality benefits.
 


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Serelaxin is a recombinant protein identical in structure to the naturally occurring H2 relaxin. 
Its efficacy and safety in AHF patients as a continuous intravenous (IV) infusion for up to 48
hours was evaluated in two multicenter, randomized, double-blind, placebo-controlled trials, 
including the dose-finding phase II study Pre-RELAX-AHF (Teerlink et al 2009), which 
determined the optimal dose of 30 μg/kg/day to be used in the phase III pivotal study 
RELAX-AHF (Teerlink et al 2013).  
In the RELAX-AHF study, 1,161 AHF patients were randomized to receive either serelaxin 
(N=581) or matching placebo (N=580) on the background of standard of care AHF treatment. 
Serelaxin was administered according to a weight-range adjusted dosing regimen at the 
nominal dose of 30 μg/kg/day. The 48-hour intravenous infusion of serelaxin produced 
dyspnea relief as demonstrated by a 19.4% treatment improvement compared to placebo 
measured over 5 days by visual analogue scale (VAS), representing one of the two primary 
efficacy endpoints in the study. In addition, serelaxin treatment reduced signs and symptoms 
of congestion and significantly reduced WHF episodes through Day 5 and the overall length 
of index hospital stay, associated with arrange of other in-hospital clinical benefits. 
Importantly, sustained benefits beyond the initial 48 hours of therapy were observed with 
serelaxin treatment, leading to a clinically and statistically significant 37% reduction in the 
risk of both CV and all-cause mortality through Day 180 (Teerlink et al 2013). These clinical 
improvements were associated with significant improvements in biomarkers consistent with 
reduction in end-organ damage in serelaxin treated patients (Metra et al 2013).  With respect 
to safety, the adverse event profile after study drug exposure was generally comparable 
between serelaxin and placebo. Although more patients treated with serelaxin had blood 
pressure decreases, the decrease was manageable; the incidence of hypotension was 
comparable between serelaxin and placebo groups.  Fewer patients in the serelaxin arm had an 
increase of serum creatinine > 0.5 mg/dL at Day 5 versus placebo (p=0.003). There were also 
fewer treatment emergent events associated with renal impairment, which may indicate 
preserved renal function. Overall, the data demonstrated that serelaxin was generally safe and 
well- tolerated.
A confirmatory phase III study RELAX AHF2 (CRLX030A2301) with randomization to 48 
hour intravenous administration of serelaxin or placebo within 16 hours of clinical 
presentation in AHF patients in geographic regions similar to RELAX-AHF trial is planned to 
further assess the effect of serelaxin on CV death and other clinical outcomes in addition to 
safety and tolerability.  The primary objective of RELAX AHF2 is to demonstrate that 
serelaxin is superior to placebo in reducing CV death in AHF patients during a follow-up 
period of 180 days. Data from this study is intended to replicate the reduction in mortality in 
AHF patients observed in the RELAX-AHF trial.
In order to evaluate the sensitivity in response to serelaxin, a double-blind, placebo-controlled, 
parallel-group study (CRLX030A2103) was conducted to evaluate the safety, tolerability, and 
PK/PD in Japanese and Caucasian healthy volunteers. In this study, a 48 hour intravenous 
infusion of serelaxin at 10, 30 or 100 μg/kg/day dose rates (based on individual body weight) 
or placebo was given to Japanese healthy subjects (N=32) and compared to a Caucasian 
cohort (n=8) also received a 48 hour intravenous infusion of serelaxin at 30 μg/kg/day.  
Japanese and Caucasian subjects were matched in a pair-wise manner by age, gender and 
 


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weight. Plasma concentrations in Japanese subjects treated intravenously with serelaxin 30 
µg/kg/day for 48 hours were similar to those in Caucasian subjects treated in the same manner. 
Values of other PK parameters (Tmax, Cmax, T1/2, CL, Vss, and MRT) were also similar in 
Japanese subjects and Caucasian subjects. In addition, statistically significant dose 
proportionality was shown for the area under the serum concentration time curve over the 
entire serelaxin dose rate range (10–100 μg/kg/day) in Japanese subjects demonstrating a 
linear PK profile. There was also no difference in blood pressure between the two populations. 
Pharmacodynamic parameters in urine (sodium, potassium, chloride, creatinine, urea, and 
osmotic pressure) showed no clinically important changes. Overall, there were no apparent 
differences with regards to safety and tolerability between the Japanese and Caucasian healthy 
subjects.
The current study is a multinational randomized, double-blind, and placebo-controlled Phase 
III clinical trial to be conducted primarily in Asian countries for the generation of clinical 
evidence in AHF patients to fulfill the requirements by the local health authorities in these 
countries.  The trial is designed to demonstrate the clinical benefits in early relief of signs and 
symptoms of congestion and prevention of in-hospital worsening of heart failure by serelaxin 
on top of standard of care.  The study will also collect evidence to evaluate the effect of 
serelaxin on the reduction of CV mortality in Asian AHF patients.
1.2
Purpose 
The purpose of this study is to evaluate the efficacy, safety and tolerability of intravenous 
infusion of 30 μg/kg/day serelaxin for 48 hours within 16 hours of clinical presentation, when
added to standard therapy, in approximately 1,520 primarily Asian AHF patients randomized 
to receive serelaxin or placebo to demonstrate superiority in early improvement in signs and 
symptoms of congestion and reduction in in-hospital worsening heart failure as evaluated by a 
clinical composite as the primary endpoint. In addition the study will also assess the effect of 
serelaxin on the cardiovascular and all-cause deaths as listed as secondary endpoint; the 
results of which will be interpreted along with the results from other global studies.
2
Study objectives
2.1
Primary objective(s)

To demonstrate that serelaxin is superior to placebo in improving the clinical composite of 
“treatment success,” “treatment failure” and “ unchanged”

Treatment success is defined as moderate or marked improvement in patient reported 
dyspnea by Likert scale AND ≥ 2 points improvement for at least 2 out of 4 physician 
assessed signs and symptoms including orthopnea, rales, edema and JVP and none of 
them deteriorating (≥ 0 point improvement) at Day 2. 
Refer to the Efficacy assessment 1 Section 6.4.1 and the physician assessment of 
signs and symptoms Section 15 Appendix 3.

Treatment failure is defined as in-hospital worsening of heart failure or re-
hospitalization due to HF or RF or death through Day 5. 
 


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
All remaining patients are classified as having unchanged treatment status if they 
meet neither the criteria for treatment success at Day 2 nor the criteria for treatment 
failure through Day 5.  
Worsening heart failure (WHF) is defined as in-hospital worsening signs and/or symptoms of 
heart failure that require an intensification of intravenous therapy for heart failure or 
mechanical ventilator, 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 mechanical ventilation, ultrafiltration, hemodialysis, 
intra-aortic balloon pump or ventricular assist device.
2.2
Secondary and other efficacy objectives
Secondary objectives

To evaluate the effect of serelaxin as compared to placebo on reducing time to in-hospital 
worsening heart failure through Day 5

To evaluate the effect of serelaxin as compared to placebo  on reducing cardiovascular 
deaths through a follow-up period of 180 days

To evaluate the effect of serelaxin as compared to placebo on reducing all-cause deaths 
during a follow-up period of 180 days
Other efficacy objectives

To evaluate the effect of serelaxin as compared to placebo on reducing time to moderate 
or marked improvements in dyspnea assessed by Likert scale through Day 5

To evaluate the effect of serelaxin as compared to placebo on changes of dyspnea by 
VAS-AUC through Day 5

To evaluate the effect of serelaxin as compared to placebo on reducing the time in index 
ICU/CCU through Day 5

To evaluate the effect of serelaxin as compared to placebo on prevention of renal 
dysfunction or worsening of renal function through Day 5

To evaluate the effect of serelaxin as compared to placebo on reducing the time to re-
hospitalization due to HF and renal failure through Day 180

To evaluate the effect of serelaxin as compared to placebo on reducing the composite 
endpoint of CV death or re-hospitalization due to HF/renal failure through Day 180

To evaluate the effect of serelaxin as compared to placebo on time to in-hospital 
worsening heart failure through Day 5 where the in-hospital worsening heart failure is 
defined by symptoms only, signs only, and both symptoms and signs

To evaluate the effect of serelaxin as compared to placebo on reducing the total
intravenous loop diuretic dose, vasoactive and inotropes drug usage through Day 5 

To evaluate the effect of serelaxin as compared to placebo on the changes from baseline in 
cardio-renal biomarkers on Days 2 and 5
Safety

To evaluate the safety and tolerability of intravenous serelaxin in AHF patients.
 


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3
Investigational plan
3.1
Study design
Figure 3-1
Study design
If the discharge visit coincides with a scheduled visit, only the discharge visit will be performed.
Presentation starts as the earliest of (1) time of presentation at either the ER/ED, ICU/CCU, outpatient 
clinic or ward, (this excludes EMS); or (2) time of first IV loop diuretic prior to arrival at the hospital (this 
includes outpatient clinic, ambulance, or hospital including emergency department) for the current 
acute HF episode.
This is a multicenter, randomized, double-blind and placebo-controlled, Phase III clinical trial 
in primarily multiple Asian countries, designed to evaluate the efficacy and safety of an 
intravenous infusion of serelaxin when added to standard of care therapy in AHF patients.  
After assessing eligibility during the screening period, patients who meet the study eligibility
criteria will be randomized 1:1 using Interactive Response Technology (IRT)/Interactive Web 
Response System (IWRS) to receive an intravenous infusion of either serelaxin or placebo in 
a double-blind manner for up to 48 hours (Figure 3-1). These patients must be randomized 
within 16 hours of presentation. Presentation starts as the earliest of (1) time of presentation at 
either the ER, ICU/CCU, outpatient clinic or ward, (this excludes EMS); or (2) time of first 
IV loop diuretic prior to arrival at the hospital (this includes in outpatient clinic, ambulance, 
or hospital including emergency department) for the current acute HF episode. 
Serelaxin (and/or matching placebo) will be administered as a continuous intravenous 
infusion for 48 hours according to a weight-range adjusted dosing regimen (see Table 5-1) at 
the nominal dose of 30 μg/kg/day. Due to the potential risk of hypotension, blood pressure 
should be monitored regularly during the administration of study drug. If at any time during 
dosing, the patient’s systolic BP is decreased by >40 mmHg from baseline but the absolute 
systolic BP is ≥100 mmHg in two consecutive measurements 15 minutes apart, the study drug 
infusion rate should be decreased by 50% for the remainder of the infusion period. If the 
patient’s systolic BP falls to <100 mmHg in two consecutive measurements 15 min apart, 
 


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study drug must be permanently discontinued. 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 measurements should be recorded
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 in Section 6.5.2. If hypotension persists beyond the 5 hours 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 hours post 
event should be captured in the source documents; only heart rate and blood pressure 
outlined in Section 6.5.2 will be entered into the eCRFs.
All randomized patients will be assessed daily up to and including Day 5, and then followed 
up at scheduled visits for a period of 180 days. They are required to re ceive standard of care 
treatment for HF during both the index hospitalization and post discharge per local and 
institutional practice guidelines. Visits to assess efficacy are scheduled on Days 5, 14 
(telephone), 30 (telephone), 60, 120 and 180. All AEs will be collected up to and including 
Day 5 and all serious adverse events (SAEs) will be collected up to and including Day 14, 
regardless of suspected causality. After Day 14 only suspected SAEs will be collected and 
reported to Novartis.    
3.2
Rationale of study design
This confirmatory Phase III study in Asian AHF patients is designed as a multicenter, 
randomized, double-blind, and placebo-controlled, study in order to assess the efficacy and
safety of intravenous infusion of serelaxin for 48 hours with a weight-range adjusted regimen 
targeted at approximately 30 μg/kg/day. The AHF patients randomized to either serelaxin or 
placebo in the study will be followed for a period of 180 days, and ar e required to receive 
standard of care background HF management during both the index hospitalization and post 
discharge according to regional or local guidelines/institutional standards.
The decision of choosing a clinical composite that is comprising of treatment success, 
treatment failure and unchanged, as the study primary endpoint is based on complex 
pathophysiology underlying AHF and the therapeutic goals of AHF treatment.  Treatment 
success at Day 2 targets an early improvement in congestion, and treatment failure through 
Day 5 aims to prevent clinical worsening of HF, re-hospitalization for HF or RF and death. 
The clinical composite endpoint of these components is designed to assess the efficacy of 
serelaxin to the standard care for early and sustainable benefits.  It is generally accepted that 
one of the most important treatment targets for AHF patients is to relieve symptoms and signs 
of congestion as early as possible (Gheorghiade et al 2006b).  While multiple signs and 
symptoms can be presented in AHF patients, dyspnea is the most common presenting 
symptom of congestion in AHF patients and the most common physician-assessed signs and 
symptoms of congestion include dyspnea on exertion, orthopnea, rales, edema and JVP
(McMurray et al 2012, Gheorghiade et al 2010, Harinstein et al 2011).  It is known that not all 
AHF patients present with all of the symptoms and signs of congestion. Different types of 
clinical symptoms and signs can be developed in AHF patients with varying severities.  
 


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Therefore, it is incomplete to evaluate the disease status of AHF by assessing a single clinical 
symptom.  In this study the treatment success at Day 2 is defined by both the moderate or 
marked improvement in patient reported dyspnea and 2 or more points of improvement in at 
least 2 out of 4 physician assessed signs of congestion and none of them deteriorating (≥ 0 
point improvement).  Thus, treatment success requires both relief of patient-reported dyspnea 
and improvement in physician-assessed signs and symptoms of congestion. This requirement 
of significant early improvement in multiple signs and symptoms of congestion for treatment 
success is stringent in recognizing that standard care is generally effective in improving some
of the symptoms, e.g. dyspnea.  Therefore, a clinical composite endpoint with treatment 
success as one of the components that is comprised of multiple signs and symptoms of 
congestion could reflect more holistically the status of congestion and a more clinically 
reliable indicator for therapeutic efficacy in clinical trials. In summary, the treatment success 
definition reflects the goals of acute heart failure treatment (ie, relief of dyspnea AND 
congestion) and represents a comprehensive assessment of the treatment effect.
The clinical composite endpoint has been used as a primary endpoint in several large scale 
Phase 3 clinical studies in AHF. The major studies include PROTECT study (Massie 2010), 
REVIVE-2 study (Packer 2013) and the ongoing TRUE-AHF study (Cardiorentis 2013). To 
assess “treatment success”, all the above mentioned 3 studies used a single patient’s self-
report clinical symptom, such as improvement in dyspnea assessed by Likert scale or 
improvement in the overall clinical status. The definition of “treatment success” in this 
RELAX current trial requires both patient-reported improvement in dyspnea assessed by 
Likert scale and physician-assessed symptoms and signs of congestion (orthopnea, edema, 
rales and JVP) at Day 2, which is relatively holistic and objective in relation to the clinical 
status of congestion and reflects the clinical practice adopted worldwide for the treatment of 
AHF. (JCS 2013, McMurray et al 2012, Yancy et al 2013, Lindenfeld et al 2010, Chinese 
Society of Cardiology 2011) If a patient is determined as treatment failure, he/she will be
excluded from the assessment of treatment success or unchanged even if the patient 
experienced improved signs and symptoms at Day 2 (i.e., the patient will be considered a 
treatment failure).
Although there are some variations in the definition of the individual components of the 
clinical composite, the definition of “treatment failure” in this study, is similar to the one used 
in the above mentioned 3 studies.  The treatment failure in the current study is defined as 
occurrence of WHF, or death or re-hospitalization due to HF or RF through Day 5.  The WHF 
is defined as worsening signs and/or symptoms of heart failure that require an intensification 
of intravenous therapy for heart failure or mechanical ventilatory, 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 mechanical 
ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or ventricular assist device. 
This definition of WHF is widely accepted (Felker et al 2010, Allen et al 2009) and applied to 
the above trials. 
The primary objective of this study is to demonstrate and confirm the efficacy of serelaxin as 
compared to placebo to improve the symptoms and signs of congestion at Day 2 and to
prevent in-hospital worsening heart failure through Day 5 in Asian AHF patients - an efficacy 
benefit that was observed in the completed RELAX-AHF study. In addition, CV death and 
 


