Clinical trial NCT02151383
Conditions: Acute Heart Failure
Keywords: Acute heart failure RELAX-AHF-PEDIATRIC PK AHF
Sponsor: Novartis Pharmaceuticals
Start date: 2014-09-05; Completion date: 2017-04-03
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study was to evaluate the safety, tolerability and pharmacokinetics of an intravenous infusion of serelaxin on top of standard of care therapy, in pediatric patients with acute heart failure (AHF)

Detailed description:
The study was terminated early and the pediatric development of serelaxin in the treatment of acute heart failure (AHF) discontinued, following the results of the phase III study RELAX-AHF-2 (CRLX030A2301/NCT01870778) study in adult patients with AHF. Whilst no new safety concerns associated with serelaxin were observed, the study in adults did not meet either of its primary endpoints

Arms: arm 1: Serelaxin was administered intravenously on top of standard therapy for acute heart failure, for a total of 48 hours.
Interventions: intervention 1: Serelaxin
Intervention descriptions: intervention 1: Serelaxin was administered intravenously for up to 48 hours.

Protocol documents:
Prot_000.pdf: 
_________________________________________________________________________________
Clinical Development
RLX030/Serelaxin
Study No. CRLX030A2208 / NCT02151383
Multicenter, open-label, dose escalation study to evaluate 
safety, tolerability and pharmacokinetics of RLX030 in 
addition to standard of care in pediatric patients from birth 
to <18 years of age, hospitalized with acute heart failure
Document type:
Amended Protocol Version
EUDRACT number:
2013-002847-28
Version number:
v04 Clean
Development phase:
II
Release date:
30-Sep-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 30-April-2013
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 4 ...........................................................................................................................10
Amendment 3 ...........................................................................................................................13
Amendment 2 ...........................................................................................................................15
Amendment 1 ...........................................................................................................................17
Protocol synopsis...............................................................................................................20
1
Introduction .......................................................................................................................25
1.1
Background............................................................................................................25
1.2
Purpose ..................................................................................................................29
2
Study objectives.................................................................................................................29
2.1
Primary objectives .................................................................................................29
2.2
Secondary objective...............................................................................................29
2.3
Exploratory objectives...........................................................................................29
3
Investigational plan ...........................................................................................................29
3.1
Study design...........................................................................................................29
3.2
Rationale of study design.......................................................................................33
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....34
3.4
Rationale for choice of comparator .......................................................................34
3.5
Purpose and timing of interim analyses/design adaptations..................................34
3.6
Risks and benefits..................................................................................................34
4
Population..........................................................................................................................36
4.1
Inclusion criteria ....................................................................................................36
4.2
Exclusion criteria...................................................................................................38
5
Treatment...........................................................................................................................41
5.1
Protocol requested treatment .................................................................................41
5.1.1
Investigational treatment.......................................................................41
5.2
Additional study treatment ....................................................................................41
5.3
Treatment arms......................................................................................................41
5.4
Treatment blinding.................................................................................................41
5.5
Treating the patient................................................................................................42
5.5.1
Patient numbering .................................................................................42
 


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5.5.2
Dispensing the investigational treatment ..............................................42
5.5.3
Handling of study treatment..................................................................42
5.5.4
Instructions for prescribing and taking study treatment........................43
5.5.5
Permitted dose adjustments of study treatment.....................................44
5.5.6
Rescue medication ................................................................................45
5.5.7
Concomitant treatment..........................................................................45
5.5.8
Prohibited Treatment.............................................................................46
5.5.9
Discontinuation of study treatment .......................................................46
5.5.10
Withdrawal of consent ..........................................................................47
5.5.11
Loss to follow-up ..................................................................................48
5.5.12
Emergency breaking of assigned treatment code..................................48
5.5.13
Study completion and post-study treatment..........................................48
5.5.14
Early study termination.........................................................................48
6
Visit schedule and assessments .........................................................................................48
6.1
Information to be collected on screening failures..................................................53
6.2
Patient demographics/other baseline characteristics .............................................53
6.3
Treatment exposure and compliance .....................................................................53
6.4
Efficacy..................................................................................................................54
6.4.1
Hemodynamic assessments...................................................................54
6.4.2
Exploratory assessments .......................................................................54
6.4.3
Appropriateness of efficacy assessments..............................................55
6.5
Safety.....................................................................................................................56
6.5.1
Physical examination ............................................................................56
6.5.2
Vital signs, respiratory parameters and clinical assessments................56
6.5.3
Height and weight .................................................................................58
6.5.4
Laboratory evaluations..........................................................................58
6.5.5
Electrocardiogram (ECG) .....................................................................59
6.5.6
Pregnancy and assessments of fertility .................................................59
6.5.7
Chest X-ray ...........................................................................................59
6.5.8
Appropriateness of safety measurements..............................................60
6.6
Other assessments..................................................................................................60
6.6.1
Resource utilization...............................................................................60
6.6.2
Pharmacokinetics and Immunogenicity................................................60
6.6.3
Pharmacogenetics/pharmacogenomics .................................................61
6.6.4
Other biomarkers...................................................................................61
7
Safety monitoring..............................................................................................................61
 


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7.1
Adverse events.......................................................................................................61
7.2
Serious adverse events (SAEs)..............................................................................62
7.2.1
Definition of SAEs................................................................................62
7.2.2
Serious adverse event (SAE) reporting.................................................63
7.3
Liver safety monitoring .........................................................................................64
7.4
Pregnancy reporting...............................................................................................65
8
Data review and database management.............................................................................65
8.1
Site monitoring ......................................................................................................65
8.2
Data collection.......................................................................................................66
8.3
Database management and quality control............................................................66
8.4
Interim safety and PK data review.........................................................................67
8.5
Adjudication Committee........................................................................................68
9
Data analysis......................................................................................................................68
9.1
Analysis sets ..........................................................................................................68
9.2
Patient demographics and other baseline characteristics.......................................68
9.3
Treatments .............................................................................................................68
9.4
Analysis of the primary variable(s) .......................................................................69
9.4.1
Variable(s).............................................................................................69
9.4.2
Statistical model, hypothesis, and method of analysis..........................69
9.4.3
Handling of missing values/censoring/discontinuations.......................70
9.4.4
Supportive analyses...............................................................................70
9.5
Analysis of secondary variables ............................................................................70
9.5.1
Efficacy variables..................................................................................70
9.5.2
Safety variables .....................................................................................71
9.5.3
Resource utilization...............................................................................72
9.5.4
Pharmacokinetics ..................................................................................72
9.5.5
Pharmacogenetics/pharmacogenomics .................................................72
9.5.6
Biomarkers............................................................................................72
9.5.7
PK/PD ...................................................................................................72
9.6
Interim analyses.....................................................................................................73
9.7
Sample size calculation..........................................................................................73
10 Ethical considerations........................................................................................................73
10.1
Regulatory and ethical compliance........................................................................73
10.2
Informed consent procedures.................................................................................73
10.3
Responsibilities of the investigator and IRB/IEC..................................................74
10.4
Publication of study protocol and results...............................................................74
 


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11 Protocol adherence ............................................................................................................74
11.1
Protocol Amendments ...........................................................................................75
12 References .........................................................................................................................76
13 Appendix 1: 
79
14 Appendix 2:
 
..81
15 Appendix 3: 25th Percentile Systolic Blood Pressure Table..............................................84
16 Appendix 4: 5th Percentile Systolic Blood Pressure Table................................................86
17 Appendix 5:
 
88
18 Appendix 6:
91
19 Appendix 7: Oxygen delivery devices and FiO2 ...............................................................92
20 Appendix 8:
93
List of tables
Table 1-1
Causes of heart failure in children and adolescents ..............................25
Table 6-1
Assessment schedule.............................................................................50
Table 15-1
25th Percentile Systolic Blood Pressure Table* ....................................84
Table 16-1
5th Percentile Systolic Blood Pressure Table (AHA PALS 
Guidelines)............................................................................................86
 
 
Table 19-1
Oxygen delivery devices and FiO2........................................................92
 


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List of abbreviations
AE
Adverse event
AHA
American heart association
AHF
Acute heart failure
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUCinf
Area under the serum concentration-time curve from time zero to infinity
AUClast
Area under the serum concentration-time curve from time zero to the time of 
the last quantifiable concentration point
AV
atrio-ventricular
BG
Blood gasses
bid
Twice a day
BP
Blood pressure
BUN
Blood urea nitrogen
cAMP
Cyclic adenosin monophosphate
Cdyn
Dynamic lung compliance
CFR
US Code of Federal Regulations
CHBP
Child-bearing potential
CL
Clearance
CPO
Country Pharma Organization
CRF
Case report form
CRO
Contract Research Organization
Css
Steady-state concentration
CV
Cardiovascular
CVP
Central venous pressure
DBP
Diastolic blood pressure
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation
eCRF
Electronic case report form
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
 