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all-cause death will be assessed as secondary endpoints in this study; the results of which will 
be interpreted along with the results from other global studies.
3.3
Rationale of dose/regimen, route of administration and duration
of treatment
The weight-range adjusted dose regimen of serelaxin (see Table 5-1 in Section 5.5.4) at the 
nominal dose of 30 μg/kg/day and studied in RELAX-AHF study will be evaluated in this 
phase III confirmatory study, and serelaxin will be administrated via continuous intravenous 
infusion for 48 hours during the most critical early period of AHF patient management to 
achieve decongestion, hemodynamic improvement and end organ protection.
For patients who experience significant systolic BP decrease during the 48-hour study drug 
infusion, protocol-specified dosing adjustments and/or discontinuations rules must be 
followed to ensure patient safety (refer details in Section 5.5.5). In the completed RELAX-
AHF study, serelaxin treatment significantly improved signs and symptoms of congestion at 
Day 2, 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 safety and tolerability 
profiles. Importantly, serelaxin provided sustained benefits beyond the initial 48 hours of 
therapy leading to a clinically and statistically significant 37% reduction in both CV and all -
cause mortality through Day 180 (Teerlink et al 2013). The favorable results of both efficacy 
and safety were observed in the RELAX-AHF study and the results from the pharmacokinetic 
(PK) study that showed no evidence of ethnic sensitivity support the adoption of the same 
weight-based dosing regimen of serelaxin administration in this confirmatory study in Asian 
AHF patients. The weight category of 30 – 39 kg for dosing is added to accommodate for the 
possibility of lower body weight in Asian population. 
3.4
Rationale for choice of comparator
The current study is designed to demonstrate that serelaxin is superior to placebo on top of 
standard of care therapy in improving the clinical composite based on improvement in
symptoms and signs of congestion and reduction in in-hospital worsening heart failure, re-
hospitalization for HF or RF or death as assessed by treatment success, treatment failure and 
unchanged. There is no evidence based therapy that has been shown to result in both short-
term clinical improvements and long- term mortality benefit in AHF and thus an active 
comparator is not available. All patients in this study, however, will be required to receive 
standard of care background HF management during the entire study period.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable
3.6
Risks and benefits 
Serelaxin infused for 48 hours in both the pre-RELAX-AHF (Teerlink et al 2009) and
RELAX-AHF study (Teerlink et al 2013) demonstrated significant improvement in dyspnea 
and signs and symptoms of congestion. It was also associated with significant reductions in 
early in-hospital worsening heart failure events and length of stay during the index 
 


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hospitalization including duration of intensive care. Reductions in both cardiovascular and all-
cause mortality were observed in the serelaxin-treated patients in RELAX-AHF. Pre-specified 
biomarker changes suggest that serelaxin therapy has a protective effect on both the heart and 
kidney, supporting the mortality benefit. 
Serelaxin was generally well-tolerated with no notable differences in the overall adverse event 
profile compared to placebo. Although blood pressure can decrease in a portion of patients 
due to the vascular mechanism of action of the drug, worse outcomes were not observed in 
these patients. The current instructions for the management of SBP, including close and 
careful monitoring as well as mandatory dose adjustment or stopping rules, which were 
utilized during RELAX-AHF, support that current safety rules and management of SBP are 
both robust and sufficient.
The risk to patients participating in study will be minimized by compliance with the eligibility 
criteria and close clinical monitoring, which proved effective during the RELAX-AHF trial. 
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 this study will be required to 
receive standard of care background HF management during hospitalization as well as the 
follow-up period of 180 days.
4
Population
The study population will consist of AHF patients who typically present with normal to 
elevated BP and decreased renal function. The study is aimed to randomize approximately 
1,520 patients that meet the eligibility criteria (inclusion criteria Section 4.1, exclusion criteria
Section 4.2), primarily, in but not limited to, Asian countries. 
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 
is determined to meet all eligibility criteria):
1. Written informed consent must be obtained before any study-specific assessment is 
performed*
2. Male or female  ≥ 18 years of age, with body weight ≥30kg and ≤160 kg
3. Hospitalized for AHF; AHF is defined as including all of the following measured at any 
time between presentation (including the emergency department and outpatient clinic) and 
the end of screening:

Persistent dyspnea at rest or with minimal exertion at screening and at the time of 
randomization

Pulmonary congestion on chest radiograph

BNP ≥500 pg/mL or NT-proBNP ≥2,000 pg/mL
4. Systolic BP ≥125 mmHg at the start and at the end of screening
 


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5. Able to be randomized within 16 hours from presentation to the hospital, including the 
emergency department and outpatient clinic.
6. Received intravenous furosemide of at least 40 mg total (or equivalent) at any time 
between presentation (this includes outpatient clinic, ambulance, or hospital including 
emergency department) and the start of screening for the study for the treatment of the 
current acute HF episode
7. Impaired renal function defined as an eGFR between presentation and randomization of ≥
25 and ≤75mL/min/1.73m2, calculated using the sMDRD formula (or modified sMDRD 
formula according to specific ethnic groups and local practice guidelines). (Levey et al 
2006; Ma et al 2006;  Matsuo et al 2009; Townamchai et al 2013).
* Patient assessments of AHF that are per current local institutional/hospital standard 
protocol or part of routine clinical care that are performed within 16 hours from presentation
are allowed before signing informed consent, and can be used to support patient screening.
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. Temperature >38.5 ° C (oral or equivalent), sepsis, active and clinically significant
infection requiring IV anti-microbial treatment or known presence or evidence of Human 
Immunodeficiency Virus (HIV) infection (based on history and/or clinical findings, 
including laboratory results obtained during screening period). 
3. 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).
4. Patients with systolic blood pressure >180 mmHg at the end of screening
5. 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
6. Patients with Hematocrit <25%, or a history of blood transfusion within the 14 days prior 
to screening, or active life-threatening gastrointestinal (GI) bleeding
7. Significant uncorrected left ventricular outflow obstruction, 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), and severe mitral stenosis
8. Current (within 2 hours prior to randomization) or planned (through the completion of 
study drug infusion) treatment with any IV vasoactive therapies, including vasodilators 
 


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(including nesiritide and carperitide), positive inotropic agents and vasopressors, or 
mechanical support (endotracheal intubation, mechanical ventilation; intra-aortic balloon 
pump or any ventricular assist device; hemofiltration, ultrafiltration or dialysis), with the 
exception of IV furosemide (or equivalent), or IV nitrates at a dose of ≤0.1 mg/kg/hour if 
the patient has a systolic BP >150 mmHg at screening.
9. Hepatic disease unrelated to HF etiology and as determined by any one of the following: 
AST and/or ALT values exceeding 3 X ULN and/or bilirubin > 1.5 X ULN at screening,  
history of hepatic encephalopathy, esophageal varices, or portacaval shunt,  diagnosis of 
cirrhosis, chronic Hepatitis B or chronic Hepatitis C infection  by any means (e.g. based 
on history,  clinical findings,  laboratory results or imaging)
10. Major surgery, including implantable devices (e.g. ICD, CRT), or major neurologic event 
including cerebrovascular events, within 30 days prior to screening
11. Any major solid organ transplant recipient or planned/anticipated organ transplant within 
1 year.  
12. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past year with a life expectancy less than 1 year
13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test
14. 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 following the cessation of study treatment. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptom thermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that 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
For Japan only: Japan approved contraceptive method should be used for patients 
that are recruited to the study
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 drug..
 


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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment she is considered not of child bearing 
potential
15. Use of other investigational drugs within 30 days prior to screening
16. History of hypersensitivity to serelaxin or its any ingredients
17. History of participating in serelaxin clinical studies 
18. Inability to follow instructions or comply with follow-up procedures
19. 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 disorders, sufficient to interfere with the patient’s 
ability to comply with the protocol instructions or follow-up procedures
5
Treatment
5.1
Protocol requested treatment
5.1.1
   Study and control drugs
Serelaxin (and/or matching placebo) 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 can be withdrawn from the vials contained in the blinded kits, injected 
into a 250 mL intravenous bag of 5% dextrose solution, and then infused through a dedicated 
IV line according to instructions in the Pharmacy Manual.
An independent pharmacist or qualified site personnel will prepare the drug for infusion 
according to the randomization number that is assigned by IRT/IWRS (Section 5.3). In 
addition an independent study field monitor will be appointed to perform the drug 
accountability at the sites.   
The roles and responsibilities of the pharmacist or qualified site personnel and the field
monitor as well as the operational aspect of this model are described in the Pharmacy Manual.
5.1.2
Additional  treatment
No additional treatment beyond study drug and control drug is included in this trial.
Nevertheless, patients randomized to either serelaxin or placebo in this study will all be 
required to receive standard of care background HF management during both the index 
hospitalization and post discharge according to the regional or local guidelines/institutional 
standard. This treatment can include but is not limited to intravenous and/or oral diuretics, 
 


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ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor
antagonists, etc.
5.2
Treatment groups
Subjects will be randomized 1:1 to receive continuous intravenous infusion of one of the 
following treatment assignments for 48 hours:

Placebo

Serelaxin (30 μg/kg/day)
5.3
Treatment assignment, randomization 
At baseline, all eligible patients will be randomized via IRT to one of the treatment groups. 
The investigator or his/her delegate will contact the IRT/IWRS after confirming that the 
patient fulfills all the inclusion/exclusion criteria. The IRT/IWRS will assign a randomization 
number to the patient, which will be used to link the patient to a treatment group and will 
specify a unique medication number 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 and concealed from patients and investigator staff. A patient randomization list 
will be produced by the IRT/IWRS 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 groups, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of 
Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s).
The randomization scheme for patients will be reviewed and approved by a member of the IIS 
Randomization Group. 
Misrandomized patients are those who have not been qualified for randomization, have been
inadvertently randomized into the study and who did not take study drug. Misrandomized
patients are defined as cases where IRT/IWRS contacts were made by the site either 
prematurely or inappropriately prior to confirmation of the patient’s final randomization 
eligibility and double-blind medication was not administered to the patient. These patients 
should subsequently be discontinued from the study.
5.4
Treatment blinding 
This will be a double-blind study. Patients, investigator staff, persons performing the
assessments, and data analysts will remain blind to the identity of the treatment from the time 
of randomization until database lock, using the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the exception of the independent
unblinded statistician, programmer and data manager/data coordinator (and assistant as 
required) from an external and independent Data Analysis Center, who need to have 
 


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access to prepare safety and/or efficacy interim analysis reports for the Data Monitoring 
Committee (DMC). The aforementioned study personnel will not be involved in any other 
trial activities.

Study drug will be prepared by an independent pharmacist or qualified site personnel.
Drug accountability at the sites will be performed by an independent study field monitor. 
Although unlikely, the independent pharmacist or qualified site personnel and the field 
monitor may potentially be unblinded due to the physical presence of the study drug 
during preparation therefore, the aforementioned study personnel will not be involved in 
any other trial activities. 

The identity of the treatments will be concealed by the use of study drugs that are identical
in packaging, labeling, schedule of administration and appearance.

Unblinding should only occur in the case of patient emergencies (see Section 5.5.12), 
and at the conclusion of the study. In the event a patient becomes unblinded for any reason 
other than safety concerns they should continue study treatment and assessments 
according to the protocol. The independent pharmacist or qualified site personnel must not 
communicate drug information to any other personnel including investigators, study 
coordinators or other pharmacists at the study site and/or sponsor involved in this trial.

In the event a patient becomes unblinded for safety reasons during the 48 hour study drug 
infusion, study drug should be discontinued and the patient should continue study 
assessments according to protocol.

The randomization codes associated with patients/subjects from whom PK samples are 
taken will be disclosed to PK analysts who will keep PK results confidential until data 
base lock.

The roles and responsibilities of the pharmacist or qualified site personnel and the field 
monitor as well as the operational aspect of this model are described in the Pharmacy 
Manual.
5.5
Treating the patient  
5.5.1
   Patient numbering 
Each patient is uniquely identified by a Patient Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. A center number 
is also assigned by Novartis to the investigative site. Once assigned to a patient, the Patient
Number will not be reused.
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given 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/IWRS. The site 
must select the CRF book with a matching Patient Number from the RDC system to enter data.
If an enrolled patient fails to be treated for any reason, the IRT/IWRS must be notified within 
2 days that the patient was not treated. The reason for not being treated will be entered on the 
Screening Epoch Study Disposition CRF.
 


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If the patient was correctly randomized in the IRT/IWRS, but treatment was not administered 
for any reason, the patient must be followed and assessments completed as per Table 6-1 for 
all the visits until Day 180 All information must be entered into the appropriate eCRFs.
5.5.2
Dispensing the study drug
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance. Blinded kits will contain 1 vial of serelaxin or placebo, enough study drug for 24 
hours of infusion.  Patients with body weight ≥115kg will need 2 vials for a 24h infusion. To 
receive the second 24 hours of study drug, the investigator’s staff will contact the IRT/IWRS
again and request a second kit.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 2 treatment arms. On the first day of the 
infusion, the independent pharmacist or qualified site personnel will identify the study drug
package(s) to dispense to the patient by contacting the IRT/IWRS and obtaining the 
medication number(s). Treatment preparation and dispensing should be performed following 
the procedure, using the material, and within the time laps specified in the Pharmacy Manual 
(see Section 5.1.1).
The study drug must not be administered to the patient by the person who prepared it.
5.5.3
Handling of study drug
5.5.3.1
Handling of study drug
Study drug 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 independent pharmacist 
or qualified site personnel and designated assistants have access. Upon receipt, all study drug
should be stored in a refrigerator at 2-8°C and protected from light 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 drug and no information about the 
patient. 
The independent pharmacist or the qualified site personnel must maintain an accurate record 
of the shipment, storage and dispensing of study drug in a drug accountability log. Monitoring 
of drug accountability will be performed by the independent field monitor (who is separate 
from the monitor who is accountable for the other portions of the study) during site visits and 
at the completion of the trial.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.12), and at the
conclusion of the study. At the conclusion of the study, and as appropriate during the course 
of the study, the independent pharmacist or the qualified site personnel will return all unused 
study drug, packaging, drug labels, and a copy of the completed drug accountability log to the 
Novartis monitor or to the Novartis address provided in the investigator folder at each site.
 


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5.5.4
Instructions for prescribing and taking study drug
The study drug infusion will begin after the signing the ICF and the completion of all 
screening procedures, and continue for 48 hours. Study drug should be administered in a 
dedicated IV line as soon as possible but no longer than 4 hours after randomization. Patients 
need to be randomized WITHIN 16 hours from the time of presentation to hospitals  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 3.5 mL fill) contained in the blinded kits, injected into a 
250 mL intravenous bag of 5% dextrose solution, and then infused at a constant rate of 10 
mL/hour. 
Details of study drug preparation and infusion as well as the roles and responsibilities of the 
independent pharmacist or qualified site personnel and the field monitor, are described in the 
Pharmacy Manual.
Table 5-1
Weight-range adjusted dosing regimen of serelaxin (or placebo)
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
5.5.5
Permitted dose adjustments and interruptions of study drug
For patients who experience a systolic BP decrease during the period of study drug infusion, 
dosing adjustments and/or discontinuations are required and must follow the guidelines 
described in Table 5-2.
Table 5-2
Dosing adjustment of study drug administration in the event of 
treatment-emergent systolic BP decrease
Changes in systolic BP during 
infusion*
Adjustments of study drug administration
Decrease >40 mmHg from pre-
treatment at baseline, 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 systolic BP to 
<100 mmHg
Permanently terminate 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.
Body weight (kg)
Serelaxin or 
placebo (mg)
Volume of serelaxin or placebo to be added to 250 mL IV 
bag of sterile 5% dextrose for intravenous infusion over a 
period of 24 hours
30-39 kg
1.5 mg
1.5 mL
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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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 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 in general for up to 1 hour in each 24-hour infusion period. If 
the infusion is stopped for longer than 1 hour, the infusion should still be allowed to continue 
as long as it is safe for the patient. This time is not to be added back to the end of the infusion 
and the timed protocol assessments are not to be adjusted. Time from initiation of study drug 
infusion to completion must not exceed 48 hours. 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.
These changes must be recorded on the Dosage Administration Record CRF.
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 and/or supportive care must be recorded on the
appropriate eCRF.
5.5.7
Concomitant treatment 
To be eligible for the study, all patients must have received IV furosemide of at l east 40 mg 
(or equivalent) at any time between presentation to emergency services (this includes 
outpatient clinic, ambulance, or hospital including emergency department)  and screening for 
the study.
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 and carperitide), positive inotropic agents and vasopressors, or mechanical support 
(intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular 
assist device), with the exception of IV furosemide (or equivalent), or IV nitrates at a dose of 
< 0.1 mg/kg/hr if the patient has a systolic BP > 150 mmHg at screening. Use of IV 
furosemide (40 mg or equivalent) is an inclusion criterion; further doses of IV furosemide can 
be administered at any time after enrollment.  Furosemide may not be administered using the 
same infusion bag or infusion line as study drug.
Major cardiovascular and non-cardiovascular classes of medication taken by a subject 
approximately 30 days prior to study drug initiation and on a daily basis while hospitalized 
through Day 5, at Discharge, Days 14 and 30 (telephone visit) and at Days 60, 120 and 180 
will be recorded. Only those medications currently being taken or those were taken within 24 
hours prior to the visit will be collected. These include but are not limited to: loop diuretics, 
other diuretics, ACE inhibitors, angiotensin receptor antagonists, beta-blocker, hydralazine, 
nitrates, calcium channel blockers, digoxin, non-steroidal anti-inflammatory agents, COX-2 
inhibitors, aminoglycoside antibiotics, inotropes, vasodilators and others (e.g. insulin, oral 
anti-diabetics, statins, anticoagulants etc.).
 


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The investigator may prescribe any additional medications during the study as dictated by the 
patients’ condition. Administration of standard treatment should in no instance be delayed or 
withheld due to patient’s participation in the study. Standard treatment includes, but is not 
limited to, administration of the major classes of medications, as described above, 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 should instruct the 
patient to notify the investigator or associated study personnel about any new medications 
he/she takes after the patient was enrolled into the study.
5.5.8
Prohibited Treatment 
Use of IV vasoactive therapies within 2 hours prior to randomization is an exclusion criterion 
(#7) with the exception of IV loop diuretics in any patient, or IV nitrates at a dose of ≤ 0.1 
mg/kg/hour if the patient has a systolic BP >150 mmHg at screening. Thus, study drug can 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 dictated by 
the patients’ condition. Administration of standard treatment should never be delayed or 
withheld due to patient’s participation in the study. The investigator should exercise caution 
when up-titrating or adding concomitant standard therapies that might decrease BP during 
study drug infusion. Investigator may consider not administering all BP lowering medication 
simultaneously. Changes to these medications during the index hospitalization should be 
recorded on the eCRF.
5.5.9
Discontinuation of study treatment
The investigator should 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:

If the patient’s systolic BP falls to <100 mmHg in two consecutive measurements 15 min 
apart, study drug must be permanently discontinued.  Measures may be taken by the 
investigator to address the decrease in blood pressure during the intervening 15 minutes, if 
clinically indicated (see details in Table 5-2).

Pregnancy

Any significant risk to the patient’s safety
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study.  They should be followed per the visit/assessment schedule illustrated in Table 6-1 until 
the study is complete. If they fail to return for these assessments for unknown reasons, every 
effort should be made to contact them.
For any patient(s) whose treatment code has been broken inadvertently for any reason, study 
drug treatment should be continued.
 


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5.5.10
Withdrawal of informed consent
Patient may voluntarily withdraw consent to participate in 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.
In this situation, 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, and the data that would have been collected at subsequent visits will 
be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessments Table 6-1.
5.5.11
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by  
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed. 
5.5.12
Emergency breaking of assigned treatment code
Emergency treatment code breaks must only be undertaken when it is required in order to 
treat the patient safely. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. 
Emergency treatment code breaks will be performed using the IRT/IWRS. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Global Trial Leader (GTL) 
that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/IWRS at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
 


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In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un -
blinding can be performed at any time. 
Any patient who is unblinded will continue in the study and complete all study assessments 
according to the protocol.
5.5.13
Study completion and post-study treatment
Patient participation will be completed 180 days after the start of the study drug infusion.
The investigator also must provide follow-up medical care for all patients who are 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.14
Early study termination 
The study can be terminated at any time for any reason by Novartis. This may include 
reasons related to the benefit risk assessment of participating in the study, practical reasons, or 
for regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient should be seen as soon as possible and treated for a prematurely withdrawn patient.
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs / ECs of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “X” or “S” when the required 
assessments and/or procedures are performed at a scheduled study visit. Patients should be 
seen for all visits on the designated day or time point, or as close to it as possible.
Patients who prematurely discontinue the investigational treatment remain in the study and 
should 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 should 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. For all 
patients it is important that the investigator collects and maintains all available contact 
information to facilitate the follow-up and to ensure that Day 180 is completed on time.
Patients eligible to participate in this study must be randomized within 16 hours of 
presentation and treatment should be started as soon as possible but no longer than 4 hours 
after randomization. Presentation starts at the earliest of (1) time of presentation either at the 
ER/ED/ICU/CCU, outpatient clinic, or ward (this excludes EMS); or (2) time of first IV loop 
diuretic prior to arrival at the hospital (this includes outpatient clinic, ambulance, or hospital 
including emergency department) for the current AHF episode.
Prospective study candidates will be identified either enroute to or upon arriving at the 
ED/ER/hospital. After identifying a potential subject, an ICF must be signed before 
performing study-related screening procedures that are not considered standard of care for 
AHF patients at that site. Procedures that are part of a site’s standard of care that are 
 


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performed within 16 hours from presentation for an individual with AHF may pre-date the 
signed ICF. The AE and SAE reporting period will begin at the time the ICF is signed.
Screening will continue until the patient has been deemed eligible for enrollment and 
randomized into the study via the IRT/IWRS.
 


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Table 6-1
Visit assessment
Epoch
Screening 
Randomized Treatment
Screen d
BaselineStudy drug infusiona
Post-treatment daily 
assessments
Follow-upc
Time points 
Hour -16 
Hour 0 Hour 6 Hour 
12
Hour 
24
Hour 
48
Hou
r 
72)
Hour 
96 
(Day 
Hour 
120 
Dischargee
Telephone 
call 
Telephon
e call
/PSW
Visits
1
101
102
103
104
105
106 107
108
109
110
111 112 199
Day
1
1
1
1
2
3
4
5b
14**
30**
60
120 180
Visit Date
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demography
X
Screening disposition
X
BNP or NT-pro-BNP for study entry X
Estimated GFR (sMDRD) for study 
entry 
X
Chest X-Ray g
S
ECGn
X
X
X
X
Medical History – Protocol Solicited 
Events
X
Medical History
X
Heart Failure and Diabetes History
X
Alcohol History
X
Drug Abuse History
X
 


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Epoch
Screening 
Randomized Treatment
Screen d
BaselineStudy drug infusiona
Post-treatment daily 
assessments
Follow-upc
Time points 
Hour -16 
Hour 0 Hour 6 Hour 
12
Hour 
24
Hour 
48
Hou
r 
72)
Hour 
96 
(Day 
Hour 
120 
Dischargee
Telephone 
call 
Telephon
e call
/PSW
Visits
1
101
102
103
104
105
106 107
108
109
110
111 112 199
Day
1
1
1
1
2
3
4
5b
14**
30**
60
120 180
Smoking History
X
Urine Pregnancy Test (CHBP 
females only) f
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
Height 
X
Physical Examination h
S
S
S
S
S
S
S
S
S
S
Blood Pressure and Heart Rate 
(pulse) measurements i
X
X
X
X
X
X
X
X
X
X
X
X
Body Temperature and Respiratory 
Rate
X
X
X
X
X
X
X
X
X
X
Systolic blood pressure decrease 
event
X
X
X
X
X
Index Heart Failure Hospitalization
X
Index Heart Failure Summary
X
Patient-reported dyspnea (Likert 
scale- as ePRO)s
X
X
X
X
X
X
X
Patient-reported dyspnea – VAS 
scale (as ePRO) t
X
X
X
X
X
X
X
X
Physician assessment of HF signs 
and symptoms 
X
X
X
X
X
X
X
X
X
 


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Epoch
Screening 
Randomized Treatment
Screen d
BaselineStudy drug infusiona
Post-treatment daily 
assessments
Follow-upc
Time points 
Hour -16 
Hour 0 Hour 6 Hour 
12
Hour 
24
Hour 
48
Hou
r 
72)
Hour 
96 
(Day 
Hour 
120 
Dischargee
Telephone 
call 
Telephon
e call
/PSW
Visits
1
101
102
103
104
105
106 107
108
109
110
111 112 199
Day
1
1
1
1
2
3
4
5b
14**
30**
60
120 180
In-hospital worsening heart failure 
assessmentW
X
X
X
X
X
X
X
X
Chemistryj
X
Hematologyj
X
Laboratory: Central labs– Chemistryk
X
X
X
X
X
X
X
Laboratory: Central labs – Hematologyk
X
X
X
X
X
X
X
Blood sample for hepatitis 
serologyx
X
Urine analysis (Dipstick)l
S
Biomarker measurementu
X
X
X
Pharmacokinetic assessmentq
X
X
X
Immunogenicity studyr
X
X
Concomitant Medicationso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital status and clinical outcome 
assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of readmission
X
X
X
X
X
Administer study medication
X
Contact IRT/IWRS
X
X
X
Non serious adverse  eventsm
X
X
X
X
X
X
X
 


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Epoch
Screening 
Randomized Treatment
Screen d
BaselineStudy drug infusiona
Post-treatment daily 
assessments
Follow-upc
Time points 
Hour -16 
Hour 0 Hour 6 Hour 
12
Hour 
24
Hour 
48
Hou
r 
72)
Hour 
96 
(Day 
Hour 
120 
Dischargee
Telephone 
call 
Telephon
e call
/PSW
Visits
1
101
102
103
104
105
106 107
108
109
110
111 112 199
Day
1
1
1
1
2
3
4
5b
14**
30**
60
120 180
Serious adverse eventsm
X
X
X
X
X
X
X
X
Follow up completion form
X
Withdrawal of Informed Consent 
Formp
X
X
PSW = premature patient withdrawal; X= assessment to be recorded in the eCRF; S= assessment to be recorded on source documentation
** Day 14 and Day 30 are telephone visits
a Study drug treatment will be administered as continuous intravenous infusion for up to 48 hours. Dosage can be adjusted under specific circumstances 
as described in Section 5.5.
b Patients discharged prior to Day 5 will return to the hospital/clinic for Day 5 procedures.
c Patients discharged prior to Day 14 will be contacted on Day 14 by telephone for follow-up. The Day 60 and Day 180 assessments will be conducted as 
outpatient visits if the patient is discharged prior. The Day 30 assessment will be conducted by telephone. If a patient fails to return for the remaining 
outpatient visit(s) the investigator should show “due diligence” by contacting the patient, family or family physician up to the time of database lock. 
d Procedures performed as part of a site’s standard of care and that are performed within 16 hours from presentation for an individual with AHF can  be 
done during the pre-screening interval and may pre-date the signed ICF.
e If Discharge Visit coincides with a scheduled visit, only the Discharge Visit will be performed.
f At screening, a locally-analyzed sample will be obtained for female patients of child-bearing potential to qualify the patient for study entry. Additional 
samples will be locally-analyzed at Discharge and at the end of study. Refer to Section 6.5.5.
g Chest X-ray may be interpreted by the study physicians or physicians attending to the patient. Interpretation and the person interpreting the radiograph 
must be recorded in the source documentation. A radiologist’s interpretation is not necessary for the purposes of the study.
h A complete physical examination will be performed at screening; an abbreviated physical examination will be performed at all other specified time 
points.  Refer to Section 6.5.1
 


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i In addition to at screening and baseline, BP and HR (pulse) measurements are to be performed at 30 and 60 minutes and then every hour for the first 6 
hours of study drug infusion, and then every 3 hours during study drug infusion, 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 up to 48 hours and then every 24 hours until the earlier of Day 5 or 
Discharge. In addition BP and HR measurements will be taken at Day 60, and Day 180 as part of vital signs assessment. 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 study personnel. The assessments made 
as per the table above would be entered in the CRFs. Assessments at other time points will be part of source document. Refer to Section 6.5.2
j Blood will be locally collected at screening . Refer to Section 6.5.3
k Blood will be collected for measurement of biochemistry, hematology and samples shipped to the central laboratory for analysis. Refer to Section 6.5.3.
m AEs will be collected from the signing of the ICF to and including Day 5.  SAEs will be collected from the signing of the ICF to and including Day 14.  
After this period, only suspected SAEs will be collected.    
lUrine dipstick will be measured locally at screening to rule out any conditions requiring further diagnostic evaluation or treatment. Refer to Section 
6.5.3.4. . 
n ECGs will be performed and interpreted locally at screening, at 48 hours, and at Day 5 or discharge, whichever occurs first. The ECG interpretation 
and person interpreting the ECG must be recorded in the source documents and in the eCRF Refer to Section 6.5.4..
o Major cardiovascular and non-cardiovascular classes of medication taken by a subject approximately 30 days prior to study drug initiation and on a 
daily basis while hospitalized through Day 5, at Discharge, and at Days 14 and 30 (telephone visit) and on Days 60, 120 and 180 will be recorded.  Only 
those medications currently being taken or those were taken within 24 hours prior to the visit will be collected.
p Withdrawal of consent form is only completed at the time 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
qPharmacokinetics – sample should be taken at 48 hours just prior to end of infusion.  If the infusion was discontinued earlier than the complete 48 hour 
infusion due to whatever the reason, the 48 hour PK serum sample will be collected just prior to the end of infusion if possible and time of collection 
should be recorded. In addition, PK samples will be collected at baseline and D60 to accompany the immunogenicity samples and support the 
interpretation of the antibody assay results. Refer to section 6.6.2
r Immunogenicity study: blood samples will be collected at baseline and on Day 60  to test the presence of anti-serelaxin antibodies in these study 
patients. Refer to Section 6.6.3.  
s Refer to the Dyspnea Measurement by Likert scale Section 16 Appendix 4
t Refer to the Dyspnea Measured by Visual Analog Scale (VAS) Section 17 Appendix 5
u Biomarkers: blood samples will be taken at baseline, Days 2 and 5. Refer to Section 6.4.4.4
 


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w Worsening heart failure is defined as in-hospital worsening signs and/or symptoms of heart failure that require an intensification of intravenous therapy 
for heart failure or mechanical ventilatory, 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 mechanical ventilation, ultrafiltration, hemodialysis, intra-
aortic balloon pump or ventricular assist device. The investigator will evaluate the patient for in-hospital worsening heart failure events at 6, 12, 24 and 48 
hours from the start of study drug infusion, and then daily while hospitalized through Day 5 or at discharge whichever is earlier.
x Blood sample will be collected at baseline and stored at the central laboratory for hepatitis serology analysis at a later date as needed in case of a 
significant liver event. Refer to Section 6.5.3.3
 


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6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch (i.e. 
randomized treatment) 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.
For 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 CRF.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
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, weight and height. Relevant medical history/current 
medical condition data includes data until the start of study drug. Where possible, diagnoses 
will be recorded rather than symptoms. 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.
6.3
Treatment exposure and compliance 
Study drug will be given IV under medical supervision. Dose Administration Record eCRF 
will be completed by the site staff including infusions times and rates.  Study drug and 
supplies must be made available for inspection by the independent field monitor for 
accountability at each visit using vials counts and information provided by the 
independent pharmacist or the qualified site personnel.
6.4
Efficacy
6.4.1
Efficacy assessment 1
The primary efficacy variable is defined as the clinical composite endpoint based on:

Treatment success defined as

Moderate /marked improvement in dyspnea by the Likert Scale at Day 2 AND   ≥2 
points improvement in ≥2 of 4 physician assessed symptoms and signs of congestion 
(orthopnea, edema, rales and JVP) and none of them deteriorating (≥ 0 point 
improvement) at Day 2
Refer to the physician assessment of signs and symptoms, Section 15 Appendix 3.

Treatment failure defined as

In-hospital worsening heart failure through Day 5 or 
 


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
All causes of death through Day 5, or re-hospitalization due to heart failure or renal 
failure though Day 5

Unchanged defined as

All remaining patients are classified as having unchanged treatment status if they 
meet neither the criteria for treatment success at Day 2 nor the criteria for treatment 
failure through Day 5.
If a patient is determined as treatment failure through Day 5, then he/she will be excluded 
from the assessment of treatment success or unchanged even if the patient experience 
improved signs and symptoms at Day 2.
Worsening heart failure (WHF) is defined as in-hospital worsening signs and/or symptoms of 
heart failure that require an intensification of intravenous therapy for heart failure or 
mechanical ventilatory, 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 mechanical ventilation, ultrafiltration, hemodialysis, 
intra-aortic balloon pump or ventricular assist device.
6.4.2
Efficacy assessment 2
Secondary endpoints will comprise:

Time to WHF through Day 5

Time to cardiovascular death during a follow-up period of 180 days

Time to all-cause death through a follow-up period of 180 days
Other efficacy endpoints will comprise:

Time to moderate or marked improvements in dyspnea by Likert scale through Day 5

Dyspnea by VAS-AUC changes through Day 5

Length of stay in index ICU/CCU

Renal dysfunction & prevention of worsening of renal function through Day 5

Time to re-hospitalization due to HF and renal impairment through Day 180

Time to CV death or re-hospitalization due to HF/RF through Day 180

Time to in-hospital worsening heart failure through Day 5 where the in-hospital worsening 
heart failure is defined by symptoms only, signs only, and by both symptoms and signs

Use of loop diuretics and vasoactive agents through Day 5

Changes in cardio-renal biomarkers (Days 2 and 5)
6.4.3
Appropriateness of efficacy assessments  
The primary efficacy endpoint is defined as the clinical composite comprised of treatment 
success at Day 2 or treatment failure or unchanged through Day 5. Treatment success is 
assessed by moderate/ marked improvement in dyspnea measured by Likert Scale at Day 2 
AND a minimum of 2 points improvement in at least 2 out of 4 physician assessed symptoms 
and signs of congestion (orthopnea, edema, rales and JVP) and none of them deteriorating (≥0 
point improvement) at Day 2 as compared to baseline. The treatment failure is defined as in-
hospital WHF, death, or re-hospitalization through Day 5. To define the treatment success by 
 