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EMR
Electronic Medical Record
ETCO2
End-tidal CO2
FiO2
Inspired oxygen fraction
GCP
Good Clinical Practice
HF
Heart failure
HR
Heart rate
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
iv
Intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
LAP
Left atrial pressure
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)
LVEF
Left ventricular ejection fraction
LVEDD
Left ventricular end-diastolic dimensions
LVESD
Left ventricular end-systolic dimensions
LVFS
Left ventricular fractional shortening
LVOTO
Left ventricular outflow tract obstruction
MAP
Mean airway pressure
MedDRA
Medical dictionary for regulatory activities 
OC/RDC
Oracle Clinical/Remote Data Capture
od
Once a day
paO2
Arterial oxygen partial pressure
PALS
Pediatric advanced life support
PAP
Pulmonary artery pressure
PEEP
Positive end-expiratory pressure
PIP
Peak inspiratory pressure
po
Oral(ly)
PK
Pharmacokinetic
RR
Respiratory rate
RRT
Renal replacement therapy
 


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RXFP1
Relaxin family peptide receptor 1
SAE
Serious adverse event
SBP
Systolic blood pressure
SaO2
Arterial oxygen saturation
SpO2
Pulse oximetry
ScvO2
Central venous oxygen saturation
SOC
Standard of care
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1/2
Terminal phase half-life
T3
Tracking, Trajectory, Trigger Software technology from EtiometryTM
TcCO2
Transcutaneous CO2
TCPC
Total cavo-pulmonary connection procedure
ULN
Upper limit of normal
VAD
Ventricular assist device
VAS
Visual analog scale
VEGF
Vascular endothelial growth factor
WHO
World Health Organization 
 


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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 system
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.
Part 
A single component of a study which contains different objectives 
or populations within that single study. Common parts within a 
study are: a single dose part and a multiple dose part, or a part in 
patients with established disease and in those with newly-
diagnosed disease.
Period
A subdivision of a cross-over study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all investigational/study treatment 
administration and all assessments (including follow-up)
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study/investigational treatment was discontinued whichever 
is later
Study drug/ treatment
Any single drug or combination of drugs administered to the patient 
as part of the required study procedures; includes investigational 
drug (s), active drug run-ins or background therapy 
Study/investigational treatment 
discontinuation
Point/time when patient permanently stops taking 
study/investigational treatment for any reason; may or may not 
also be the point/time of premature patient withdrawal
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
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
 


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Protocol synopsis
Protocol number
CRLX030A2208
Title
Multicenter, open-label, dose escalation study to evaluate safety, 
tolerability and pharmacokinetics of RLX030 in addition to standard of care 
in pediatric patients from birth to <18 years of age, hospitalized with acute 
heart failure
Brief title
PK and safety of serelaxin when added to standard of care in pediatric 
patients hospitalized with acute heart failure
Sponsor and Clinical 
Phase
Novartis/Phase II
Investigation type
Biologic
Study type
PK and safety
Purpose and rationale
The purpose of this open-label, dose escalation study is to evaluate safety, 
tolerability and pharmacokinetics of 48 hour iv serelaxin (RLX030) infusion 
in addition to standard of care (SOC) therapy in pediatric patients from 
birth to <18 years of age, who are hospitalized with AHF. 
 
 
 
Primary Objectives
Primary Objectives

To evaluate the safety and tolerability of an iv serelaxin infusion in 
addition to standard of care in hospitalized pediatric patients with AHF

To investigate the effects of age on the pharmacokinetics of serelaxin 
given as iv infusion in addition to standard of care in hospitalized 
pediatric patients with AHF
Secondary Objective
Secondary objective
To evaluate the hemodynamic effects of different doses of serelaxin given 
as an iv infusion in addition to standard of care in hospitalized pediatric 
patients with AHF (efficacy parameters: arterial blood pressure, ), left atrial 
pressure (LAP), pulmonary artery pressure (PAP – systolic and diastolic)
central venous and arterial oxygen saturation, urine output, and blood 
lactate levels)
Study design
This is a multicenter, open-label, dose-escalation study to evaluate the 
safety, tolerability and pharmacokinetics of RLX030 in addition to standard 
of care in pediatric patients from birth to <18 years. A fixed dose titration 
scheme will be used for this study. A total duration of 48 hours is planned 
for the constant iv serelaxin infusion with dose escalations every 16 hours.
A low-dose group and a high-dose group will be enrolled sequentially in 
every age cohort. During this 48-hour treatment period, the serelaxin dose 
rates to be administered are 3 µg/kg/day, 10 µg/kg/day and 30 µg/kg/day 
in the low-dose group; 10 µg/kg/day, 30 µg/kg/day and 100 µg/kg/day in 
the high-dose group. These dose rates are anticipated to be safe in the 
pediatric population and are based on the dose range investigated in 
adults with AHF.
 


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A minimum of 30 male or female pediatric patients will be enrolled in this 
study with 3 patients in each low-dose group for age cohorts 1, 2, 3 and 4; 
and 6 patients in each high-dose group for age cohorts 3 and 4, and 3 
(maximum 6) patients in each high-dose group for age cohorts 1 and 2.
The four age cohorts are as follows:

Cohort 1: 6 to <18 years [3 low-dose patients, 3 high-dose patients 
(maximum 6)]

Cohort 2: 1 to <6 years [3 low-dose patients, 3 high-dose patients 
(maximum 6)]

Cohort 3: infants 1 month to <1 year [3 low-dose patients, 6 high-dose 
patients]

Cohort 4: neonates birth to <1 month [3 low-dose patients, 6 high-dose 
patients]
Age cohorts will be enrolled sequentially from age cohort 1 to 4, within 
each dose group. For each age cohort, patients will be enrolled first into 
the low-dose group and if it is considered safe after a review of all 
available safety and pharmacokinetic (PK) data, up to and including study 
day 5, then patients will be enrolled into the low-dose group for the 
succeeding age cohort. Patients cannot be enrolled into the high-dose 
group for a given age cohort until data from the low-dose group of that 
same age cohort and the high-dose group of the preceding age cohort 
(where present) has been reviewed and it is considered safe to proceed.
Population
The study population will consist of 30 male or female pediatric patients 
(birth to <18 years of age) hospitalized with the following: signs and 
symptoms of AHF who have a requirement for a stable dose of vasoactive 
and/or inotropic agents and, in patients with medical etiologies of AHF, 
echocardiographic evidence of reduced ventricular function. 
Both, medical and post-surgical 
 
 
etiologies of AHF can be included in the study.
 
 
 
Key Inclusion criteria
(see protocol for full 
details)
1.
Male or female, 
, with body weight ≥2.5 kg 
to ≤120 kg
2.
Hospitalized in an intensive/critical care unit or continuously 
monitored step-down unit with the following:
a.
signs and symptoms of AHF of any etiology and
b.
a stable dose of vasoactive and/or inotropic agents 
 
 
 
 
c.
 
 
 
 
 
 
 


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3.
Systolic blood pressure (SBP) consistently equal to or greater than 
the calculated 25th percentile SBP for age and gender as 
described in the protocol.
4.
Stable pulmonary function, i.e. patient is extubated or is stable on 
ventilator support.
Key Exclusion criteria
(see protocol for full 
details)
1.
Hypovolemia
2.
Moderate to severe left ventricular outflow tract (including sub-
valvular, valvular and supra-valvular), mitral stenosis or aortic arch 
obstruction 
3.
Patients with single ventricle physiology before their Fontan 
operation (However, single ventricle patients post Glenn operation 
before their Fontan/Total cavo-pulmonary connection procedure
(TCPC) can be enrolled.)
4.
Patients on ECMO or VAD
5.
Patients with fixed pulmonary hypertension (i.e. ≥6 Wood Units, 
unable to reduce <6 Wood Units with medical therapy)
6.
Patients with blood lactate levels >5 mmol/L at the time of 
enrollment
7.
Birth < 36 weeks post-conceptual age (applies only to children 
<1year old at baseline)
8.
Confirmed or clinically suspected systemic infection (sepsis) or 
severe localized infection requiring iv antibiotics
9.
Dyspnea or acute lung injury primarily due to non-cardiac causes 
10. Patients with severe renal impairment; those known to have 
significant renal disease and those having current or planned renal 
replacement therapy 
11. Excessive use of inotropic and/or vasoactive agents at screening 
[vasoactive score >20 (Davidson et al. 2012): dose of dopamine + 
dobutamine + (epinephrine x 100) + (norepinephrine x 100) + 
(phenylephrine x 100) + (milrinone x 10) + (vasopressin x 10,000)] 
12. Current or planned use of the following concomitant medication 
during the duration of the study drug infusion: levosimendan, 
 