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improvement in signs and symptoms at Day 2 is to evaluate the early therapeutic effect of 
serelaxin for the relief of congestion; to define the treatment failure as WHF, death and re-
hospitalization through Day 5 is to assess the therapeutic effect is sustained by preventing 
these in-hospital worsening HF events. If a patient is determined as treatment failure, he/she 
will be excluded from the assessment of treatment success or unchanged even if the patient 
experienced improved signs and symptoms at Day 2.
By applying this clinical composite endpoint definition to the data of the completed RELAX-
AHF study, the post-hoc analysis showed that the patients who met the definition of 
“treatment failure” comprised 11.9% in placebo group and 6.4% in the serelaxin group, and 
the relative risk reduction (RRR) in favor of serelaxin was 45%. The patients who met the 
definition of “treatment success” comprised 26.0% in placebo group and 31.7% in the 
serelaxin group (the relative increase in the proportion of “treatment success” was 22%). 
Using the analysis of maximum likelihood estimates, the serelaxin treatment showed 
statistically significant benefits in the clinical composite endpoint compared to placebo (p < 
0.001).
6.4.4
Other efficacy assessments
6.4.4.1
Assessment of AHF signs and symptoms
The investigator will evaluate the signs and symptoms of heart failure, including patient’s 
dyspnea on exertion or at rest, orthopnea, rales, JVP, peripheral edema, and the patient’s 
assessment of dyspnea (Refer to Section 15 Appendix 3). These evaluations will be done at 
baseline, 6, 24 and 48 hours from start of study drug infusion, and then daily while 
hospitalized through Day 5, at Discharge, and Day 60.  These evaluations should be done at 
the same time of day, each day, in the same position, and hospital/clinic setting, preferably by 
the same assessor.  To ensure consistency, if the same assessor cannot perform the daily 
assessments, the second assessor should evaluate the patient together with the first assessor at 
least once prior to performing the assessments independently. Only physicians who have 
completed the training of the protocol based standardized measurements can obtain the 
physician assessed signs and symptoms for this study. 
6.4.4.2
Worsening of heart failure
Worsening heart failure (WHF) is defined as in-hospital worsening signs and/or symptoms of 
heart failure that require an intensification of intravenous therapy for heart failure or 
mechanical ventilatory, 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 mechanical ventilation, ultrafiltration, hemodialysis, 
intra-aortic balloon pump or ventricular assist device.
The investigator will evaluate the patient for early in-hospital worsening heart failure events 
at 6, 12, 24 and 48 hours from the start of study drug infusion, and then daily while 
hospitalized through Day 5 or at discharge whichever is earlier (Refer to Table 6-1).  These 
evaluations should be done at the same time of day, each day, in the same position, and 
hospital/clinic setting, preferably by the same assessor.  To ensure consistency, if the same 
assessor cannot perform the daily assessments, the second assessor should evaluate the patient 
 


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together with the first assessor at least once prior to performing the assessments independently. 
Only physicians who have completed the training of the protocol based standardized 
measurements can obtain the physician assessed signs and symptoms for this study.  
Index in-hospital worsening heart failure events will be adjudicated by the CEC.  The 
procedures of the adjudication will be described in the CEC Charter.
6.4.4.3
Re-hospitalization
Re-hospitalization will be defined as all unplanned hospitalization (including admission to a 
hospital or any attendance in an acute care setting e.g. ED, or in another health care facility) 
of 24 hours or greater, regardless of whether the patient was admitted to the hospital. 
6.4.4.4
Biomarkers
Biomarkers related to cardiac and renal function/injury will be obtained from 
blood. Biomarkers sample will be collected at baseline, 48 hours and at Day 5 post infusion.
These analyses will be used to elucidate the effect of serelaxin and to explore drug effect 
versus baseline biomarkers of risk. Biomarkers such as but not limited to NTproBNP, high 
sensitivity troponin T, and Cystatin C. This list may be changed or expanded further as it is 
recognized that more relevant or novel biomarkers may be discovered. Biomarker analysis 
may be performed during the process of this study or after its completion as new, more 
relevant biomarkers are identified. Specific handling of the biomarker samples will be 
described in detail in the Laboratory Instruction Manual.
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 adverse events (AEs)/ SAEs, changes in vital signs, physical 
examination findings, and clinical laboratory test results (chemistry and hematology). All AEs 
will be assessed up to and including Day 5 and SAEs will be assessed up to and including Day
14. Any SAEs experienced after Day 14 should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
6.5.1
Physical examination
An overall physical examination will be performed by the investigational staff at screening
and include the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. 
An abbreviated physical examination will be performed at all other visits and include the 
examination of general appearance.
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 made 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 (Section 7.1). Significant findings made 
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 
 


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completed signed Serious Adverse Event form must be faxed to the local Novartis Drug 
Safety and Epidemiology Department (DS&E) faxed within 24 hours after awareness of the 
SAE.
Subjects discharged post study drug infusion (48 hours) but prior to Day 5 will be required to 
return for a physical examination as an outpatient at Days 5.
6.5.2
Vital signs 
Body temperature and respiration rate will be measured at Screening, Baseline, at 24 and 48 
hours after start of study drug infusion and daily until Day 5 or discharge and on Days 60 and 
180, Patients discharged prior to Day 5 will return to the hospital/clinic for Day 5 procedures.
BP and heart rate (pulse) measurements will be performed at Screening, 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 up to 48 hours and then every 
24 hours until the earlier on Day 5 or discharge and at Days 60 and 180. BP and HR are
preferred to be measured with the patient in the same position and with the same equipment 
using the same arm throughout study drug infusion. If different instruments are used, then 
calibration of these instruments is required and logs are documented by the site and verified 
by the monitor. These measurements may be made and recorded by trained healthcare 
personnel as part of their routine clinical duties, as well as study personnel. If at any time 
during dosing, the subject’s systolic blood pressure is decreased by > 40 mm Hg from 
baseline but is ≥ 100 mmHg in 2 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 2 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.
Height and weight 
Height in centimeters (cm) or inches (inch) will be measured at Screening.
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 Days 1-5, Discharge, Day 60 and 180. If 
patient’s body weight cannot be measured at Screening because of the patient physical 
condition, a verbal weight will be acceptable. Weight should be obtained as soon as the 
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6.5.3
Laboratory evaluations 
A local laboratory will be used for analysis of all specimens collected at screening according 
to Table 6-1. The laboratory name and value must be entered into the eCRF page.  Fasting for 
the blood collection samples is optional.
A central laboratory will be used for the analysis of all baseline and post-baseline specimens
collected according to Table 6-1. All central laboratory results will be communicated by the 
central lab to the investigators and the sponsor.  Details on the collection, shipment of samples 
and reporting of results by the central laboratory are provided in the laboratory manual.
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.
6.5.3.1
Hematology
The following hematology tests will be measured locally at screening and centrally at baseline 
and post-baseline: RBC, hemoglobin, hematocrit, platelet, and white blood cell count, 
including differentials.
6.5.3.2
Clinical chemistry   
The following serum chemistry tests will be measured locally at screening and centrally at 
baseline and post-baseline: sodium, potassium, glucose, blood urea nitrogen (BUN) or urea, 
AST, ALT, alkaline phosphatase, total bilirubin, calcium, uric acid and creatinine. In addition, 
BNP/NT pro-BNP, eGFR and hemoglobinA1c will be measured locally at screening only.
6.5.3.3
Blood sample for hepatitis serology
A blood sample will be collected at baseline and stored at the central laboratory for hepatitis 
serology analysis in case of a significant liver event.
6.5.3.4
Urinalysis
The following tests are included in the dipstick urinalysis: blood, glucose, ketones, leukocytes, 
pH, and protein will be measured locally at screening.
6.5.4
Electrocardiogram (ECG) 
Triplicate 12 lead 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. 
 


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Triplicate 12 lead ECGs are collected at 48 hours and at Day 5 or discharge, whichever occurs 
first. The original ECGs on non-heat-sensitive paper / and a certified copy on non-heat 
sensitive paper, appropriately signed, should be collected and archived at the study site.  ECG 
findings will be recorded in the source documents and on the eCRF.
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.
6.5.5
Pregnancy and assessments of fertility 
At screening, a locally-analyzed urine pregnancy test will be performed for all females of 
childbearing potential. A positive urine pregnancy test should be confirmed with a serum 
pregnancy test. Urine pregnancy test will be repeated at Discharge and the end of the study. 
Any subject with positive confirmed serum pregnancy test at Screening will be excluded from 
participating in the study.
6.5.6
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments 
6.6.1
Resource utilization 
Analyses will be undertaken, as appropriate, to assess the effects of treatments on healthcare 
resource utilization (RU) parameters.
At Visit 1 (screening), prior heart failure hospitalizations, relevant medical conditions and 
therapies, and prior procedures will be collected. Throughout the index hospitalization, the 
level of health care resource utilization will be assessed by the overall length of stay, length of 
time in specific inpatient care units, and procedures rendered during hospital stay. The 
frequency and duration of subsequent inpatient hospitalization will be recorded along with the 
primary reason for the hospital admission and discharge, length of time in specific inpatient 
care units, and procedures rendered. The frequency of urgent care for AHF lasting more than
24 hours and the procedures rendered will also be recorded.
All attempts will be made to collect RU variables in all patients throughout the duration of the 
study in order to avoid selection bias. There may also be circumstances when the collection of 
such data after completion of the study may be warranted.
6.6.2
Pharmacokinetics 
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Blood samples for PK will be taken at baseline, 48 hr and Day 60. The 48 hr PK sample 
should be taken prior to the end of infusion. If the infusion was discontinued earlier than the 
complete 48 hr infusion due to whatever the reason, the 48 hr PK serum sample will be 
collected just prior to the end of infusion if possible and time of collection should be recorded. 
The PK samples at baseline and Day 60 are collected as a part of immunogenicity analysis 
package.
Blood sample will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein contra-lateral to the site of the infusion.  If an indwelling cannula is used, a 0.5 
mL discard will be taken before he PK sample in case the indwelling cannula was flushed 
with saline.  Serum separator tubes will be used to collect serum for the determination of 
serelaxin concentrations
For pharmacokinetic analysis of serelaxin, approximately 2 mL blood will be drawn into a 
serum separator tube. Instructions regarding the sample collection and handling including 
clotting time, centrifuge temperature and duration, storage and shipment are described in the 
Laboratory Manual.  
All samples will be given a unique sample number (as listed in Appendix 6). The first aliquots 
should be sent to the bioanalytical center on dry ice, while the back-up aliquots should be sent 
to the same address after assurance that the first aliquots arrived in good condition. For 
detailed instructions on labeling and shipment of samples, please refer to the Laboratory 
Manual. 
Pharmacokinetic bioanalytical method
Serelaxin will be determined in serum by a validated Enzyme Linked Immuno Sorbent Assay 
(ELISA) 
 
 
 
 
The detailed method descriptions of the PK assay will be included in the corresponding 
bioanalytical report.
6.6.3
Immunogenicity
Immunogenicity blood collection and processing
Blood samples for immunogenicity will be taken at baseline and on Day 60.  They will be 
taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein contra-
lateral to the site of infusion. If an indwelling cannula is used, a 0.5 mL discard will be taken 
before the immunogenicity sample in case the indwelling cannula was flushed with saline. 
Serum separator tubes will be used to collect serum for the evaluation of anti-serelaxin 
antibodies. 
For assessment of immunogenicity (anti-serelaxin antibody), approximately 3 mL blood will 
be drawn into a serum separator tube. Instructions regarding the sample collection and 
handling including clotting time, centrifuge temperature and duration, storage and shipment 
are described in the Laboratory Manual.  
 


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All samples will be given a unique sample number (as listed in Appendix 6). The first 
aliquots should be sent to the bioanalytical center on dry ice, while the back-up aliquots 
should be sent to the same address after assurance that the first aliquots arrived in good 
condition and whenever possible together with the next shipment of first aliquots. For detailed 
instructions on labeling and shipment of samples, please refer to the Laboratory Manual.
Immunogenicity analytical methods
Anti-serelaxin antibodies will be evaluated in serum in a validated four-tiered assay approach.
All samples are initially screened for potential immunogenicity in the screening assay. Any 
positive screen results are confirmed using an immunodepletion assay. If a sample 
immunodepletes, it is considered confirmed positive and the sample moves to a third tier 
titration assay. Confirmed positive samples will also be tested for neutralization of serelaxin
biological activity using a validated bioassay. The detailed method descriptions of the 
immunogenicity assays will be included in the corresponding bioanalytical data reports.
6.6.4
Pharmacogenetics/pharmacogenomics 
Pharmacogenetics will not be performed in this study.
7
Safety monitoring
All AEs will be collected up to and including Day 5, and all SAEs will be collected up to and 
including Day 14, regardless of suspected causality. After Day 14 only suspected SAEs will 
be collected and databased.    
7.1
Adverse events 
An AE is any untoward medical occurrence (e.g, 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
until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
In this study, non-serious AEs will be collected through Day 5, SAEs will be collected 
through Day 14.
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test findings, 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, 
 


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
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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying AEs. Alert ranges for labs and other test abnormalities are included in 
Appendix 1.
AEs with an onset up to and including Day 5 must be recorded in the Adverse Events CRF 
under the signs, symptoms or diagnosis associated with them accompanied by the following 
information.

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment (yes/no)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported

whether it constitutes a SAE (See Section 7.2 for definition of SAE) and which 
seriousness criteria have been met

action taken regarding study treatment
All AEs should be treated appropriately. Treatment may include one or more of the following: 

no action taken (i.e. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this AE

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition 
of SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
The investigator must 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 should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
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7.2
Serious adverse events
7.2.1
Definition of serious adverse event
A SAE is defined as 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:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

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

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
Serious adverse event reporting
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 only be reported to 
Novartis if the investigator suspects a causal relationship to study treatment.
 


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the  Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess the relationship of each SAE to each specific 
component of the study treatment (if the study treatment consists of several components)
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis.Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site.
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an IN to inform all investigators involved in any study 
with the same study treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
Study-specific unblinding 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 unblinded for expedited reporting to competent authorities/relevant ECs and 
investigators. In such cases, regulations allow an exemption from SUSAR unblinding and 
expediting aimed at ensuring the validity of an outcome study (European Commission 
ENTR/CT13 Guideline 2006, FDA Guidance 2012). Therefore, the rules for unblinding 
SUSARs during the 14-day SAE collection period will be applied as follows.
1. Events that will not be unblinded
A SUSAR will not be unblinded if the event is considered consistent with one of the efficacy 
endpoints: non-CV death, CV death, worsening heart failure, re-hospitalization due to HF, and 
re-hospitalization due to renal failure. 
Note: Worsening heart failure is defined as in-hospital worsening signs and/or symptoms of 
heart failure that require an intensification of intravenous therapy for heart failure or 
mechanical ventilatory, renal or circulatory support. Such treatment can include the 
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heart failure, or institution of mechanical support such as mechanical ventilation, 
ultrafiltration, hemodialysis, intra-aortic balloon pump or ventricular assist device.
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 as blinded 
reports. INs will not be issued for these events.  
2. Endpoint events that will be unblinded
There is a subset of SAEs, which will require unblinding and 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

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 unblinding 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 Day 14, respectively, SUSARS 
considered consistent with the following SAE Preferred Terms will not be unblinded and 
reported in an expedited timeframe to regulatory agencies, ECs or investigators during the 
course of the study:
abdominal pain, acute coronary syndrome, acute pulmonary oedema, anaemia, angina pectoris 
*, anxiety, arthralgia, asthenia, azotaemia, back pain, blood creatinine *, blood pressure *, 
blood urea nitrogen *, bronchitis *, cardiac arrest, cardiac arrhythmias (all Preferred Terms 
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, 
 


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hyperkalemia, hyperlipidemia, hypertension *, hyperuricaemia, hypoglycemia, hypokalemia, 
hypernatremia, hypotension *, implantable defibrillator *, influenza *, insomnia, loss of 
consciousness, muscle spasm, musculoskeletal pain, myocardial infarction*, nasopharyngitis, 
nausea, oedema, oedema due to cardiac disease, oedema peripheral, osteoarthritis, pain in 
extremity, pericardial effusion, pleural effusion, pneumonia *, presyncope, pulmonary 
hypertension, pulmonary oedema, 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 as blinded reports. INs will not be issued for these events.  
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / AEs have to be considered during the course 
of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal 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.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver eCRF pages.

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
 


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
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 liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the
possible relationship to the study treatment.
Any SAE experienced during pregnancy and unrelated to the pregnancy must be reported on a
SAE 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 CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization.   
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
 


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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 CRF 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 CRFs 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 OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained.
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
8.3
Database management and quality control 
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions.
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, 
who will also manage the database. The database will be sent electronically to Novartis (or a 
designated CRO).
Each occurrence of a code break via IRT/IWRS will be reported to the clinical team and 
monitor. The code break functionality will remain available until study shut down or upon 
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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 AE and SAE data throughout the 
trial in a semi-unblinded manner. Should the DMC make recommendations on the conduct of 
the trial that are considered to have significant bearing on the safety of the patients, this will 
be communicated by Novartis to HAs, ECs and investigators within an appropriate timeframe.
Details regarding the DMC process will be available in relevant DMC charter.
8.5
Adjudication Committee 
An external and independent CEC will review and adjudicate index in-hospital WHF, CV 
deaths and re-hospitalizations.  The CEC will be responsible for classifying all death events 
(e.g., CV and non-CV death) and for determining whether pre-specified endpoint criteria were 
met for index in-hospital WHF, re-hospitalization due to heart failure or renal failure. The 
detailed definitions of the endpoints, required documentation, and the adjudication process 
will be provided to all sites in a separate CEC Manual.
9
Data analysis 
9.1
Analysis sets
The following analysis populations will be defined for statistical analysis:

Randomized (RAN) set - All patients who received a randomization number, regardless 
of receiving trial medication

Safety set (SAF) - All patients who received any amount of study drug and have at least 
one post-baseline safety assessment. Of note, the statement that a patient had no AEs also 
constitutes a safety assessment. Patients will be analyzed according to treatment received. 
Patients who received any amount of serelaxin will be included in the serelaxin treatment 
group.