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nesiritide
13. Planned surgery <48 hours after screening
14. Patients with uncorrected coronary abnormalities that predisposes 
them for myocardial ischemia
15. History or current diagnosis of cardiac electrocardiographic 
abnormalities indicating significant risk of safety for patients 
participating in the study such as: 
16. Concomitant clinically significant cardiac arrhythmias, e.g., 
sustained ventricular tachycardia, and clinically significant second 
or third degree AV block, unless they are successfully managed 
with a pacemaker or anti-arrhythmic medication
17. History of familial long QT syndrome or known family history of 
Torsades de Pointes
18. Any major solid organ transplant recipient within 1 year of 
transplantation 
19. Any major solid organ transplant recipient who presents with 
severe organ rejection
20. 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
21. Females of child-bearing potential
(girls who have reached
menarche), unless they are using highly effective methods of 
contraception during dosing of study treatment and for the duration 
of the study
22. Any clinically significant bleeding that occurs after screening and 
prior to infusion of study drug
23. Any indication of clinical instability, based on the investigator’s 
judgement, preceding enrollment and/or prior to the infusion of 
study drug
Investigational and 
reference therapy
Serelaxin is administered in a continuous iv infusion for a total of 48 hours. 
Dose rates of 3 µg/kg/day, 10 µg/kg/day and 30 µg/kg/day in the low-dose 
group; 10 µg/kg/day, 30 µg/kg/day and 100 µg/kg/day in the high-dose 
group will be used.
Efficacy assessments
The hemodynamic effects of different doses of serelaxin will be assessed 
at baseline, prior to each dose escalation and at approximately 24 hours 
after the end of the infusion, as a secondary objective. The following 
hemodynamic measurements will be assessed (as available): arterial BP 
and central venous pressure (CVP), left atrial pressure (LAP), pulmonary 
artery pressure (PAP – systolic and diastolic), central venous and arterial 
oxygen saturation, urine output, and blood lactate
levels.
(Note: 
Hemodynamic effects will also be assessed for safety at additional time 
points during the study as outlined in the protocol.)
Safety assessments

Physical Exam

Vital signs, respiratory parameters and clinical assessments (including 
hemodynamic effects)

Laboratory evaluations
 


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
ECG

Adverse events/SAEs
Other assessments
Data analysis
The PK parameters Css and CL will be mainly summarized descriptively 
by age cohort and dose within each dose group. A graphical presentation 
will be employed to show mean and individual RLX030 concentration-time 
profiles for each age cohort and each dose group. 
 
Safety data including adverse events, laboratory, vital signs and ECG data 
will be summarized by age cohort and dose group and for all patients as 
appropriate as well. Hemodynamic assessments will be also provided by 
age cohort and dose group and for all patients.
 
 
Key words
Acute 
Heart 
Failure, 
Pediatrics, 
Congenital 
Heart 
Disease, 
Cardiomyopathy
 


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1
Introduction
1.1
Background
Heart failure (HF) has been defined as “constellation of structural and functional 
abnormalities, elevated filling pressures, neurohormonal activation, and signs and symptoms” 
(Kim JJ et al. 2008). It is, in many ways, a much more heterogeneous disease in children than 
it is in adults. First, the classical signs and symptoms observed in adults with HF such as 
exertional dyspnea, pitting edema or jugular venous pulsation, are often absent (or difficult to 
detect) in children depending on their age and underlying disease. Second, there is a multitude 
of etiologies of pediatric HF (see Table 1-1) which contrasts with HF in the adult population. 
Third, there are multiple mechanistic factors that can lead to cardiac failure including 1) 
decreased contractility (e.g. cardiomyopathy, sepsis, myocarditis, post-surgical low cardiac 
output syndrome), 2) volume overload (e.g. pulmonary hypercirculation secondary to left-to-
right shunts, valvular regurgitations), 3) pressure overload (e.g. sub-valvular or valvular
stenosis, or supra-valvular obstructions like coarctation of the aorta), 4) diastolic dysfunction 
(e.g. tetralogy of Fallot, myocardial stunning) or 5) changes in systemic or pulmonary 
vascular resistance (e.g. primary or idiopathic pulmonary hypertension, systemic hypertension) 
(Epstein and Wetzel 2006). HF in children can be a transient problem, for example after open 
heart surgery and cardiopulmonary bypass for congenital heart disease, can follow a more 
protracted course with bouts of acute decompensations (similar to adult heart failure) or lead 
to terminal HF and death. Patients with terminal HF may be eligible for cardiac 
transplantation and may benefit from mechanical support (Extracorporeal Membrane 
Oxygenation [ECMO] or Ventricular Assist Device [VAD]) as a bridging therapy.
Table 1-1
Causes of heart failure in children and adolescents
Rhythm disorders
Brady- or tachy- arrhythmias
Lack of AV synchrony
Volume overload
Intracardiac shunts (congenital heart disease)
Extracardiac shunts (e.g. AV malformation, aneurysm of vein of Galen)
Valvular regurgitation (congenital, endocarditis, traumatic, rheumatic fever)
Pressure overload
Cardiac obstruction (valvular or intracardiac abnormalities, congenital or acquired)
Extracardiac obstruction (coarctation of aorta, pulmonary hypertension, embolism, 
hypertension)
Cardiomyopathies – systolic or diastolic dysfunctions
Hypoxia
Post-open heart surgery (post-bypass low cardiac output syndrome)
Myocarditis (viral or bacterial)
 


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Metabolic disorders
Hypoglycemia
Hypocalcemia and Vitamin D deficiency
Acidosis
Hypothyroidism
Hypothermia
Glycogen storage disease
Carnitine deficiency
Mucopolysaccharidoses
Endomyocardial fibroelastosis
Familial dilatative cardiomyopathy
Hypertrophic cardiomyopathy
Cardiac trauma
Duchenne’s muscular dystrophy
Friedreich’s ataxia
Drug intoxication or toxicity (chemotherapy)
Sickle cell disease
Coronary disease
Anatomic anomalies of the coronaries (implantation or trajectory)
Kawasaki’s disease
Polyarteritis nodosa
High cardiac output failure
Sepsis
Thyrotoxicosis
Severe anemia
Liver failure
Reference: modified from Barry 2010
Etiologies of HF are age dependent with hypoxia, AV malformations, congenital heart disease 
(CHD, and related surgery), myocarditis and tachyarrhythmias being the most common in 
neonates, congenital heart disease (and related surgery), AV malformations, anomalous 
coronary arteries, metabolic cardiomyopathies, tachyarrhythmias, Kawasaki’s disease and 
acute hypertension (haemolytic uremic syndrome) seen most frequently in infants and 
toddlers and rheumatic fever, hypertension (glomerulonephritis), myocarditis, endocarditis, 
cor pulmonale (cystic fibrosis), drug toxicity (radiation, doxorubicin, anthracycline) and 
thyrotoxicosis as well as cardiomyopathy most commonly seen in older children and 
adolescents (Madriago 2010).
The overall incidence and prevalence of pediatric HF (acute and chronic) is unclear, largely 
because there is no accepted universal classification applied to its many forms. The largest HF 
burden comes from children born with congenital malformations, which occurs in 
approximately 8 per 1000 live births of which 1-2 per 1000 develop HF (Kay 2001). Although 
cardiomyopathy is relatively rare (around 1 per 100,000 children according to Lipshultz 2003 
and Nugent 2003), approximately 40% of patients who experience cardiomyopathy develop 
HF of such severity that it leads to transplantation or death (Madriago 2010). Overall, a HF 
incidence of 10.4% has been reported in patients <16 years with heart disease (congenital or 
 


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acquired – Massin 2008) and a 2 to 7.7/100,000 incidence of HF in the general pediatric 
population (Tseng 2010, Neumann 2009), with the highest incidence in infants and children 
between 0 and 4 years old (21.7/100,000).
The clinical manifestation of acute heart failure (AHF) depends on the age of the patient. In 
children and adolescents, signs and symptoms are similar to the ones observed in adults, 
namely fatigue, exercise intolerance, dyspnea and orthopnea. Peripheral edema, pulmonary
rales and increased jugular venous pressure might be difficult to detect in smaller children but 
are more commonly present in older children and adolescents. Abdominal pain can be a 
prominent feature. Heart failure might be more difficult to diagnose in newborns and infants. 
Prominent manifestations include central cyanosis, tachypnea, tachycardia, poor feeding, 
excessive perspiration, poor weight gain, irritability and weak cry. Signs of increased work of 
breathing (retractions, nasal flaring, wheezing, grunting), venous stasis (hepatosplenomegaly, 
ascites, rarely edema) and poor peripheral perfusion (mottling, cool extremities, delayed 
capillary refill, gastrointestinal symptoms) can be detected but rales might be difficult to hear 
on auscultation (Kantor 2010).
Current standard of care (SOC) of AHF includes, almost always, diuretics, oxygen and 
potentially iv vasoactive substances like vasodilators (e.g. sodium nitroprusside, nipride), 
inotropes (levosimendan or more commonly catecholamines like dopamine, epinephrine) or 
inodilators (e.g. milrinone, dobutamine). Ventilatory support (continuous positive airway 
pressure or invasive mechanical ventilation) can help with gas exchange in the congested lung 
and reduction of left ventricular afterload. Mechanical circulatory support (ECMO or VADs) 
can be indicated in severe cases and heart transplant might be needed for terminal HF. The 
goals of AHF therapy, in paediatric patients as in adults, is to stabilize the patient’s vital 
functions, diagnose and treat underlying causes if possible and  transition to outpatient therapy 
(Kantor 2010, Kantor 2010a).
Relaxin (H2) is a naturally occurring peptide hormone that has been associated with many of 
the maternal hemodynamic and renovascular adjustments in response to the demands of 
pregnancy, such as dilation of systemic and renal blood vessels and increase in global arterial 
compliances (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). It is known that nitric oxide, endothelial endothelin type B 
receptor, vascular endothelial growth factor (VEGF) and cAMP act as mediators for the 
vasodilatory as well as other anti-fibrotic and anti-inflammatory effects of relaxin (Bani et al 
1998; Danielson et al 1999; Dschietzig et al 2003; Du et al 2010).
 
 
 
 
 
 
 
 
 


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Serelaxin is a recombinant protein identical in structure to the naturally occurring H2 relaxin. 
Its efficacy and safety in adult AHF patients as a continuous 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 2009) and the phase III 
pivotal study RELAX-AHF (Teerlink 2013).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The purpose of this study is to provide pharmacokinetic and short-term safety information in 
the pediatric patient population from birth to <18 years of age. 
 
 
 
 
 
 
 


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1.2
Purpose
The purpose of this open-label, dose escalation study is to evaluate safety, tolerability and 
pharmacokinetics of an iv serelaxin (RLX030) infusion in addition to standard of care (SOC)
therapy in pediatric patients from birth to <18 years of age, who are hospitalized with AHF. 
 
 
 
 
2
Study objectives
2.1
Primary objectives

To evaluate the safety and tolerability of an iv serelaxin infusion in addition to standard of 
care in hospitalized pediatric patients with AHF

To investigate the effects of age on the pharmacokinetics of serelaxin given as iv infusion 
in addition to standard of care in hospitalized pediatric patients with AHF
2.2
Secondary objective

To evaluate the hemodynamic effects of different doses of serelaxin given as an iv 
infusion in addition to standard of care in hospitalized pediatric patients with AHF 
(efficacy parameters: arterial blood pressure, left atrial pressure (LAP), pulmonary artery 
pressure (PAP – systolic and diastolic), central venous and arterial oxygen saturation, 
urine output, and blood lactate levels)
2.3
Exploratory objectives
 
 
 
 
 
3
Investigational plan
3.1
Study design
This study uses an open-label, dose escalation design in order to evaluate safety, tolerability 
and pharmacokinetics of RLX030 in addition to standard of care in pediatric patients from 
birth to <18 years. Hospitalized patients in an intensive/critical care unit or a continuously 
monitored step-down unit with the following criteria will be screened for inclusion:
 


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1. signs and symptoms of AHF and
2. a requirement for a stable dose of vasoactive and/or inotropic agents [defined as a 
2-hour period without major changes (i.e. >20% increase/decrease) in the infusion 
rate] and
3. echocardiographic evidence of reduced ventricular function
The same criteria apply for patients after open heart surgery except criterion number 3. 
(echocardiographic evidence of reduced ventricular function). Post-operative patients can only 
be included ≥6 hours after surgery for patients 0 to <1 year old and ≥12 hours after surgery for 
patients 1 to <18 years old. Patients who present with AHF following open heart surgery until 
1 month after the intervention are considered post-operative patients for the purpose of this 
study. Echocardiographic examination within 24 hours prior to enrollment can be considered 
as 
the 
screening 
examination, 
including 
the 
trans-esophageal 
or 
trans-thoracic 
echocardiography in the immediate post-operative period. The screening echocardiographic 
examination in post-surgical patients is to be performed after completion of the surgery in a 
hemodynamically stable patient.
If a patient is found to be eligible for study entry during screening and at the baseline 
evaluation, the patient will enter the study and can start the 48-hour treatment period. Study 
participants will be assessed daily to day 5, at day 14 and at day 28 (telephone contact) (see 
Table 6-1 for details. Patients will be followed for serious adverse events for 30 days after 
completion or discontinuation from the study and all serious adverse events occurring within 
this time frame are to be reported to Novartis (see Section 7.2.2).
 
 A total duration of 
48 hours is planned for the constant iv serelaxin infusion with dose escalations every 16 hours. 
A low-dose group and a high-dose group will be enrolled sequentially in every age cohort. 
During this 48-hour treatment period, the serelaxin dose rates to be administered are 3 
µg/kg/day, 10 µg/kg/day and 30 µg/kg/day in the low-dose group; 10 µg/kg/day, 30 
µg/kg/day and 100 µg/kg/day in the high-dose group 
 These dose rates are 
anticipated to be safe in the pediatric population and are based on the dose range investigated 
in adults with AHF.
Thirty (30) male or female pediatric patients (minimum) will be enrolled in this study with 3 
patients in each low dose group for age cohorts 1, 2, 3 and 4; and 6 patients in each high-dose 
group for age cohorts 3 and 4, and 3 (maximum 6) patients in each high dose group for age 
cohorts 1 and 2. The four age cohorts are as follows:

Cohort 1: 6 to <18 years [3 low-dose patients, 3 high-dose patients (maximum 6)]

Cohort 2: 1 to <6 years [3 low-dose patients, 3 high-dose patients (maximum 6)]

Cohort 3: infants 1 month* to <1 year [3 low-dose patients, 6 high-dose patients]

Cohort 4: neonates birth to <1 month* [3 low-dose patients, 6 high-dose patients]
*1 month = 30 days
 


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Age cohorts will be enrolled sequentially from age cohort 1 to 4, within each dose group. For 
each age cohort, patients will be enrolled first into the low-dose group and if it is considered 
safe after a review of all available safety and pharmacokinetic (PK) data, up to and including 
study day 5, then patients will be enrolled into the low-dose group for the succeeding age 
cohort. Patients cannot be enrolled into the high-dose group for a given age cohort until data 
from the low-dose group of that same age cohort and the high-dose group of the preceding age 
cohort (where present) has been reviewed and it is considered safe to proceed. 
 
Enrollment within each dose group will be temporarily stopped 4 times for the low dose group 
and 3 times for the high dose group during the study for a review of safety and PK data as 
follows:
Low Dose Group

1st enrollment stop for low-dose, safety and PK data review after completion (up to day 5) 
of 3 low-dose patients in age cohort 1

2nd enrollment stop for low-dose, safety and PK data review after completion (up to day 5) 
of 3 low-dose patients in age cohort 2

3rd enrollment stop for low-dose, safety and PK data review after completion (up to day 5) 
of 3 low-dose patients in age cohort 3

4th enrollment stop for low-dose, safety and PK data review after completion (up to day 5) 
of 3 low-dose patients in age cohort 4.
High Dose Group

1st enrollment stop for high-dose safety and PK data review after completion (up to day 5) 
of 3 high-dose patients in age cohort 1

2nd enrollment stop for high-dose, safety and PK data review after completion (up to day 5) 
of 3 high-dose patients in age cohort 2

3rd enrollment stop for high-dose, safety and PK data review after completion (up to day 5) 
of 6 high-dose patients in age cohort 3
Note: For a given age cohort, high-dose patients can only be enrolled after 3 low-dose patients 
have been enrolled in that age cohort and 3 patients have been enrolled in the high-dose group 
of the preceding age cohort (as applicable), and their safety and PK data reviewed, and it is 
considered safe to proceed. For any additional high-dose group, age cohort 1 or 2 patients (i.e. 
beyond the 3 required patients), their data will be reviewed at the next available PSRC 
meeting. 
 


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3.2
Rationale of study design
This first open-label study in pediatric patients from birth to <18 years, hospitalized with AHF, 
is designed to evaluate the safety, tolerability and pharmacokinetics of escalating doses of 
serelaxin
 
 
Qualifying study participants will receive serelaxin during the hospitalization in 
addition to SOC therapy for AHF according to local guidelines or institutional standards. 
 