Full analysis set (FAS) - All patients in the RAN population who were not 
misrandomized patients*. Following the intent-to-treat (ITT) principle, patients are 
analyzed according to the treatment they have been assigned to at the randomization 

Per protocol set (PPS) – all patients in the FAS who received any amount of study 
medication and have no major protocol deviations (as defined in VAP module 3).
* Misrandomized patients are those who have not been qualified for randomization, have been 
inadvertently randomized into the study and who did not take study drug. Misrandomized 
patients are defined as cases where IRT/IWRS contacts were made by the site either 
prematurely or inappropriately prior to confirmation of the patient’s final randomization 
eligibility and double-blind medication was not administered to the patient. These patients 
should subsequently be discontinued from the study. 
 


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9.2
Patient demographics and other baseline characteristics
Subject  demographics  (age,  sex,  ethnicity,  race,  weight  and  height)  and  baseline 
characteristics will be summarized for the RAN and FAS. Screening BNP, NT pro-BNP and 
estimated eGFR, laboratory values as reported by the investigator will be summarized with 
standard descriptive statistics. The number and percentages of patients meeting all eligibility 
criteria at screening will also be provided. The number and percentage of patients who were 
hospitalized for heart failure in the past year and patients on IV nitrates at the time of 
randomization will both be presented. Inclusion and exclusion criteria violations will be listed. 
Medical history data will be summarized by treatment group. Continuous variables will be 
summarized by n, mean, median, standard deviation, minimum, maximum, and categorical 
variables will be summarized using frequency and percentage.
Treatment groups will be compared using the Chi-square test for categorical variables or 
using t-test for continuous variables. The p-values will be provided for descriptive purpose 
and 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.
 


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9.3
Treatments 
Overall study drug administration details will be summarized for the RAN population. This 
will include time from presentation to randomization (hours), time from randomization to 
study drug administration (hours), study drug administered (yes/no), reason study drug not 
administered, actual study drug received, and the number of days infused (one or two). Study 
drug administration will also be summarized in the Safety Set. The duration of study drug 
administration (in hours) and the total volume of study drug administered (estimated from the 
total time and rate of infusion) will be summarized. In addition, the number of patients whose 
study medication dose was lowered or discontinued prematurely, and the reasons for 
discontinuation, will be summarized by treatment group.
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date, respectively, will be summarized by therapeutic class, PT, and treatment 
group for the randomized population.
9.4
Analysis of the primary variable(s)
The primary analysis and the analyses of all secondary and other efficacy endpoints will be 
based on the Full Analysis Set (FAS), following the intention-to-treat principle.
9.4.1
Variable(s)
The primary efficacy variable will be the trichotomous clinical composite endpoint based on 
(i) treatment ‘success’ of congestion improvement of dyspnea in Likert (moderately and 
markedly improvement) and at least 2 points improvement for at least 2 out of 4 signs and 
symptoms variables at Day 2, (ii) treatment ‘failure’ of in-hospital worsening heart failure, 
death or re-hospitalization due to HF or RF through Day 5 and (iii) neither as ‘no change’.
 


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9.4.3
Handling of missing values/censoring/discontinuations
The components of trichotomous clinical composite endpoint are all categorical variables.  
Missing categorical value will be replaced with the last preceding non-missing value.  These 
will include dyspnea Likert scale at Day 2, four signs and symptoms at Day 2 and in-hospital 
worsening heart failure through Day 5.  In the evaluation of treatment success for the four 
signs and symptoms, the change from baseline will need to be calculated. If there is a missing 
baseline value, say a patient with missing JVP at baseline, this patient’s change of JVP at Day 
2 will be set as 0-point improvement, i.e., will not be contributed as 2-point improvement for 
JVP.  
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
There are three secondary variables: 

WHF through Day 5

CV death through Day 180  

All-cause death through Day 180. 
All of these secondary variables are time-to-event variables.  The hypothesis will be tested
based on the FAS at a significance level of 0.025 (one-sided).  
The three secondary variables will be tested using hierarchical testing procedure in controlling
overall α of 0.05 (Bretz, et al 2009).  If primary endpoint is significant, WHF will be tested 
first at α of 0.05.  If WHF is significant at the same α level then will proceed to test CV death 
and only if CV death is significant then will test all-cause death at α of 0.05.  
Time to WHF through Day 5 will be analyzed using Gehan’s generalized Wilcoxon test.
Patients died in the 5-day period will be considered as having WHF event. Patients without an
event will be censored at the earlier of the last contact date or 120 hours after randomization. 
Kaplan-Meier curves will be presented graphically by treatment group and Kaplan-Meier
estimates for selected time points with 95% confidence intervals will be tabulated.
For CV death and all-cause death will be analyzed with a log-rank test. Number and
percentage of patients who died from cardiovascular reasons based on the number of
patients in the population as denominator will be provided by treatment group. The hazard
 


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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, for CV death and all-cause death, 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.
For CV death, a patient without an event will be censored at the earlier of:

Date of death for non-CV related causes

The last date at which the vital status was known

Day 180
For all-cause death, a patient without an event will be censored at the last date at which the 
vital status was known or at Day 180.
 
 
Other efficacy variables
Other efficacy variables will comprise:
1. Time to moderate or marked improvements in dyspnea by Likert scale through Day 5
2. Dyspnea by VAS-AUC changes through Day 5
3. Length of stay in index ICU/CCU
4. Renal dysfunction & prevention of in-hospital worsening of renal function through Day 5
5. Time to re-hospitalization due to HF and renal failure through Day 180
6. Time to CV death or re-hospitalization due to HF/RF through Day 180
7. Time to in-hospital worsening heart failure through Day 5 where the in-hospital worsening 
heart failure is defined by symptoms only, signs only, and by both symptoms and signs
8. Use of loop diuretics and vasoactive agents through Day 5
9. Changes in cardio-renal biomarkers (Days 2 and 5)
Time to moderate or marked improvements in dyspnea by Likert scale through Day 5
(variable number 1) will be analyzed by Wilcoxon rank-sum test. Other time to event 
variables (5, 6 and 7) will be analyzed by presenting Kaplan-Meier estimates and testing with 
the log rank test.  Change from baseline variables (2) will be analyzed using ANCOVA model 
with baseline VAS as a covariate. Variables representing the number of days or multi-
categorical variables (3) will be analyzed using the Wilcoxon rank-sum test.  The categorical 
variables (4 and 8) will be analyzed using chi-squared tests.
Detailed biomarker analyses (9) (changes in cardio-renal biomarkers at Days 2 and 5) will be
included in the Statistical Analysis Plan.
 


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9.5.2
Safety variables 
The incidence of AEs recorded through Day 5 and the incidence of SAEs recorded through 
Day 14 will be presented for the Safety Set. Incident AEs will be considered those AEs with 
an onset date and time after the initiation of study drug.  Adverse events with an onset 
between informed consent and study drug initiation will be listed separately. Adverse events 
will be coded using MedDRA. All reported AEs will be summarized by system organ
class (SOC) and preferred term by treatment groups. Serious AEs (SAEs) will be
summarized similarly.
In addition, AEs will be summarized by time period of onset: from study drug initiation up 
to and including Day 5, or from Day 6 up to and including Day 14. After Day 14 only 
suspected serious adverse events will be collected and reported to Novartis.  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,
and study-drug-related SAEs, SAEs with an outcome of death, and SAEs leading to study
drug discontinuation will be summarized by percentages and frequencies. Percentages will
be based on the number of patients in the Safety Set. For the analysis by time period of
onset, the percentages will be based on the number of patients in the Safety Set with the
corresponding AE form completed.
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), summary statistics of raw data and change 
from baseline (means, medians, standard deviations, 1st and 3rd quartiles, Q1 and Q3) and
by flagging of notable values in data listings.
For vital signs, descriptive statistics will be provided for values and change from baseline at 
each assessment time point for pulse, respiratory rate, body temperature, and weight. 
Treatment groups will be compared for changes from baseline using t-tests.
The number and proportion of patients who experience a confirmed blood pressure decrease 
event during study drug administration will be provided. Among patients who experience a 
confirmed blood pressure decrease event, the events will be further characterized. Summaries 
will be provided separately for those confirmed events 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 
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9.5.3
Resource utilization 
Summary statistics on hospital length of stay in index ICU/CCU for the initial and subsequent 
hospitalizations, as well as procedures rendered during these hospitalizations 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 will not be collected in this study.
9.5.5
Pharmacokinetics 
Steady state concentration (Css) will be estimated based on the serum concentration 
determined at the 48 hr time point prior to the end of infusion. Systemic clearance will be 
calculated using the rate of infusion and Css for each patient as indicated below:
Clearance (mL/hr/kg) = Rate of infusion (µg/kg/hr) /Css (µg/mL).
Since only sparse PK time points for serelaxin serum concentration will be collected, no other 
PK parameters will be determined in this study. 
Concentrations below the assay LLOQ (BLQ) will be treated as zero for PK parameter 
calculations.
Descriptive statistics for serelaxin concentrations will be listed by time points (for baseline 
and 48hr samples only) to include arithmetic mean, geometric mean with its corresponding 
90% confidence interval, median, SD, CV, min and max.  A value of “0” will be used for 
samples that are BLQ in these calculations and therefore be excluded from geometric mean 
calculations. Descriptive statistics include arithmetic mean, geometric mean with its 
corresponding 90% confidence interval, median, SD, CV, min and max will also be provided 
for the two PK parameters, Css and clearance.
Subgroup analysis on Css and CL to assess the potential effects of various extrinsic and 
intrinsic factors on the PK of serelaxin may be performed as appropriate. These factors may 
include but not limited to age, gender, race, country of origin, concomitant medications, etc. 
Details of these analyses will be described in the Statistical Analysis Plan.
Serelaxin serum concentration will be assayed in Day 60 samples as well, in order to 
demonstrate the lack of drug interference with the immunogenicity assay, but this data will be 
included only as part of the immunogenicity results but not in the PK results.
9.5.6
Immunogenicity 
Anti-serelaxin antibodies will be measured in serum samples collected at the Day 60 time 
point.  To account for individual variability in background of each subject and to check for 
endogenous interference and/or pre-existing anti-serelaxin antibodies, anti-serelaxin 
antibodies will also be measured at baseline.  Frequencies and percentages will be computed 
for occurrence of anti-RLX030 antibodies at each time point.  Listings for subjects with a 
 


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positive screening result at any time point will include subject number, time point, 
immunodepletion result, titer, and neutralizing antibody result.
9.5.7
Pharmacogenetics/pharmacogenomics 
Not applicable
9.5.8
Biomarkers 
Summary statistics for the baseline values, the post-baseline values, and the change from 
baseline will be provided by treatment group for the FAS and Safety Set.
9.5.9
PK/PD
Not applicable
9.6
Interim analyses 
It is planned to establish an external and Independent Data Monitoring Committee (DMC) to 
monitor patient safety data on a regular basis during the course of the study. For this study, it 
is likely DMC will review safety data in a regular frequency, e.g., every six months. DMC 
may request additional safety data review. Such safety analyses do not inflate the type I error 
for the primary efficacy hypothesis testing and thus require no multiplicity adjustments. 
There will be no formal efficacy interim analysis.
9.7
Sample size calculation
A sample size of 1,520 AHF patients will need to be randomized 1:1 to serelaxin and placebo.  
This study will have 80% power at a two-sided type-I error of 5% to detect a distributional
shift with a common odds ratio of 0.75 between the distributions of placebo and serelaxin
 
 
 
 
 
 
The sample size re-estimation is anticipated to be conducted when about 70% of patients have 
enrolled and the event rates will be calculated based on patients who have data at least 
through Day 5. If the pooled observed event rates of treatment failure and treatment success 
 


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(assessed on a blinded basis) are much lower than expected based on RELAX-AHF data, 
sample size may be increased to preserve the target study power.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, 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 must be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she must indicate 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 (e.g.. all of the procedures described in the protocol). The 
process of obtaining informed consent must be documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP 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 child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibility of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
 


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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.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances  an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
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 prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
 


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study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
 


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biomarkers in the relaxin in acute heart failure (RELAX-AHF) development program 
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Packer M, Colucci W, Fisher L, et al (2013) Effect of levosimendan on the short-term clinical 
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Park HS, Kim H, Sohn JH, et al (2010) Combination of Uric Acid and NT-ProBNP: A more 
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Shiba N and Sjimokawa H (2008) Chronic heart failure in Japan: Implications of the CHART 
studies.  Vascular Health and Risk Management; 4(1):103–113.
Teerlink JR, Metra M, Felker GM, et al (2009) Relaxin for the treatment of patients with 
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outcomes in patients with acute systolic heart failure – Report from the Korean Heart Failure 
Registry Circ J; 76:1151-1158.
 


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Appendix 1: Clinically notable laboratory values and vital   
signs
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 Guidance 
AST (SGOT)
See Section 7.3 Liver Guidance
BUN
>100% increase
Creatinine
>100% increase
Total bilirubin
See Section 7.3 Liver Guidance
Alkaline phosphatase See Section 7.3 Liver Guidance
Potassium
>25% increase, >25% decrease
Calcium
>20% increase, >20% decrease
Uric acid
>100% increase
 


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Appendix 2: Liver event and laboratory trigger definitions 
and follow-up requirements
Table 14-1
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS
3 x ULN < ALT / AST5 x ULN
1.5 x ULN <TBL2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP >2 × ULN (in the absence of known bone pathology)
TBL >2 × ULN (in the absence of known Gilbert syndrome)
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 events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s 
Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, 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
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
 


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Criteria
Actions required
Follow-up monitoring
Preferred Term
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.
dFractionated bilirubin includes testing for total bilirubin, direct bilirubin, and indirect bilirubin
 


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15
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 -15 cm H2O
Presence of venous wave throughout respiratory cycle with wave 
sometimes ≥ 4 cm H2O above clavicle and typically increased with 
hepatojugular reflux (HJR).  Patients with values of >10 cm H2O and 
positive HJR should be graded in this category.
>15 cm H2O
Same as above with different cut-off value in cm H2O
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.
 


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Appendix 4: Dyspnea Measurement by Likert Scale
Patient will be presented with the following question: “We would like to measure how you 
think your breathing is. Please circle the number next to the description that best indicates 
how you are breathing right now, compared to the time just prior to you first started the study 
drug.”

3 = Markedly better

2 = Moderately better

1 = Minimally better

0 = No change

-1 = Minimally worse

-2 = Moderately worse

-3 = Markedly worse
Guidelines:

All assessments will be done with patient lying in bed; the head of bed should be at 30º, 
oxygen off for 3-5 minutes before starting assessment.

If oxygen off is not tolerated, put oxygen back on the patient and assess immediately,
asking the patient to describe how he or she felt when the oxygen was off.
 


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Appendix 5: Dyspnea Measured by Visual Analog Scale 
(VAS)
Visual analog scale (VAS): Patient will be presented with the following question: “Please 
draw a horizontal line on the scale to show how you think your breathing is right now. The 
number “0” equals the worst your breathing has ever felt and the number “100” equals the 
best you have ever felt.”
Guidelines:

All assessments will be done with patient lying in bed; the head of bed should be at 30º, 
oxygen off for 3-5 minutes before starting assessment.

If oxygen off is not tolerated, put oxygen back on the patient and assess immediately,
asking the patient to describe how he or she felt when the oxygen was off.
 


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Appendix 6: Blood collection log for PK and immunogenicity 
samples
Study 
Phase
Visit 
No.
Study 
Day
Time 
post 
start of 
infusion 
(hr)
PK
IG
Total 
Volum
e
Sampl
e Size 
(mL)
Sampl
e No.
Dose 
Ref. ID
Size 
(mL)
Sampl
e No.
mL per 
visit
Baseline
101
D1
0 (Pre)
2
101
1
3
201
5
Treatment
105
D2
48*
2
102
1
--
--
2
Follow-up
110
D60
1440
2
103
1
3
202
5
* 48hr sample taken prior to the end of infusion. . If the infusion was discontinued earlier than the 
complete 48 hour infusion due to whatever the reason, the 48 hour PK serum sample will be 
collected just prior to the end of infusion if possible and time of collection should be recorded.
 