 
 
 
 


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3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
 
 
 
 
 
 
 
3.4
Rationale for choice of comparator
Not applicable
3.5
Purpose and timing of interim analyses/design adaptations
 
 
 
3.6
Risks and benefits
In adults, hospitalization and worsening heart failure with accompanying end organ damage, 
such as worsening renal function and myocardial injury, are both associated with increased 
mortality. In two adult AHF studies (pre-RELAX-AHF, Teerlink et al, 2009 and RELAX-
AHF, Teerlink et al, 2013)  a 48 hour serelaxin infusion on top of SOC led to a significant 
relieve of dyspnea and congestion, the presenting elements of AHF in adults, compared to 
placebo on top of SOC. This was associated with a significant reduction in early worsening of 
HF (defined as intensification of HF therapy) and length of (index) hospitalization and 
intensive care unit stay 
 
 
 
 
 
 
Overall, serelaxin (on top of SOC) was well-tolerated with an adverse event profile 
comparable to placebo (on top of SOC). Although  slightly more hypotension-related adverse 
events were reported in the serelaxin treatment arm versus placebo due to its vasodilatory 
effects, without a dose-response or exposure-response relationship, the use of stringent blood 
pressure inclusion criteria and the management of blood pressure decreases during serelaxin 
 


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infusion (i.e. mandated 50% dose reduction and/or discontinuation if pre-specified blood 
pressure decreases were met) have demonstrated that serelaxin-induced hypotensive effects 
were generally mild and easily manageable without causing harm and the majority of patients 
were able to stay on drug.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 several safeguards are included in the CRLX030A2208 study design in 
order to reduce the risk in this new patient population as much as possible. First, a low-dose 
group, dosed at 3, 10 and 30 μg/kg/day (within-patient dose escalation every 16 hours) will be 
enrolled ahead of every high-dose group, which is dosed at 10, 30 and 100 μg/kg/day (also 
within-patient dose escalation every 16 hours). The high-dose group will only be enrolled if 
the review of safety and PK data (up to day 5) from the low-dose group shows that it is safe to 
do so. Second, age cohorts will be enrolled sequentially and younger age cohorts will only be 
allowed into the study once the review of safety and PK data (up to day 5) from the preceding 
older age cohort shows that it is safe to do so. Third, the risk to the patient will also be 
minimized by compliance with the inclusion/exclusion criteria that aim to recruit patients with 
mild to moderate hemodynamic impairment, excluding the sickest and most vulnerable 
individuals in this population.
Female patients of child bearing potential should be informed that taking the study drug may 
involve unknown risks to the fetus, if pregnancy were to occur during the study. Informed 
consent (and assent where required) that outlines the risks as well as protocol specific safety 
rules to adhere to the contraception requirements for the duration of the study has to be signed. 
In the case of any concerns regarding compliance with these requirements the patient should 
be excluded or discontinued from the study. In addition, females of child bearing potential 
 


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 are required to
have a negative serum pregnancy test before entering the study.
Refer to the IB for additional information regarding the safety profile of serelaxin.
 
 
 
 
 
4
Population
The study population will consist of a minimum of 30 male or female pediatric patients (birth 
to <18 years of age) hospitalized with the following: signs and symptoms of AHF who have a 
requirement for a stable dose of vasoactive and/or inotropic agents and, in patients with 
medical etiologies of AHF, echocardiographic evidence of reduced ventricular function. Both, 
medical and post-surgical 
 
 
etiologies of AHF can be included in the study.
 
 
 
 
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent by parent(s)/legal guardian(s) for the pediatric patient must 
be obtained before any study-specific assessment is performed . A consent or assent 
may also be required for some patients depending upon their age and local 
requirements
2. Male or female, 
, with body weight ≥2.5 kg to ≤120 kg (basis 
for inclusion criteria weight: pre-operative weight for post-operative patients and 
weight on hospital admission for non-surgical patients)
3. Hospitalized in an intensive/critical care unit or continuously monitored step-down 
unit with the following:
a) signs and symptoms of AHF of any etiology
and
b) a stable dose of vasoactive and/or inotropic agents
c)
 
 


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4. Systolic blood pressure (SBP) consistently equal to or greater than the calculated 25th
percentile SBP for age and gender per Appendix 3. 
 
 
 
 
 
5. Stable pulmonary function, i.e. patient is extubated or is stable on ventilator support.
 
 
 
 
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. Hypovolemia
2. Moderate to severe left ventricular outflow tract (including sub-valvular, valvular and 
supra-valvular), mitral stenosis or aortic arch obstruction (evidence of peak gradient 
≥40 mmHg on echocardiographic or BP measurements)
3. Patients with single ventricle physiology before their Fontan operation (However, 
single ventricle patients post Glenn operation before their Fontan/Total cavo-
pulmonary connection procedure (TCPC) can be enrolled.)
4. Patients on ECMO or VAD (excluded because of the potential interference of the 
extracorporeal circuit with the PK profile of serelaxin)
5. Patients with fixed pulmonary hypertension (i.e. ≥6 Wood Units, unable to reduce <6 
Wood Units with medical therapy)
6. Patients with blood lactate levels >5 mmol/L at screening (excluded because of the 
possibility of a compensated shock)
7. Birth < 36 weeks post-conceptual age (applies only to children <1year old at baseline)
8. Confirmed or clinically suspected systemic infection (sepsis) or severe localized 
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9. Dyspnea or acute lung injury primarily due to non-cardiac causes 
10. Patients with severe renal impairment, those known to have significant renal disease 
(e.g. significant renal dysplasia) and those having current or planned renal replacement 
therapy [Severe renal impairment is defined in cohort 1 to 3 as 
eGFR <30 
mL/min/1.73m2 (Hogg et al. 2003), calculated using the modified Schwartz formula 
(eGFR = 0.41 x height (cm)/Scr (mg/dl) - Schwartz et al. 2009) and in cohort 4 as 
urine output <0.5mL/kg/hour for the 24 hours prior to screening, or anuria for the 12 
hours prior to screening (derived from the neonatal RIFLE criteria; Ricci 2013).]
11. Excessive use of inotropic and/or vasoactive agents at screening [vasoactive score >20;
Davidson et al. 2012: dose of dopamine + dobutamine + (epinephrine x 100) + 
(norepinephrine x 100) + (phenylephrine x 100) + (milrinone x 10) + (vasopressin x 
10,000)]
12. Current or planned use of the following concomitant medications during the duration 
of the study drug infusion: levosimendan, nesiritide
13. Planned surgery <48 hours after screening
14. Patients with uncorrected coronary abnormalities that predispose them for myocardial 
ischemia
15. History or current diagnosis of cardiac electrocardiographic abnormalities indicating 
significant risk of safety for patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained 
ventricular tachycardia, and clinically significant second or third degree AV 
block, unless they are successfully managed with a pacemaker or anti-
arrhythmic medication

History of familial long QT syndrome or known family history of Torsades de 
Pointes
16. Any major solid organ transplant recipient within 1 year of transplantation
17. Any major solid organ transplant recipient who presents with severe organ rejection
18. 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
19. Severe malnutrition
20. Post-operative bleeding >5 mL/kg/hour for ≥2 consecutive hours at any time 4 hours 
prior to screening
21. Any advanced, severe or unstable disease that may interfere with the primary or 
secondary study outcome evaluations or put the patient at special risk
22. 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 
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23. Females of child-bearing potential (girls who have reached menarche), unless they are 
using highly effective methods of contraception during dosing of study treatment and 
for the duration of the study. 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, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  
In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the sole partner for that 
subject

Use of oral (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS) or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception
In case of use of oral contraception women should have been stabile on the same 
pill for a minimum of 3 months before taking study treatment.
Note: In case local regulations deviate from the contraception methods listed 
above, local regulations apply and will be described in the respective ICF.
24. Use of other investigational drugs within 30 days or 5 half-lives prior to screening, 
whichever is longer
25. History of hypersensitivity to serelaxin or to drugs of similar chemical classes
26. History of previous serelaxin administration 
27. Inability of the patient or the parents/legal guardians to follow instructions or comply 
with follow-up procedures
28. 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.
29. Any clinically significant bleeding that occurs after screening and prior to infusion of 
study drug
30. Any indication of clinical instability, based on the investigator’s judgement, preceding 
enrollment and/or prior to the infusion of study drug
 


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5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Escalating doses of serelaxin will be administered in a continuous iv infusion for a total of 48 
hours. Dose rates of 3 µg/kg/day, 10 µg/kg/day and 30 µg/kg/day will be used in the low-dose 
group and dose rates of 10 µg/kg/day, 30 µg/kg/day and 100 µg/kg/day will be used in the 
high-dose group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2
Additional study treatment
No additional treatment beyond the investigational treatment is required for this trial. 
However, patients in this study will all be required to receive SOC management of AHF 
during both hospitalization and after discharge according to the regional or local guidelines 
and/or institutional standard.
5.3
Treatment arms
All enrolled patients will receive serelaxin in this open–label study.
5.4
Treatment blinding
Not applicable for this open-label study.
 


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5.5
Treating the patient
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank eCRF book available from the electronic data 
capture (EDC) system. 
 
 
 
 
 
 
5.5.2
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with open label study medication.
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label. 
 
 
 
 
 
5.5.3
Handling of study treatment 
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. Technical complaints are to be reported to the respective 
Novartis CPO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment 
 
 
 


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5.5.3.2
Handling of other study treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
The study drug infusion will begin after informed consent has been given in writing (ICF 
signed by parent/guardian and patient consent or assent where applicable) and the completion 
of all screening/baseline procedures, and will continue for a total 48 hours (16 hour infusion 
per dose level). The study drug should be administered via a peripheral or central iv line or 
port, as soon as possible, but no more than 5 hours after enrollment (i.e. confirmation of 
eligibility for the study and the baseline IRT contact where a medication number is assigned). 
Compatible filters and syringes which have been tested and qualified for use with serelaxin, 
must be used to prepare and administer the study drug.  
 
The required amount of study drug will be calculated for each patient for each dose titration 
level and will be withdrawn from the 6 mL vials (with 3.5 mL fill) contained in the study drug 
kits, added to a syringe of 5% dextrose solution (10% dextrose may also be considered), and 
then infused at a constant rate over a period of 16 hours for each titration level. 
 
 
Each dose level is infused over 16 hours. Dose escalation should only occur if

the patient does not fulfill any requirement for dose adjustment or discontinuation (see 
Section 5.5.5 Permitted dose adjustments of study treatment) on the preceding infusion 
rates, and

the investigator considers dose escalation to be safe based on his global clinical 
assessment, including an evaluation of the patient’s hemodynamic status (including 
physical examination (Section 6.5.1), vital signs and hemodynamic parameters, 
arterio-venous oxygen extraction) and a comparison of his/her current condition with 
the one before starting serelaxin and before the previous dose escalation.
If the investigator considers it unsafe, based on his/her global clinical assessment, to increase 
the serelaxin dose to the next dose level the patient should remain on the same dose level for 
another 16 hours (if tolerated). At the end of this 16 hour period, another global clinical 
assessment must be done to determine whether or not it is safe to escalate the dose. If it is 
deemed safe at that time, the dose is increased to the next dose level in the sequence of the 
assigned dose group (i.e. low-dose or high-dose group), not the initially planned dose level, 
for the remainder of the 48 hour infusion time. For example, if a patient receives 3µg/kg/day 
for 16 hours and a decision is taken to that the patient should not be up-titrated to the next 
dose level, they are to be dosed at 3µg/kg/day for another 16 hours, if tolerated. If after the 
second 16 hours at 3µg/kg/day, a decision is taken to up-titrate the patient, they would then 
 


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receive a 10µg/kg/day, for 16 hours, again if tolerated. The total infusion time of serelaxin 
should not exceed 48 hours regardless of dose titration. All assessments, including PK 
sampling, should continue per protocol even if the dose rate is not escalated.
Study drug will be dispensed only by study staff qualified to perform that function under 
applicable local laws and regulations for the study site(s), according to the protocol and 
Assessment Schedule (see Table 6-1).
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 of study treatment
This section describes the actions that are required if a systolic BP decrease (i.e. <5th
percentile for age) occurs during the administration of study drug and is confirmed by two 
measurements taken 10 minutes apart (in patients with intermittent BP measurements) or by a 
consistent measurement over ≥5 min (in patients with invasive continuous BP measurements).
This event is considered a “systolic blood pressure decrease event” (SBPDE) and must be 
recorded as such on the appropriate eCRF.
If the SBP falls to <5th percentile for the age of the patient (AHA PALS guidelines 2010, 
Kleinman 2010, see Appendix 4) and is a confirmed SBPDE per the criteria in the previous 
paragraph, then the following steps are required:
1) In all patients:
Assess the patient and treat alternative causes of hypotension (consider 
hypovolemia, arrhythmia, heart-lung interactions, concomitant medications, 
pneumothorax or pericardial tamponade, hardware malfunction or measuring error 
etc.)
2) As clinically indicated, the following steps should be taken, preferentially in the 
indicated order (however, the options can be applied in sequence or separately at the 
investigator’s discretion):
1. Increase the infusion rate of inotropic and/or vasoactive drugs as clinically 
indicated up to a vasoactive score of 20 and/or
2. Reduce the serelaxin infusion rate by 50% and/or
3. Discontinue serelaxin infusion
Patients who tolerate the reduced serelaxin infusion rate should remain on this reduced
infusion rate for the remainder of the 48 hour infusion period, as tolerated. The exact time and 
date of the reduction of the study drug infusion rate must be recorded on the Drug 
Administration Record case report form. All assessments, including PK sampling, should 
continue per protocol even if the dose rate is reduced. Time from initiation of study drug 
infusion to completion must not exceed a total of 48 hours.
Dosing may be discontinued at any time at the discretion of the investigator. Reasons for 
which the investigator may discontinue the study drug include, but are not limited to, serious 
or intolerable AEs suspected to be causally related to study drug. In the event that study drug 
 


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administration is discontinued, regardless of the reason, the patient will continue to be 
followed at all study visits defined in the protocol. PK sampling should follow the schedule 
that is planned for after completion of the study drug (see Section 6.6.2). The exact time and 
date of study drug discontinuation must be recorded.
Re-administration of study drug, once terminated, is not allowed.
Changes in study drug dose 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 
Concomitant medications/Significant non-drug therapies in the eCRF.
5.5.7
Concomitant treatment
The investigator may prescribe any additional medications and/or supportive care during the 
study as dictated by the patient’s condition, except for those listed in Section 5.5.8 Prohibited 
Treatment. 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 iv, enteral or topical medications, transfusion of blood 
products mechanical ventilation, diagnostic examinations, positioning, endotracheal and 
oropharyngeal suctioning, physio- or ergotherapy, as needed. Any medication or non-medical 
therapy added, discontinued or modified during the study should be recorded on the eCRF. 
The investigator should instruct the patient and/or legal guardian to notify the investigator or 
associated study personnel about any new medications he/she takes after the patient was 
enrolled into the study.
 
 
 
 
 
 


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All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded.
 
 
5.5.8
Prohibited Treatment 
Subjects will not be enrolled in the study if concomitant therapy for AHF includes current or 
planned treatment with levosimendan or nesiritide during the study. This is because of the 
potential for the administration of these drugs to interfere with the study endpoints.
Patients on ECMO, VAD or RRT will not be enrolled because of the potential interference of 
the extracorporeal circuit with the PK profile of serelaxin.
After enrollment, the investigator may prescribe any additional medication as dictated by the 
patient’s 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. Changes to any co-medication or non-medical treatment during the hospitalization 
should be recorded on the eCRF.
5.5.9
Discontinuation of study treatment
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:

Withdrawal of informed consent or assent

Intolerable adverse events, thought to be related to study drug, which persist

If the SBP falls <5th percentile for the age of the patient (AHA PALS guidelines 2010, 
Kleinman 2010, see Appendix 4) and is considered a confirmed SBPDE, then follow the 
instructions outlined in Section 5.5.5.

Use of prohibited treatment as per Section 5.5.8

Pregnancy

Surgical intervention during the study drug infusion

A patient should not remain in the ICU/CCU or a continuously monitored step-down Unit 
for the sole purpose of study drug infusion. The decision to discharge a patient from the 
ICU/CCU or a continuously monitored step-down unit should be made per SOC. If the 
serelaxin infusion is still ongoing at the time of transfer out of the ICU/CCU or a 
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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 as specified in Section 5.5.11.
Patient withdrawal: Patients/legal guardians may voluntarily withdraw consent or assent for 
any reason at any time. 
Withdrawal of consent or assent occurs only when a patient/legal guardian does not want to 
participate in the study anymore and, does not want any further visits or assessments and, 
does not want any further study related contacts and does not allow analysis of already 
obtained biologic material.
If a patient/legal guardian withdraws consent or assent, the investigator must make every 
effort to determine the primary reason for this decision and record this information. Study 
treatment must be discontinued and no further assessments conducted. All biological material 
that has not been analyzed at the time of withdrawal must not be used. Further attempts to 
contact the patient/legal guardian or patient are not allowed unless safety findings require 
communicating or follow-up.
Patients/legal guardians can refuse to participate in specific aspects of the study and/or take 
study medication at any time without withdrawing consent.  Investigators should make every 
effort to accommodate the needs of the patients to make it possible for them to continue to 
participate in the remaining aspects of the study.  
Lost to follow-up: For patients whose status is unclear because they fail to appear for study 
visits without stating an intention to withdraw, the investigator should show "due diligence" 
by contacting the patient, legal guardians, family or family physician as agreed in the 
informed consent and by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc. A patient should not be considered 
lost to follow-up until his/her scheduled end of study visit would have occurred.
The investigator must also contact the IRT (Interactive Response Technology) to register the 
patient’s discontinuation from the study drug. 
 
 
5.5.10
Withdrawal of consent 
Patients may voluntarily withdraw consent/assent 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.
If a patient withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Investigational study drug 
treatment must be discontinued and no further assessments conducted. All biological material 
 


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that has not been analyzed at the time of withdrawal must not be used. Further attempts to 
contact the patient are not allowed unless safety findings require communicating or follow-up.
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 withdraw, the investigator should show "due diligence" by contacting the
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until his/her 
scheduled end of study visit would have occurred.
5.5.12
Emergency breaking of assigned treatment code
Not applicable
5.5.13
Study completion and post-study treatment
Patient participation will be completed 28 days after the start of the study drug infusion. The 
investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.14
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient 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 the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
 
 
Patients should be seen for all 
visits on the designated day or time point, or as close to it as possible.
 