SAP_001.pdf: 
Clinical Development 
RLX030A/Serelaxin 
CRLX030A2302 / NCT02007720
A multicenter, randomized, double-blind, placebo 
controlled phase III study to evaluate the efficacy, safety 
and tolerability of serelaxin when added to standard 
therapy in acute heart failure patients
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Amendment 1.0 
Release date: 
23 August 2017 
Number of pages: 
29 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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RAP Module 3 
 
RLX030A/CRLX030A2302 


Novartis 
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RAP Module 3 
 
RLX030A/CRLX030A2302 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
1 
Introduction ......................................................................................................................... 7 
2 
Statistical methods planned in the protocol and determination of sample size ................... 7 
2.1 
Subject and treatment .............................................................................................. 7 
2.1.1 
Analysis population ................................................................................. 7 
2.1.2 
Protocol deviation (PD) and subject classification ................................. 8 
2.1.3 
Time window, baseline and post-baseline definitions, and missing 
data handling ........................................................................................... 9 
2.1.4 
Subgroup definitions ............................................................................. 10 
2.1.5 
Subject disposition ................................................................................ 11 
2.1.6 
Background and demographic characteristics ....................................... 12 
2.1.7 
Medical history ...................................................................................... 12 
2.1.8 
Other subject history information ......................................................... 13 
2.1.9 
Study medication ................................................................................... 13 
2.1.10 
Concomitant medications, surgical and medical procedures ................ 13 
2.2 
Efficacy evaluation ................................................................................................ 15 
2.2.1 
Primary efficacy variable and analyses ................................................. 15 
2.2.2 
Secondary efficacy variables and analyses ........................................... 17 
2.2.3 
Other efficacy variables and analyses ................................................... 18 
2.3 
Pharmacokinetic evaluations ................................................................................. 20 
2.4 
Safety evaluation ................................................................................................... 21 
2.4.1 
Adverse events ...................................................................................... 21 
2.4.2 
Laboratory data ..................................................................................... 23 
2.4.3 
Vital signs.............................................................................................. 25 
2.4.4 
Electrocardiogram (ECG) ..................................................................... 25 
2.4.5 
Confirmed blood pressure decreases ..................................................... 26 
2.4.6 
Pregnancy test results ............................................................................ 26 
2.4.7 
Liver toxicity function and liver events ................................................ 26 
2.5 
Interim analysis ...................................................................................................... 28 
2.6 
Other topics ............................................................................................................ 28 
2.6.1 
Resource utilization ............................................................................... 28 
2.6.2 
Health-related Quality of Life ............................................................... 28 
2.6.3 
Immunogenicity .................................................................................... 28 
2.7 
Determination of sample size ................................................................................ 29 


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3 
References ......................................................................................................................... 29 
 
List of tables 
Document History – Changes compared to previous version of RAP module 3. ...................... 2 
Table 2-1 
Major protocol deviations resulting in exclusion of subjects from 
analysis populations ................................................................................ 8 
Table 2-2 
Non-protocol deviation criteria resulting in exclusion of subjects 
from analysis populations ....................................................................... 9 
Table 2-3 
Specification of key subgroups at screening ......................................... 11 
Table 2-4 
Specification of additional subgroups at screening ............................... 11 
Table 2-5 
List of efficacy endpoints and analyses ................................................ 15 
Table 2-6  
Safety risk and event of interest search specification ........................... 22 
Table 2-7 
Clinically notable laboratory abnormalities for selected tests .............. 24 
Table 2-8 
Criteria for evaluating liver toxicity ...................................................... 27 
Table 2-9 
Sample size for alpha=0.05, power=80% and common odds 
ratio=0.75 .............................................................................................. 29 


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 List of abbreviations 
ACE  
Angiotensin Converting Enzyme 
ACM 
All-cause mortality 
AE 
Adverse Event 
AHF  
Acute Heart Failure 
ALP 
Alanine Phosphatase 
ALT  
Alanine Aminotransferase 
ARB  
Angiotensin-II Receptor Blocker 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below limit of quantification 
BNP  
Brain Natriuretic Peptide 
BP 
Blood pressure 
BPDE 
Blood pressure decrease event 
BUN 
Blood Urea Nitrogen 
CBPDE 
Confirmed blood pressure decrease event 
CCU  
Coronary care unit 
CEC  
Clinical Endpoints Committee 
CI  
Confidence interval 
CL 
Clearance 
CPK  
Creatinine Phosphokinase 
CRF  
Case Report Form 
CSR  
Clinical Study Report 
Css 
Steady state concentration  
 
  
CV 
Cardiovascular 
CVD 
CV death 
CVDR 
CV death or rehospitalizaiton due to heart failure or renal failure 
CWHF 
Clinical worsening heart failure 
dL  
Deciliter 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EF 
Ejection fraction 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
HF  
Heart failure 
ICU 
Intensive Care Unit 
ITT  
Intent-to-treat 
IV  
Intravenous 
kg  
Kilogram 


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LFT 
Liver Function Toxicity 
LLOQ 
Lower limit of quantification 
LOS 
Length of hospital stay 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg  
Milligram 
min  
Minute 
mL  
Milliliter 
mmHg  
Millimeters mercury 
NYHA 
New York Heart Association 
PASS 
Physician assessment (of HF) signs and symptoms  
PD 
Protocol Deviation 
PPS  
Per Protocol Set 
PT 
Preferred Term 
RAN 
Randomized Set 
RAP 
Report and Analysis Preparation 
RBC  
Red Blood Cell 
SAE  
Serious adverse event 
SAF 
Safety Set 
SBP  
Systolic Blood Pressure 
 
 
SGOT 
Glutamic Oxaloacetic Transaminase 
SGPT 
Glutamic Pyruvic Transaminase 
sMDRD  
Simplified Modification of Diet in Renal Disease 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TBL  
Total Bilirubin 
ULN 
Upper Limit of Normal 
VAS 
Visual analog scale 
WHF  
Worsening heart failure 
WHO-DD 
World Health Organization Drug Dictionary 
μg  
Microgram 
 


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1 
Introduction 
The purpose of this document is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for protocol CRLX030A2302 (also referred as 
Study RELAX-Asia).  
This study is to evaluate the efficacy, safety and tolerability of intravenous infusion of 30 
μg/kg/day serelaxin for 48 hours, when added to standard therapy, in approximately 1,520 
Asian acute heart failure (AHF) patients. 
2 
Statistical methods planned in the protocol and 
determination of sample size 
 
 
 
 
Data will be analyzed according to the data analysis section 9 of the study protocol which will 
be included in Appendix 16.1.1 of the CSR. 
Unless otherwise stated, summary tables/figures/listings will be on all subjects included in the 
population under consideration. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented. Kaplan-Meier curves will be provided for time-to-event variables.  
 
 
 
2.1 
Subject and treatment 
2.1.1 
Analysis population  
For analysis purposes, subjects will be classified accordingly into following analysis sets as 
defined below:  
• Screened set (SCR) – All subjects who signed the informed consent. The SCR includes 
only unique screened subjects. 
• Randomized population (RAN): All subjects who received a randomization number, 
regardless of receiving trial medication 
• Full analysis set (FAS): All subjects in the RAN population who were not misrandomized 
subjects*. Following the intent-to-treat (ITT) principle, subjects are analyzed according to 
the treatment they have been assigned to at the randomization. 
*Misrandomized Subjects are those who have not been qualified for randomization, have 
been inadvertently randomized into the study and who did not take study drug. 
Misrandomized subjects are defined as cases where IRT/IWRS contacts were made by the 


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site either prematurely or inappropriately prior to confirmation of the patient’s final 
randomization eligibility and double-blind medication was not administered to the patient. 
These subjects should subsequently be discontinued from the study. 
• Safety population (SAF): All subjects who received any amount of study drug and have 
at least one post-baseline safety assessment. Of note, the statement that a patient had no 
adverse events also constitutes a safety assessment. Subjects will be analyzed according to 
treatment received. Subjects who received any amount of serelaxin will be included in the 
serelaxin treatment group. 
• Per-protocol population (PPS): All subjects in the FAS who received any amount of 
study medication and who do not have any protocol deviations that could confound the 
interpretation of analyses conducted on the FAS. This PPS is used to assess robustness of 
the primary and key secondary analysis results. 
Note subjects who did not meet inclusion/exclusion criteria but inadvertently randomized and 
received the study drug are not referred as misrandomized subjects per definition in this trial. 
They will be included in RAN, FAS, SAF populations but not in PPS. 
2.1.2 
Protocol deviation (PD) and subject classification 
In general protocol deviations will be categorized as following: 
• Selection criteria not met 
• Subject not withdrawn as per protocol (not defined in the study) 
• Treatment deviation 
• Prohibited concomitant medication (not defined in the study) 
• Other 
Protocol deviations are identified prior to clinical database lock/unblinding and entered into a 
dedicated data panel as part of the locked database.
 
   
The major protocol deviations resulting in exclusion of subjects from an analysis population 
are outlined in the table below:  
Table 2-1 
Major protocol deviations resulting in exclusion of subjects from 
analysis populations 
PD category 
Deviation 
Excluding from analysis set 
RAN 
FAS 
SAF 
PPS 
Selection criteria not 
met 
Missing informed consent (INCL01) 
 
x 
x 
x 
 
Patient hospitalized for reasons of non-AHF event 
(INCL04) 
 
 
 
x 
 
Systolic BP <125 mmHg at the start and/or at the 
end of screening (INCL08) 
 
 
 
x 
 
Time from presentation to randomization >16 
hours (INCL09) 
 
 
 
x 
 
Dose of IV furosemide between presentation and 
 
 
 
x 


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PD category 
Deviation 
Excluding from analysis set 
RAN 
FAS 
SAF 
PPS 
start of screening is < 40 mg (INCL10) 
 
eGFR is <25 or > 75 mL/min/1.73m2 at screening 
(INCL11) 
 
 
 
x 
 
Dyspnea is primarily due to non-cardiac causes 
(EXCL01) 
 
 
 
x 
 
Sepsis or active infection requiring IV anti-
microbial treatment reported at screening 
(EXCL26) 
 
 
 
x 
 
AHF is due to significant arrhythmias (EXCL04) 
 
 
 
x 
Treatment derivation 
Serelaxin infusion administered in dilutent other 
than the recommended 5% dextrose (TRT02) 
 
 
 
x 
 
Wrong study drug kit administered (TRT06) 
 
 
 
x 
 
Subject misrandomized (TRT11) 
 
x 
x 
x 
All exceptional cases, problems and the final decisions on the allocation of subjects to 
populations will be fully defined and documented before data base lock (in particular before 
breaking the blind where applicable) and will be fully identified and summarized in the 
clinical study report.  
Table 2-2 
Non-protocol deviation criteria resulting in exclusion of subjects from 
analysis populations 
Criterion 
Excluding from analysis set 
RAN 
FAS 
SAF 
PPS 
Subject randomized but not receiving any dose of double-blind 
study medication 
 
 
x 
x 
2.1.3 
Time window, baseline and post-baseline definitions, and missing 
data handling  
Screening phase (Hour -16): The screening phase is the time period prior to randomization, 
which should be within 16 hours after presentation. After obtaining written informed consent, 
the subject will be evaluated for eligibility to participate in to the study. 
 All references to index hospitalization refer to the initial hospitalization for acute heart failure 
(AHF). 
Baseline (Hour 0/Day 1):  The assessments identified in the eCRF as baseline assessments 
will be used as the baseline reference for all analyses. The baseline date and time will be 
considered the date and time of initiation of study drug, or randomization if the subject was 
not treated with study drug. If the value is missing, the last value at screening visit will be 
used.               
Post-baseline phase: The post-baseline phase begins at the time when study drug 
administration starts (Hour 0/Day 1) and ends with the last study assessment/last follow-up or 
the death of subject. For subjects who did not receive study drug, the post-baseline phase 
begins at time of randomization.     
Time window: For the scheduled post-baseline visits, time window is not defined; the data 
will be used as reported in eCRFs (i.e., the actual assessment times will not be used to 


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reclassify the time point at which a measure was taken). The by-visit report will be presented 
by protocol scheduled visit. Time-to-event analyses will be based on actual date and time as 
reported when available. 
Missing data handling 
Missing data handling for efficacy endpoints are discussed in Section 2.2, Efficacy evaluation. 
In general, missing values of other assessment/measurement will not be imputed unless 
otherwise specified.  
The dates for efficacy endpoint events and AE events should be reported as instructed in 
eCRFs. If a partially missing date cannot be resolved after data query, the following is the 
general rule for imputation as necessary only if the calculation is needed (e.g., to calculate 
time-to-event): 
a) if only the month of the event is known, then the 15th day of this month will be 
imputed for a missing day in case the month and year are after the month and year of 
double blind treatment start. If the month and year are equal to the double blind 
treatment start then the event date will be imputed by the treatment start date. 
b) if only the year of the event is known, then the 1st July will be imputed for a missing 
day and month in case the 1st July is after double-blind treatment start (otherwise 
treatment start date will be used), or 
c) for events occurring between two visits after randomization, without other information 
available, the date/time in the middle  of these visits will be used. 
 
 
 
 
  
 
Adverse Events with incomplete start dates will be considered treatment emergent (incident) 
if it is not obvious from the partial date whether the event onset was after study drug was 
initiated. 
For lab data which exceed limit of detection, e.g. data reported as >8 or >10, the threshold 
value 8 or 10 will be used in the summary descriptive statistics, and original reported data will 
be listed in the listings.  
2.1.4 
Subgroup definitions 
The subgroups are defined based on subjects’ status at screening (if screening value is not 
collected, Hour 0 value will be used).  
Key subgroups that will be considered in subgroup analyses of the primary and key secondary 
endpoints are listed in Table 2-3. 


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Table 2-3 
Specification of key subgroups at screening 
Variable 
Source 
Categories 
Age group 
Derived 
<65, ≥65; <75, ≥75 years 
Sex 
eCRF 
Male, Female 
Preserved ejection fractions/Reduced 
ejection fractions (PEF/REF)  
(most recent value in last 12 months) 
Derived 
<50%,  ≥50%; <40%, ≥40% 
(CRF: heart failure and diabetes history) 
Prior history of heart failure  
eCRF 
Yes, No (CRF: heart failure and diabetes history) 
 
 
 
  
Table 2-4 
Specification of additional subgroups at screening 
Variable 
Source 
Categories 
Systolic blood pressure  
Derived 
<140, ≥140 mmHg 
Heart rate  
Derived 
< 80, ≥ 80 bpm 
History of Ischemic heart disease 
eCRF 
Yes, No (CRF: heart failure and diabetes history) 
History of diabetic mellitus 
eCRF 
Yes, No (CRF: heart failure and diabetes history) 
History of atrial fibrillation or flutter 
eCRF  
Yes, No (CRF: protocol solicited medical history) 
Time from presentation to randomization  
Derived 
<2, 2-10, >10 hours 
Intravenous (IV) nitrate use at 
randomization 
eCRF 
Yes, No  
Lymphocytes  
Local Lab, 
Derived  
≤12, >12% 
eGFR 
Local Lab, 
Derived 
<30, ≥30; <50, ≥50; <60, ≥60  mL/min/1.73 m2  
2.1.5 
Subject disposition 
The number of subjects randomized (RAN) and included in each analysis population (FAS, 
PPS, and SAF) will be presented by treatment group. The number of subjects screened, 
completed and discontinued from screen phase, and the reasons for screen failures will be 
provided. The number and percentage of subjects in the FAS who completed, discontinued the 
study, and the reason for discontinuation will be presented for each treatment group and 
overall (treatment groups combined).  
The number of subjects screened and randomized per country will be presented for FAS. 
For each subject, the length of follow-up (days) will be computed by subtracting the study 
drug initiation date (or the randomization date for subjects not treated with study drug) from 
the end of study date 
.      


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2.1.6 
Background and demographic characteristics 
Subject   demographics   (age,   sex,   ethnicity,   race,   weight, height and BMI)   and   
baseline characteristics will be summarized for the FAS populations. Screening BNP, NT pro-
BNP and estimated eGFR, laboratory values as reported by the investigator will be 
summarized with standard descriptive statistics. The number and percentage of subjects who 
were hospitalized for heart failure in the past year and subjects on IV nitrates at the time of 
randomization will both be presented.  
For baseline comparability, treatment groups will be compared using the chi-squared test for 
categorical variables and using t-test for continuous variables. The p-values will be provided 
for descriptive purpose and 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. 
In addition, violations of inclusion and exclusion criteria and other protocol deviations will be 
listed. Major protocol deviations resulting in subject exclusion from any analysis (Table 2-1) 
will be summarized by treatment group for RAN population. 
2.1.7 
Medical history 
Medical history data will be summarized by treatment group for FAS. 
Protocol solicited medical history  
The number and percentage of subjects will be presented for each protocol solicited event as 
pre-printed list in eCRFs.  
Heart failure and diabetes history  
The number and percentage of subjects including but not limited to who had history of heart 
failure, New York Heart Association (NYHA) class, primary heart failure etiology 
(ischemic/non-ischemic), who were hospitalized for heart failure, ejection fraction (<40%, 
≥40%; <50%, ≥50%), who were on heart transplant list, and who had history of diabetes 
mellitus will be presented for FAS. The number of HF hospitalization in the past year and 
ejection fraction (%) will also be presented. 
Other medical history 
 
 
 The number and percentage of subjects with each medical condition will be 
provided by treatment group for the FAS. 