 If a patient/legal guardian 
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 at day 28 and at the 
end of the 30 days following the last study visit. Documentation of attempts to contact the 
patient should be recorded in the source documentation.
After identifying a potential patient, an ICF (and Assent, if applicable) must be signed by the 
parent(s)/legal guardian(s) (and Assent signed by the patient, as applicable) before performing 
study-related screening procedures that are not considered standard of care for AHF patients 
 


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at that site.  Procedures that are part of a site’s standard of care 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 or screen 
failed.
 


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Table 6-1
Assessment schedule
 


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6.1
Information to be collected on screening failures
All patients for whom informed consent has been signed but who do not enter the treatment 
epoch of the study will have the study completion page for the screening epoch completed and 
will have demographic, inclusion/exclusion, and serious adverse event (SAE) data collected. 
Adverse events (AEs) that are not SAEs will be followed by the investigator and collected 
only in the source data.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, ethnicity, weight and height. Relevant medical history/current 
medical condition data includes data until the start of study drug. Diagnoses and not 
symptoms will be recorded on the eCRFs, where possible. 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. Infusion times and rates will be 
recorded in the eCRF.  Study drug and supplies must be made available for inspection by the 
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6.4
Efficacy
6.4.1
Hemodynamic assessments
The hemodynamic effects of different doses of serelaxin will be assessed as a secondary 
endpoint in this study. This will be done at baseline, prior to each dos e escalation and at 
approximately 24 hours after the end of the infusion. Hemodynamic effects will also be 
assessed for safety at additional time points during the study as outlined in Section 6.5.2. The 
following hemodynamic measurements will be assessed for efficacy (as available): arterial BP 
and central venous pressure (CVP), left atrial pressure (LAP), pulmonary artery pressure 
(PAP – systolic and diastolic), central venous and arterial oxygen saturation, urine output, and 
blood lactate levels.
 
 
6.4.2
Exploratory assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4.3
Appropriateness of efficacy assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.5
Safety
6.5.1
Physical examination
A complete 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 before every 
dose escalation as part of the global hemodynamic assessment noted in Section 5.5.4, and is to 
include the examination of general appearance and vital signs.
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 related to the physical 
examination made after signing the informed consent, up to and including Day 14, which 
meet the definition of an AE must be recorded on the Adverse Event section of the eCRF 
(Section 7.1). Significant findings related to the physical examination 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 completed 
signed Serious Adverse Event form must be provided to the local Novartis Drug Safety and 
Epidemiology Department (DS&E) faxed within 24 hours after awareness of the SAE.
6.5.2
Vital signs, respiratory parameters and clinical assessments
Vital signs, respiratory parameters and clinical assessments will be performed at multiple time 
points as described below.  These measurements may be made and recorded by trained 
healthcare personnel as part of their routine clinical duties, as well as by study personnel.
Vital signs, respiratory parameters and clinical assessments to be evaluated:
-
HR, SBP, Mean Arterial Pressure (derived), DBP
-
RR (respiratory rate of the patient)
-
SpO2 (pulse oximeter)
-
Hourly per kg urine output
-
ETCO2 (end-tidal (expiratory) CO2) or TcCO2 (transcutaneous CO2), if available
-
CVP (central venous pressure) and LAP (left atrial pressure), if available
-
PAP (pulmonary artery pressure – systolic and diastolic), if available
-
Ventilation parameters (where available – for spontaneously breathing patients only 
FiO2 [according to the table in Appendix 7] should be recorded):
o
Mode of ventilation:
invasive,
non-invasive
mechanical ventilation or 
spontaneous breathing
o
FiO2 (Oxygen fraction in the inspired gas) [according to the table in Appendix 
7] should be recorded in addition to the ventilator parameters (PIP, PEEP, 
MAP, VT) specified in Section 6.4.2
 


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-
Oxygenation index (FiO2xMAP)/PaO2 (for patients on mechanical ventilation only) 
and PaO2/FiO2 ratio, will be calculated
-
Co-medication and dose (including [dose – per min or hour] or [infusion rate + 
concentration] for continuous infusions, e.g. inotropes, vasoactive drugs, sedation and 
analgesia)
-
Discontinued co-medications during the interval (all medications)
-
Non-medical therapies in the interval (including but not limited to the following: 
physiotherapy, ergotherapy, endotracheal suctioning or repositioning, mobilization, 
transportation)
Vital signs, respiratory parameters (including the ventilator parameters PIP, PEEP, MAP, V T
specified in Section 6.4.2) and clinical assessments must be closely monitored during the 
infusion of the study drug. The time points to be collected in the eCRF for the evaluation of 
vital signs, respiratory parameters and clinical assessments (hourly time points are 
approximate) are as follows:
-
Baseline
-
Every 2 hours for 4 hours at the start of each of the three dose levels
-
Every 4 hours for the remainder of each infusion period
-
Every 4 hours during the 24 hours post discontinuation or completion of study drug 
infusion
-
Thereafter, every 8 hours until day 5 for as long as the patient is hospitalized. If the 
patient is discharged prior to day 5, then approximately q24 hr. as an outpatient, up to
and including day 5.
-
And, anytime there is a clinically significant change in any of the above parameters or 
an AE/SAE indicative of worsening heart failure (see 
for examples), at 
any time point during the study. The clinical context should be described by the 
investigator.
 
 
 
 
 
 
 
 
 
 


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6.5.3
Height and weight
Height/length in centimeters (cm) will be measured at Screening.
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at Screening and Days 1-5, and 14. The basis for the Inclusion Criteria weight (i.e. 
2.5 -120 kg) is as follows: pre-operative weight for post-operative patients and weight on 
hospital admission for non-surgical patients. Body weight during critical care unit stay is to be 
recorded only if available as per standard of care.
6.5.4
Laboratory evaluations
A combination of central and local laboratories, depending on the type of analysis and the 
time point, will be used for analysis of all screening, baseline and post-baseline specimens 
collected according to Table 6-1. 
 
For local laboratory results, the laboratory name, test values and the normal ranges relevant to 
the age of the patient must be entered into the eCRF page. Laboratory values that exceed the 
boundaries of a notable laboratory abnormality for this patient population should be assessed 
for AEs and additional evaluations should be performed, as judged appropriate by the 
investigator. If a laboratory abnormality induces clinical signs and symptoms, or requires 
therapeutic intervention, this is considered an AE. The diagnosis or medical condition must be 
entered on the AE screen of the eCRF. If a laboratory abnormality 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. 
 
 
 
 
 
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, MCV, MCH, white blood cell count with 
differential counts, and platelet count will be measured. Hematology parameters will be 
analyzed by the Central Lab, if blood volume permits.
6.5.4.2
Clinical chemistry
Blood urea nitrogen (BUN), creatinine, total bilirubin, AST, ALT, alkaline phosphatase, 
lipase, amylase, lactate dehydrogenase (LDH), sodium, potassium, chloride, calcium, 
phosphorous, magnesium, bicarbonate, total protein, albumin, uric acid, glucose, cholesterol 
 


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and triglycerides will be measured in a central laboratory, if blood volume permits. If not, 
results from routine testing in the local laboratory will be recorded in the eCRF.
6.5.4.3
Blood gas analysis and lactate
The arterial and central venous samples have to be taken at the same time in order to allow 
accurate calculation of the arterio-venous oxygen extraction. In patients without arterial line 
the oxygen saturation from the pulse oximeter should be recorded. 
 
 
 
 
 
 
6.5.4.4
Urinalysis
Dipstick measurements for specific gravity, protein, glucose and blood will be performed 
locally.
6.5.5
Electrocardiogram (ECG)
ECGs should be recorded in the supine position, if possible after at least 10 minutes rest to 
ensure a stable baseline. A standard 12-lead ECG will be performed at screening and at the 
end of study drug infusion (note: if paper, 3 copies of the same tracing are to be provided). 
ECGs will be read locally for study entry and diagnostic purposes and will also be read by a 
Central ECG Reader. The centrally read ECG data will be used for analysis. Each ECG 
tracing should be labeled with the study and patient number, patient initials (if applicable), 
date, and kept in the source documents at the study site. Clinically significant abnormalities 
should be recorded on the relevant section of the Medical History/AE eCRF, as appropriate.
6.5.6
Pregnancy and assessments of fertility
At screening, a locally-analyzed serum pregnancy test will be performed for all females 11 
years of age and older and for all females <11 years of age, who are of childbearing potential 
(menstruation has started). Any patient with a positive pregnancy test at Screening will be 
excluded from participating in the study. A serum pregnancy test will also be performed 
locally at the Study Day 14 or the last in-person discontinuation visit for all females 11 years 
of age and older and for all females <11 years of age, who are of childbearing potential 
(menstruation has started).
6.5.7
Chest X-ray
A chest X-ray (i.e. standard anterio-posterior view of a thoracic radiograph, in upright 
position at end-inspiration or end-inflation if possible) should be done within 12 hours of the 
screening visit. If a study related chest X-ray requires permission by local regulatory 
authorities and approval has not been obtained, patients may only be included if a SOC chest 
X-Ray, done within 12 hours of the screening visit, is available. The chest X-ray may be 
 


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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. Findings 
such as pleural (or pericardial – if possible) effusion, lung infiltrates or atelectasis, increased 
vascular markings, cardio-thoracic index, signs of enlargement of any heart chamber, line, 
catheter and endotracheal tube placements should be graded (light, moderate, severe – where 
appropriate) and described in the source document. A radiologist’s interpretation is not 
necessary for the purposes of this study.
6.5.8
Appropriateness of safety measurements
The safety assessments selected for this trial are standard assessments for demonstrating 
safety in this pediatric patient population.
6.6
Other assessments
Pharmacokinetic evaluations (serum) will be done for all patients as described in Section 6.2.
6.6.1
Resource utilization
Data regarding healthcare resource utilization will not be collected in this study.
6.6.2
Pharmacokinetics and Immunogenicity
 
 
 
 
 
Pharmacokinetic (PK) parameters will include Css (steady state concentration, estimated by 
C16hr, C32hr and C48hr for each dose level) and CL (clearance, estimated using Css).  
Additional non-compartmental and compartmental PK analyses may be performed and 
parameters will be generated based on the suitability of the data.
 