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2.1.8 
Other subject history information 
Drug abuse, smoking, and alcohol histories will also be summarized for the FAS by 
presenting the number and percentage of subjects for each pre-printed questionnaire. 
2.1.9 
Study medication 
In general, study drug administration details will be summarized for the FAS and SAF 
populations. This will include time from presentation to randomization (hours), time from first 
IV loop diuretic for the current AHF episode to randomization (hours), time from earlier of 
presentation to hospital or first IV loop diuretic to randomization (hours), on IV nitrates at 
randomization (yes/no), time from randomization to study drug administration (hours), study 
drug administered on either day (yes/no), reason study drug not administered, actual study 
drug received, and the number of days infused (one or two).  
The duration of study drug administration (in hours) and the total volume of study drug 
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, including dose decreased due to blood 
pressure decrease (yes/no) will be summarized by treatment group. 
2.1.10 
Concomitant medications, surgical and medical procedures 
Unless specified, the use of all concomitant medications will be summarized using the SAF 
population. 
Major cardiovascular and non-cardiovascular classes of medication taken by a subject 
approximately 30 days prior to study drug initiation and on a daily basis while hospitalized 
through Day 5, at Discharge, and at Day 14 and other follow-up visits will be recorded. At 
each visit, only those medications currently being taken or those were taken within 24 hours 
prior to the given visit will be collected. These medications are predefined by the code lists 
and will be collected in each of following eCRFs: 
• IV loop diuretic medications for heart failure (collected since initial presentation of 
HF) 
• IV medications other than loop diuretics(collected since initial presentation of HF) 
• Other non-IV prior medications (30 day prior to screening, within 24 hours at each 
visit)  
• Other prior and concomitant medications 
 
IV loop diuretic medications 
IV loop diuretic medications for heart failure include Bumetanide, Etacrynic acid, Ethacrynic 
acid, Furosemide, Torasemide, Torsemide and Piretanide.  
The number and percentage of subjects using each medication will be summarized by 
protocol scheduled time point. Each time point reflects medication use within the preceding 
24 hours.   


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The total daily dose for each medication will also be presented at each time point. In addition, 
cumulative use (total dose as the sum from Day 1) at 48 hours (24 hours/Day 1 and 48 
hours/Day 2), and at Day 5 (from 24 hours/Day 1 to Day 5) in furosemide equivalent (mg) 
will be summarized. The calculation of furosemide equivalents (mg) for Bumetanide, 
Etacrynic acid/Ethacrynic acid ,Torsemide/Torsemide acid and Piretanide are actual dose (mg) 
multiplied by constant 40, 0.8, 2, or 6.67, respectively.  
Doses will be imputed as zero for study days where no use was reported. 
 
 
   
IV medications other than loop diuretics 
Other IV medications include not limited to Dopamine, Dobutamine, Milirinone, Enoximone, 
Norepinephrine, Epinephrine, Nesiritide, Levosimendan, Isosorbide Dinitrate, Nitroglycerin, 
Nitroprusside, Phenylephrine, Caperitide and Other (including but not limited to Danshen).  
The number of subjects using each medication will be presented in the same way as IV loop 
diuretic medications.  
The average dose over the time administered of the medication will be presented separately 
for each medication at each reported time point. No equivalent dose unit among other IV 
medications will be converted.  
Note that the frequency (number and percentage) of subjects using IV loop diuretic and 
vasoactive agents through Day 5 is an efficacy endpoint and it’s discussed in Section 2.2.3. 
Other non-IV prior medications & other non-IV medications 
The number and percentage of subjects using other non-IV medications will be summarized 
for each of the time periods for general, ACE inhibitor (ACEi), angiotensin inhibitor (ARB), 
ACEi or ARB, beta blocker, PO loop diuretics, other PO diuretics,  calcium channel blockers,  
aldosterone antagonist and cardiac glycosides.  
The number (%) of subjects who have these medications initiated during their index 
hospitalization and subjects who have these medications increased during the period 
following discharge from the index hospitalization will also be presented. 
The average daily dose administered will be summarized at each time point for each 
medication within the loop diuretics, ACEi, ARB, beta blocker, aldosterone antagonist, ARNi 
and direct renin inhibitor.  
Other non-IV medications taken prior to and after the start of study drug will be presented by 
the ATC and preferred terms.       
Other prior and concomitant medications 
All other concomitant medications (not included in above classes) and significant non-drug 
therapies, 30 days prior to screening and ongoing basis until subjects completed or 
discontinued from the study, will be summarized respectively by ATC therapeutic class, 
preferred term, and treatment group for the SAF population. 
Alternative medicine or herbal medicine will also be presented for the SAF population.  


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2.2 
Efficacy evaluation 
The Full Analysis Set (FAS) is the primary analysis population for efficacy analyses, 
following the intention-to-treat principle. Per-protocol (PPS) population will be used in the 
supportive analysis for primary and key secondary efficacy parameters (Table 2-5). 
Table 2-5 
List of efficacy endpoints and analyses 
Endpoint 
Analysis set 
Analysis method 
Primary efficacy endpoint (α=0.025, 1-sided) 
1 
Trichotomous composite  
     (success, failure, no change) 
FAS/PPS 
Ordered logistic-regression 
(proportional odds) model that 
includes treatment and 
 
as factors (primary analysis is on 
FAS)  
 
 
FAS 
Ordered logistic-regression model 
including treatment only (sensitivity 
analysis 1) 
 
 
FAS 
van Elteren extension of the Wilcoxon 
test stratified by 
 
(sensitivity analysis 2) 
Secondary efficacy endpoints  
(if primary endpoint is significant, then test in the order listed below at α=0.05 each)  
1 
Time (hours) to WHF through Day 5 
FAS/PPS 
Gehan’s generalized Wilcoxon test 
2 
Time (days) to CV death through Day 180  
FAS/PPS 
Kaplan-Meier estimates and log-rank 
test 
3 
Time (days) to all-cause death through Day 180. 
FAS 
Kaplan-Meier estimates and log-rank 
test 
Other efficacy endpoints (at α=0.05, no multiplicity adjustment) 
1 
Time (hours) to moderate or marked improvements 
in dyspnea by Likert scale through Day 5 
FAS 
Wilcoxon rank-sum test 
2 
Dyspnea by VAS-AUC changes (from baseline) 
through Day 5 
FAS 
ANCOVA  
3 
Length of stay (# of days) in index ICU/CCU 
FAS 
Wilcoxon rank-sum test 
4 
Renal dysfunction or worsening of renal function 
through Day 5 
FAS 
chi-squared test 
5 
Time (days) to re-hospitalization due to HF and 
renal failure through Day 180 
FAS 
Kaplan-Meier estimates and log rank 
test 
6 
Time (days) to CV death or re-hospitalization due 
to HF/RF through Day 180 
FAS 
Kaplan-Meier estimates and log rank 
test 
7 
Time to in-hospital worsening heart failure through 
Day 5 defined by symptoms and signs 
 
Kaplan-Meier estimates and log rank 
test 
8 
Use of loop diuretics and vasoactive agents 
through Day 5 
FAS 
chi-squared test 
9 
Changes in cardio-renal biomarkers (Day 2 and 
Day 5) 
FAS 
Summary statistics, see Section 2.2.3 
2.2.1 
Primary efficacy variable and analyses 
2.2.1.1 
Primary efficacy variable  
The primary efficacy variable is the trichotomous clinical composite endpoint based on  


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(i) treatment ‘success’: as of congestion improvement of dyspnea in Likert (moderately 
and markedly improvement) AND at least 2 points improvement for at least 2 out 
of 4 signs and symptoms variables (orthopnea, edema, rales and JVP)  at Day 2  
(ii) treatment ‘failure’: as of in-hospital worsening heart failure (WHF), all causes of death, 
or re-hospitalization due to heart failure (HF) or renal failure (RF) through Day 5 
(iii) no change: neither of (i) or (ii) 
If a patient meets (i) and (ii), he will only be counted as ‘failure’ (ii).   
For missing Day 2 Likert or signs and symptoms, the previous available post baseline values 
will be used.  
2.2.1.3 
Handling of missing values/censoring/discontinuations 
The components of trichotomous clinical composite endpoint are all categorical variables.  
Missing categorical value will be replaced with the last preceding non-missing value. These 
will include dyspnea Likert scale at Day 2, four signs and symptoms at Day 2 and worsening 
heart failure through Day 5. In the evaluation of treatment success for the four signs and 
symptoms, the change from baseline will need to be calculated. If there is a missing baseline 
value, say a subject with missing JVP at baseline, this subject’s change of JVP at Day 2 will 
be set as 0-point improvement, i.e., will not be contributed as 2-point improvement for JVP.   


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2.2.2 
Secondary efficacy variables and analyses 
There are three secondary variables:  
• WHF through Day 5 
• CV death through Day 180   
• All-cause death through Day 180  
All of these secondary variables are time-to-event variables. The hypothesis will be tested 
based on the FAS at a significance level of 0.025 (one-sided).   
The three secondary variables will be tested using hierarchical testing procedure in controlling 
overall α of 0.05 (Bretz et al 2009).  If primary endpoint is significant, WHF will be tested 
first at α of 0.05.  If WHF is significant at the same α level then will proceed to test CV death 
and only if CV death is significant then will test all-cause death at α of 0.05.   
WHF through Day 5 
Time to WHF through Day 5 will be analyzed using Gehan’s generalized Wilcoxon test. 
Subjects died in the 5-day period will be considered as having WHF event. Event date and 
time will be used at calculating the time to event for better precision, and convert it back to 
days.  
Time-to-event (days) = (first event date/time– baseline date/time),  
For those subjects without events, the censoring date will be the earlier of  
• Hour 120 (5 days) 
• The last date at which the vital status was known, including last visit or contact 
Kaplan-Meier curves will be presented graphically by treatment group and Kaplan-Meier 
estimates for selected time points with 95% confidence intervals will be tabulated. 
In addition, analyses will be performed using a modified definition of WHF, e.g. subjects with 
(1) worsening signs AND symptoms or (2) IV intervention and/or mechanical support. 
Another sensitivity analyses that exclude subjects whose only symptom is abdominal 
bloating/discomfort or fatigue/decreased exercise tolerance will also be provided.  
CV death through Day 180 
CV death will be analyzed with a log-rank test. The time-to-event will be calculated days by 
subtracting the randomization date from the event date. Number and percentage of subjects 
who died from cardiovascular reasons based on the number of subjects in the population as 
denominator will be provided by treatment group. 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.     


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In addition, 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. 
For CV death, a patient without an event will be censored at the earlier of: 
• Date of death for non-CV related causes 
• The last date at which the vital status was known, including last visit or contact 
• Day 180 
An adjudicated death with unknown cause will be classified as a CV death. Similarly, 
investigator suspected deaths of unknown cause will be classified as CV deaths.  
All-cause death through Day 180 
All-cause death through Day 180 will be analyzed similarly to CV death through Day 180. A 
patient without an event will be censored at the last date at which the vital status was known 
(including last visit or contact) or at Day 180. 
Of note, CV death and all-cause death will be two efficacy variables for bridging with other 
global studies. 
2.2.3 
Other efficacy variables and analyses 
Other efficacy variables are listed along with primary and secondary endpoints in Table 2-5. 
Time to moderate or marked improvements in dyspnea assessed by Likert scale through 
Day 5 
Subject-reported dyspnea by Likert scale will be summarized by frequency table at each 
scheduled time point through Day 5 as defined in protocol. Time to moderately or markedly 
improvement comparing with baseline will be analyzed by Wilcoxon rank-sum test, based on 
discrete scheduled hours.  
Since the assessment only occurs on the scheduled visits, the nominal scheduled day will be 
used directly to determine the time to event.   
For those subjects without an event, the censoring date will be the earlier of: 
• Day 6 
• The last date at which the vital status was known, including last visit or contact 
AUC of changes from baseline in patient-reported dyspnea by VAS scale through Day 5 
The area under the curve of the change from baseline in dyspnea VAS scale (VAS AUC) will 
be computed by trapezoidal rule after applying the data handling conventions and 
computations as described below.  
Subjects who die or have a worsening heart failure event (either during the index hospital or 
rehospitalization due to heart failure) will have their score imputed to be the worst observed 
score in any subject at any time point in the respective analysis population carried forward 
from the day of death or WHF regardless of whether their original data are missing. 


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For post-baseline visual analog scale (VAS) values otherwise missing, a missing score will be 
imputed using linear interpolation between the last preceding and first following non-missing 
values. If no following non-missing value is available, the last available preceding value will 
be carried forward. A missing baseline score will be imputed as the earliest, non-missing 
score within 24 hours for the subject minus the average change from baseline in the study 
population to that time point; post-baseline scores for subjects for whom a missing baseline 
cannot be thus imputed will be included in the analysis as no change from baseline.  Except 
for subjects who die or who experience WHF, subjects who are missing all post-baseline 
dyspnea VAS scores will be included in the analysis as having no change from baseline at any 
time point.   
Descriptive statistics of the area under the curve for the dyspnea VAS change from baseline 
scores will be presented at each time interval of interest by treatment group. Treatment groups 
will be compared by presenting the mean difference and corresponding 95% CI and using 
ANCOVA model with baseline VAS as a covariate.  
For those subjects who have at least one post-baseline assessment, their AUC will be 
approximated by ∑mk=2wk ỹk, where ỹk = 0.5(yk + yk-1), wk = (tk – tk-1)/(tm – t1), and yj is the 
change-from-baseline in dyspnea VAS value at time tj, for j = 1, …, m, in which t1 < …< tm. 
m is the number of measurements for a subject and t1 is time of the baseline, that is, t1 = 0 and 
y1 = 0. The scheduled time will be used in the calculation.  
In addition, descriptive statistics for the baseline values, the post-baseline values, and the 
change from baseline value will be provided at each scheduled time point by treatment group.  
Length of stay in index ICU/CCU 
The length (days) of stay in ICU/CCU will be obtained from eCRF page directly. If the 
information is missing in eCRF page or subjects who die during the initial hospitalization, the 
maximum number of days in the ICU/CCU over all subjects in FAS will be assigned. It will 
be analyzed using a Wilcoxon rank sum test.  
Renal dysfunction or in-hospital worsening of renal function through Day 5 
Worsening renal function is defined as an increase in serum creatinine of ≥ 0.3 mg/L (27 
μmol/L), from the values measured at baseline. A subject who meets the criteria at any time 
during the 5 days after infusion will be counted once; the chi-squared test will be performed 
for comparing two treatments. 
Number and percentage of subjects will be displayed by treatment and visit for the following 
category: ≥ 0.3 mg/L increase in serum creatinine. 
Additional summaries of serum creatinine and eGFR are discussed in Section 2.4.2.2, Clinical 
chemistry. 
Time to CV death or rehospitalization due to heart failure (HF)/renal failure (RF) 
through Day 180 
Time-to-event (in days) will be calculated using time of first event of adjudicated CV death or 
adjudicated rehospitalization due to HF/RF minus time of randomization. If the reason for 
adjudicated death or rehospitalization is unknown, it will be considered as the event.  The 
analysis and censoring method will be performed similarly to time-to-CV death.  


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Time to rehospitalization due to heart failure (HF) or renal failure (RF) through Day 
180 
Time-to-event (in days) will be calculated using time of first event of adjudicated 
rehospitalization due to HF or RF minus time of randomization. If the reason for adjudicated 
rehospitalization is unknown, it will be considered as the event.  
The analysis and censoring method will be performed similarly to time-to-all-cause-death.  
Due to competing risk between death and rehospitalization, the difference in mortality 
between the treatment groups may mislead the results. In this case, the composite endpoint of 
Time to CV death or rehospitalization due to heart failure (HF)/renal failure (RF) through Day 
180 provides more reliable results.  
Time to in-hospital worsening heart failure through Day 5 by symptoms and signs 
Time-to-event (in days) will be calculated using time of first event of in-hospital worsening 
heart failure through Day 5. The worsening heart failure is defined by symptoms only, signs 
only, and by both symptoms and signs. The analysis and censoring method will be performed 
similarly to time-to-WHF.  
Use of IV loop diuretic and vasoactive agents through Day 5 
The subjects with intravenous diuretic and vasoactive therapy (yes/no) during 5 days after 
study medication infusion will be analyzed using chi-squared test.  
The medications of interest are collected in two eCRF pages: “IV loop diuretic medications 
for heart failure” and “IV medications other than loop diuretics” (Section 2.1.10). The 
summaries of doses for those medications are also addressed in Section 2.1.10.  
Change from baseline in cardio-renal biomarkers through Day 2 and Day 5 
Biomarkers related to cardic and renal function/injury including but not limited to high 
sensitivity troponin T, NT-proBNP, and Cystatin C will be collected at baseline, at 48 hours 
(Day 2) and 120 hours (Day 5) post infusion. This list of potential biomarkers may be 
changed or expanded further as it is recognized that more relevant or novel biomarkers may 
be discovered.  
Details are described in the separate biomarker statistical analysis plan. 
2.3 
Pharmacokinetic evaluations 
All subjects with at least one available valid (i.e. not flagged for exclusion) PK concentration 
measurement, who received serelaxin infusion and experienced no protocol deviations with 
relevant impact on PK data will be included in the pharmacokinetic (PK) data analysis. Steady 
state concentration (Css) will be estimated based on the serum concentration determined at the 
48 hour time point prior to the end of infusion. Systemic clearance will be calculated using the 
rate of infusion and Css for each subject as indicated below:  
Clearance (mL/hr/kg) = Rate of infusion (µg/kg/hr) /Css (µg/mL) 
Where the rate of infusion is the actual dosing rate calculated as below for each individual 
subject: 


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where VolRLX is the volume of serelaxin drawn from the vials and added to a volume VolSol 
of the solution contained in the infusion bag, ConRLX is the concentration of the serelaxin 
stock solution in the vial (1000 µg/mL), Flow is the flow rate of the solution from the infusion 
bag, and Weight is the body weight measured at Day 1 pre-dose baseline. Since only sparse 
PK time points for serelaxin serum concentration will be collected, no other PK parameters 
will be determined in this study.  
Missing values or those below the assay LLOQ (BLQ) will be indicated in the data listings 
and treated as zero for PK parameter calculations and presentation. 
Descriptive statistics for serelaxin concentrations will be listed by time points (for baseline 
and 48hr samples only) to include arithmetic mean, geometric mean with its corresponding 
90% confidence interval, median, SD, CV, min and max.  A value of “0” will be used for 
samples that are BLQ in these calculations and therefore be excluded from geometric mean 
calculations. Descriptive statistics include arithmetic mean, geometric mean with its 
corresponding 90% confidence interval, median, SD, CV, min and max will also be provided 
for the two PK parameters, Css and clearance (CL). 
Subgroup analysis on Css and CL to assess the potential effects of various extrinsic and 
intrinsic factors on the PK of serelaxin may be performed as appropriate. These factors may 
include but not limited to renal function (e.g. eGFR), age, gender, race or ethnicity, country, 
concomitant medications, etc. 
Serelaxin serum concentration will be assayed in Day 60 samples as well, in order to 
demonstrate the lack of drug interference with the immunogenicity assay. This data will be 
included only as part of the immunogenicity results but not in the PK results (see Section 
2.6.3). 
2.4 
Safety evaluation 
Safety evaluations including AE, SAE, laboratory, vital sign, confirmed blood pressure 
decreases, ECG etc. will be reported for safety population (SAF) by treatment as received. 
2.4.1 
Adverse events 
2.4.1.1 
AEs and SAEs 
The incidence of AEs recorded through Day 5 and the incidence of SAEs recorded through 
Day 14 will be presented for the Safety population. Incident AEs will be considered those 
AEs with an onset date and time after the initiation of study drug. Adverse events with an 
onset between informed consent and study drug initiation will be listed separately. Adverse 
events will be coded using latest version of MedDRA. All reported AEs will be summarized 
by system organ class (SOC) and preferred term (PT) by treatment groups. Serious AEs 
(SAEs) will be summarized similarly. Percentages will be based on the number of subjects in 
the SAF. 


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In addition, SAEs will be summarized by time period of onset: from study drug initiation up 
to and including Day 5, or from Day 6 up to and including Day 14. All AEs through Day 14 
will also be provided. After Day 14 only suspected serious adverse events will be collected 
and reported to Novartis. Additionally, a summary of AEs by PT and severity, using the worst 
reported severity grade for each event for the subject, will be provided. For analysis purposes, 
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, and study-drug-related SAEs, SAEs with an outcome of death, and SAEs leading to 
study drug discontinuation will be summarized by percentages and frequencies. For the 
analysis by time period of onset, the percentages will be based on the number of subjects at 
risk for AEs at the beginning of the period in the Safety Set. For each adverse event listed, the 
verbatim and coded terms, the corresponding severity, relationship to study drug, seriousness 
(yes/no), and start and stop date and time of the event will be specified and displayed by 
treatment group and subject number.  
Detailed AE listings will also be provided. 
2.4.1.2 
Selected AEs 
AEs representing identified and potential safety risk in addition to events of interest will be 
grouped.  The incidence (absolute and relative frequency) of each potential risk will be 
summarized by treatment group. Odds ratios and associated 95% confidence intervals 
comparing serelaxin with placebo will be presented using the Mantel-Haenszel test. In 
addition, subjects experiencing each of these risks will be listed.  Such safety risks and events 
of interest are displayed in below table.   
Table 2-6  
Safety risk and event of interest search specification 
 
Type of Risk 
Specification 
Safety risk 
 
Hypotension 
     NMQ ‘Hypotension’ (Broad)     
Hemoglobin/ hematocrit transient 
decrease 
SMQ ‘Haemorrhages’ (Broad) 
HLGT ‘Anaemias nonhaemolytic and marrow 
depression’ 
SMQ ‘Haematopoietic erythropenia’ (Broad) 
Fetotoxicity and teratogenicity 
SMQ ’Pregnancy and neonatal topics’ (Broad) 
Event of interest  
 
Hypokalemia 
NMQ ‘Hypokalemia’ (Broad)  
Menorrhagia/Metrorrhagia 
HLGT ‘Menstrual cycle and uterine bleeding disorders’ 
Potential promotion of cancers 
SMQ ‘Malignancies’ (Broad) 
Immunogenicity/Hypersensitivity 
SMQ ‘Hypersensitivity’ (Broad) 
SMQ ‘Angioedema’(Broad) 
SMQ ‘Anaphylactic reaction’(Broad) 
SOC ‘Immune system disorders’ 
HLGT ‘Immunology and allergy investigations’ 
HLGT ‘Administration site reactions’ 


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Type of Risk 
Specification 
SMQ ‘Severe cutaneous adverse reactions’(Broad) 
Cardiac failure 
SMQ ’Cardiac  failure’ (Broad) 
 
QT prolongation 
SMQ ‘Torsade de pointes/QT prolongation’ (Broad) 
SMQ ‘Cardiac arrhythmias’ (Broad) 
Thromboembolic events 
SMQ ‘Embolic and thrombotic events’ 
Renal impairment 
SMQ ‘Acute renal failure’ (Broad) 
Respiratory failure 
SMQ ‘Respiratory failure’ (Broad) 
Hepatotoxicity 
SMQ ‘Drug related hepatic disorders – comprehensive 
search’ (Broad) 
AEs with an onset between informed consent and study drug initiation will be listed.  
2.4.2 
Laboratory data 
According to protocol, a central laboratory will be used for the analysis of all baseline and 
post-baseline specimens collected, except for hematology and clinical chemistry at screening, 
it will be done locally and the result will be entered into eCRF.  
2.4.2.1 
Hematology 
The following hematology tests will be measured locally at screening and centrally at baseline 
and post-baseline: RBC, hemoglobin, hematocrit, platelet, and white blood cell count, 
including differentials. 


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2.4.2.2 
Clinical chemistry    
The following serum chemistry tests will be measured locally at screening and centrally at 
baseline and post-baseline: sodium, potassium, glucose, blood urea nitrogen (BUN) or urea, 
AST, ALT, alkaline phosphatase, total bilirubin, and creatinine. In addition, BNP/NT pro-
BNP, eGFR and hemoglobinA1c will be measured locally at screening only. 
Hematology and clinical chemistry data from central lab will be summarized for safety 
population by presenting shift tables using extended normal ranges (baseline to most extreme 
post-baseline value), summary statistics of raw data and change from baseline (means, 
medians, standard deviations, 1st and 3rd quartiles (Q1 and Q3), and by flagging of notable 
values in data listings. Shift tables are based on the cross-classification of the number of 
subjects with clinical laboratory values below (low), within (normal), or above (high) normal 
ranges for each laboratory test.  
The number and percentage of subjects with clinically notable laboratory results after baseline 
will be presented. Clinically notable laboratory values are defined below.  
Table 2-7 
Clinically notable laboratory abnormalities for selected tests 
Parameter 
Criteria (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) 
defined in Section 2.4.7.1 (liver toxicity) 
AST (SGOT) 
defined in Section 2.4.7.1 (liver toxicity) 
BUN 
>100% increase 
Creatinine 
>100% increase 
Total bilirubin (TBL) 
defined in Section 2.4.7.1 (liver toxicity) 
Alkaline phosphatase 
(ALP) 
defined in Section 2.4.7.1 (liver toxicity) 
Potassium 
>25% increase, >25% decrease 
Calcium 
>20% increase, >20% decrease 
Uric acid 
>100% increase 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal range 
The data from local and central laboratory will be presented separately. All laboratory data 
from central lab will be listed for each subject. Laboratory values that are outside the normal 
ranges will be flagged high (H) or low (L). Data from local laboratory will be listed separately 
by lab. 
 


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Creatinine and eGFR 
eGFR will be calculated using simplified Modification of Diet in Renal Disease (sMDRD). 
The proportion of subjects with >= 0.3 mg/dL increase, >=0.5 mg/dL increase, >= 1.0 mg/dL 
increase, and >50% increase from baseline in serum creatinine levels at each time point, and 
at any time point, will be presented.  
The proportion of subjects with decreases from baseline eGFR of >25%, >40%, >50%, 
and >30 mL/min/1.73 m2 at each time point, and at any time point, will be presented.  
In addition, worsening renal function based on serum creatinine and plasma cystatin-C values 
as one of efficacy variables is defined and discussed in Section 2.2.3. 
Blood sample for hepatitis serology 
A blood sample will be collected at baseline and stored at the central laboratory for hepatitis 
serology analysis in case of a significant liver event (refer to Section 2.4.7). 
2.4.3 
Vital signs 
For vital signs, descriptive statistics will be provided for values and change from baseline at 
each  assessment  time  point  for  pulse,  respiratory  rate,  body  temperature,  and  weight. 
Treatment groups will be compared for changes from baseline using t-test. 
Blood pressure and pulse during 48 hours drug infusion and 48 hours post infusion will also 
be listed. 
2.4.4 
Electrocardiogram (ECG) 
 
 
 
The following quantitative variables will be summarized: ventricular rate, PR interval, QRS 
duration, QT interval, and corrected QT interval (QTc).   
The number and percentage of subjects with the following criterion will be presented. 
• QT > 500 msec  
• QT > 480 msec  
• QT > 450 msec 
• QT increases from baseline >= 30 msec 
• QT increases from baseline >= 60 msec 
• PR > 200 and <= 220 msec 
• PR > 220 msec 
• PR increases from baseline > 25% (PR > 200 msec) 
• QRS > 110 and <= 120 msec 
• QRS > 120 msec 
• QRS changes from baseline > 25% (QRS > 110 msec) 


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• Heart rate >100 beats per minute 
• Heart rate < 50 beats per minute 
QT data will be analyzed for the Fridericia (primary) corrections. 
In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, 
total) with the maximum on-study result (normal, abnormal, not available, total) will be 
provided for each variable. 
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
subject listing of all quantitative ECG parameters.  
2.4.5 
Confirmed blood pressure decreases 
The number and proportion of subjects who experience a confirmed blood pressure decrease 
event during study drug administration will be provided.  Among subjects who experience a 
confirmed blood pressure decrease event, the events will be further characterized with respect 
to impact on study drug administration (dose decreased or study drug discontinued), the 
timing of event onset relative to study drug initiation, the magnitude of the blood pressure 
decrease at its onset and the trough blood pressure recorded, the blood pressure measurements 
after study drug discontinuation, outcome, treatment(s) required, and whether considered 
symptomatic, i.e. an AE. Summaries will be provided separately for those confirmed events 
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.  
Course of blood pressure after the occurrence of first CBPD up to Day 5 will be presented.  
To further investigate the impact of CBPD, the following analyses will be performed.  
• Baseline characteristics by CBPD subgroup (yes/no). 
• Concomitant medications by CBPD subgroup (yes/no). 
• AEs associated with the occurrence of the CBPD. 
2.4.6 
Pregnancy test results  
Positive results will be presented in listing. 
2.4.7 
Liver toxicity function and liver events 
Liver event and laboratory trigger definitions are defined in Appendix 2 of protocol.  
2.4.7.1 
Liver toxicity function 
The liver toxicity (LFT abnormality) will be identified with the Adverse Event (jaundice and 
“Drug-related hepatic disorders - severe events only” SMQ AE), and the laboratory 
parameters mainly AST (aspartate aminotransferase; also known as SGOT), ALT (alanine 
aminotransferase; also known as SGPT), ALP (alkaline phosphatase) and TBL (total bilirubin; 
conjugated (direct) and unconjugated (indirect) bilirubin). 


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The standard SMQ-PT table and odds ratio will be used to provide the number and percentage 
of subjects with hepatic disorders as mentioned in Section 2.4.1.2, Selected AEs.  
The laboratory parameters for liver function will be shown in the laboratory standard tables as 
discussed in Section 2.4.2.2. 
In addition, summary tables will be provided on the number and percentage of subjects who 
meet the following criteria at post baseline. 
Table 2-8 
Criteria for evaluating liver toxicity 
Parameter 
Criterion 
ALT or AST 
ALT or AST > 3xULN 
 
ALT or AST > 5xULN 
 
ALT or AST > 8xULN 
 
ALT or AST > 10xULN 
 
 
Hy’s category 
ALT or AST >3x ULN and TBL >1.5x ULN 
 
ALT or AST > 3xULN & TBL > 2xULN 
 
ALT or AST > 5xULN & TBL > 2xULN  
 
ALT or AST > 8xULN & TBL > 2xULN  
 
ALT or AST > 10xULN & TBL > 2xULN 
 
ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN 
 
 
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/AST <3x ULN and ALP <2x ULN 
 
 
Isolated ALP 
ALP >1.5x ULN &  ALT and AST <3x ULN and TBL <1.5x ULN 
 
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 
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total 
bilirubin; ULN: upper limit of normal.  
Plots showing the relationship between TBL and ALT or AST (eDish plot) will also be 
provided.  
2.4.7.2 
Liver events 
For subjects who are identified with a liver event, additional information will be collected as 
pre-printed in the following eCRFs: 


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2.5 
Interim analysis 
There will be no formal efficacy interim analysis.  
However to monitor subject safety data on a regular basis during the course of the study, an 
external independent data monitoring committee (DMC) has been established and will review 
safety data two times a year as planned in the DMC charter. DMC may request additional 
safety data reviews as needed. Such safety data reviews do not inflate the type I error for the 
primary efficacy hypothesis testing and thus require no multiplicity adjustments.  
 
 
 
2.6 
Other topics  
2.6.1 
Resource utilization  
Summary statistics on hospital length of stay (days) for the index hospitalization and  length 
of ICU/CCU stay for the index and subsequent hospitalizations, as well as procedures 
rendered during these hospitalizations will be provided by treatment group for FAS.  
2.6.2 
Health-related Quality of Life 
Health related quality of life assessments will not be collected in this study. 
2.6.3 
Immunogenicity  
Anti-serelaxin antibodies will be measured in serum samples collected at the Day 60 time 
point. To account for individual variability in background of each subject and to check for 
endogenous interference and/or pre-existing anti-serelaxin antibodies, anti-serelaxin 
antibodies will also be measured at baseline. The analysis will be done for all subjects who 
received any study treatment and who had an anti-serelaxin antibody measurement performed. 


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Results of the anti-serelaxin antibody 
assays (including anti-serelaxin antibody 
positive/negative, titer, and neutralizing antibody positive/negative) will be listed by treatment 
group, subject and sampling time. Incidence rate of positive anti-serelaxin antibodies and 
neutralizing antibodies will be computed and summarized by treatment group and sampling 
time. 
2.7 
Determination of sample size 
A sample size of 1,520 AHF subjects will need to be randomized 1:1 to serelaxin and placebo.  
This study will have 80% power at a  two-sided type-I error of 5% to detect a distributional 
shift with a common odds ratio of 0.75 between the distributions of placebo and serelaxin as 
presented in the table below, where the distribution of categories of the clinical composite 
endpoint in placebo were based on data from RELAX-AHF (RLXN.C.003).   
 
 
 
3 
References 
1. Bretz F, Maurer W, Brannath W, and Posch M (2009) A graphical approach to 
sequentially rejective multiple test procedures. Statistics in Medicine 28, 586-604 
2. Levey AS, Coresh J, Balk E, et al (2003) National Kidney Foundation Practice Guidelines 
for Chronic Kidney Disease:  Evaluation, Classification, and Stratification. Ann Intern 
Med; 139:137-147. 
3. Metra M, Ponikowski P, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, 
Tsushung HA, Severin T, Unemori E, Voors AA, Teerlink JR (2013). Effects of serelaxin 
in subgroups of patients with acute heart failure: results from RELAX-AHF. European 
Heart Journal;34:3128-3136.