 
 
 
 
 
 
 
 
 
 


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6.6.3
Pharmacogenetics/pharmacogenomics
Pharmacogenetics will not be performed in this study.
6.6.4
Other biomarkers
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product (see Section 6.5.2 and 
for additional 
information regarding AEs indicative of worsening heart failure).
The occurrence of adverse events 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, or other 
assessments.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
 


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patients and identifying AEs. Alert ranges for laboratory and other test abnormalities are 
included in 
AEs should be recorded in the Adverse Events eCRF 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 investigational treatment (yes/no)

its duration (start and end dates) or, if the event is ongoing, an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE)

action taken regarding investigational treatment. All AEs should be treated appropriately. 
Treatment may include one or more of the following: 

no action taken (i.e., further observation only) 

investigational treatment permanently discontinued due to this AE 

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
The investigator should also instruct each patient to report any new adverse event (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 
reported to Novartis.
7.2
Serious adverse events (SAEs)
7.2.1
Definition of SAEs
An 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
 


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
is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has 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, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
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 (see Annex IV, ICH-E2D Guideline).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization (see 
Section 6.5.2 and 
for additional information regarding SAEs indicative of 
worsening heart failure).
SAEs are monitored continuously and have also special reporting requirements; see Section 
7.2.2.
7.2.2
Serious adverse event (SAE) reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 
days period should only be reported to Novartis if the Investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
 


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submitted within 24 hours of the Investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
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 the study drug,
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 investigational treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the Investigator for 
Health Authority reporting. Novartis may need to issue an Investigator Notification (IN) to
inform all Investigators involved in any study with the same investigational treatment that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
7.3
Liver safety monitoring
 
 
 
 
 
 
 
 
 


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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.
 
 
 
 
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that investigational
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
 


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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
 
 
 
 
 
 
8.2
Data collection
 
 
 
 
 
 
 
 
 
 
 
8.3
Database management and quality control
 
 
 
 
 
 
 
 
 
 
 


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8.4
Interim safety and PK data review
As described in Section 3.1, Study design, 
, age cohorts will be enrolled sequentially, within each dose 
group, from age cohort 1 to 4. For each age cohort, 3 patients will be enrolled first into the 
low-dose group and if it is considered safe after review of all available safety and PK data (up 
to and including study day 5), then patients will be enrolled into the low-dose group for the 
succeeding age cohort. No patients will be enrolled into the high-dose group for a given age 
cohort until data from the low-dose group of that same age cohort and the high-dose group of 
the preceding age cohort is reviewed and it is considered safe to proceed. Data review is 
anticipated to include the following, when available:

AEs and SAEs and their causal relationship to the study drug

Hypotension events, dose adjustments and discontinuations

Evidence of pharmacodynamic interactions between serelaxin and co-medications

Vital signs, respiratory parameters and clinical assessments

Blood chemistry, hematology, blood gas and serum lactate levels, and renal 
biomarkers (as available)

PK
 
 
 
 
 
 
 


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8.5
Adjudication Committee
Not required.
9
Data analysis
9.1
Analysis sets
The following analysis populations will be defined for the statistical analysis:

Screened set (SCR) – All subjects who signed the informed consent.

Enrolled set (ES) – All subjects to whom study treatment has been assigned.

Safety set (SAF) – All subjects in the ES who were exposed to study drug regardless of 
the exposure duration, and have at least one post-baseline safety assessment. Of note, the 
statement that a subject had no adverse events also constitutes a safety assessment.

The PK analysis set (PK) will include all subjects with at least one available valid (i.e. not 
flagged for exclusion) PK concentration measurement, who received any study drug and 
experienced no protocol deviations with relevant impact on PK data.
The number and percentage of subjects in the ES who completed the study and who 
discontinued the study, and the reason for discontinuation, will be presented for each age 
cohort and over all subjects, by dose group.
 
9.2
Patient demographics and other baseline characteristics
Subject demographics (age, age cohort, 
 sex, 
ethnicity, race, weight and height) and baseline characteristics [heart failure history, mode of 
ventilation (invasive, non-invasive, spontaneous breathing)] will be summarized by age cohort 
and overall for the ES. Screening 
eGFR will be 
summarized with standard descriptive statistics.  Medical history data will be summarized by 
age cohort and dose group and for all subjects.  Continuous variables will be summarized 
using n, mean, median, standard deviation, minimum, maximum, and categorical variables 
will be summarized using frequency and percentage. 
 
 
9.3
Treatments
Overall study drug administration details will be summarized by age cohort and dose group 
(low-dose group, high-dose group) and for all subjects for the SAF population. This will 
include study drug administered (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 by dose group and by age cohort as well as 
for all patients. In addition, the number of patients whose study medication dose was lowered 
 


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or discontinued prematurely, and the reasons for discontinuation, will be summarized by age 
cohort and dose group and for all subjects.
Concomitant medications and significant non-drug therapies, prior to and after the start date 
of treatment, respectively, will be summarized by therapeutic class, preferred term, age cohort 
and dose group for the SAF population.
9.4
Analysis of the primary variable(s)
There are two primary objectives for this study, the assessment of safety and tolerability and 
the assessment of pharmacokinetics.
The statistical methods for the assessment of safety and tolerability (rate of adverse events, 
routine assessment of laboratory parameters including those for renal function) are 
summarized in Section 9.5.2. The statistical methods for the pharmacokinetics variables are 
discussed in this section.
9.4.1
Variable(s)
Pharmacokinetic parameters will include Css (steady state concentration, estimated by C16hr, 
C32hr and C48hr for each dose level), and CL (clearance, estimated using the following 
equation: CL=Rate of infusion/Css). Refer to Section 6.6.2
for time points for 
pharmacokinetic (PK) assessments.
9.4.2
Statistical model, hypothesis, and method of analysis
The PK parameters Css and CL will be mainly summarized descriptively by age cohort and 
dose within each dose group. A graphical presentation will be employed to show mean and 
individual RLX030 concentration-time profiles for each age cohort and each dose group.
 
 
 
 
 
 
 
 
 
The PK parameters Css and CL may be pooled across dose group (high/low-dose) within each 
age cohort and summarized as appropriate by dose level and age cohort for 10 µg/kg/day and 
30 µg/kg/day, respectively.
 
 
 


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9.4.3
Handling of missing values/censoring/discontinuations
No imputation will be done for missing values at 16, 32 or 48 hours for the estimation of Css, 
or at any planned time points for the by-visit summaries. Only values recorded in the data 
base will be used for the by-visit summaries at these time point.
9.4.4
Supportive analyses
 
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
Hemodynamic parameters (secondary)
Secondary endpoints will be assessed at baseline, prior to each dose escalation, and at 24 hr 
post end of infusion. Secondary endpoints will include an assessment of hemodynamic effects 
on routinely measured hemodynamic parameters as listed below:

arterial BP

central venous pressure (CVP)

left atrial pressure (LAP) and pulmonary artery pressure (PAP– systolic and diastolic), 
if available

central venous and arterial oxygen saturation

urine output 

blood lactate levels
For arterial BP, CVP, LAP, PAP, central venous and arterial oxygen saturation, urine output 
and blood lactate levels, the absolute values at baseline and each time point (when these 
parameters are measured), as well as the change from baseline will be descriptively 
summarized by age cohort and dose group and for all patients. 
 
 
 
 
 
 
 
 


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a 
 
 
 
 
 
 
 
 
 
9.5.2
Safety variables
Adverse events, SAEs and Death
Adverse events (AEs, SAEs and AEs leading to discontinuation) will be summarized by 
cohort and dose group and for all subjects in the SAF for the entire study period, during each 
of the 16 hour dose escalation periods and over the post infusion period.  Adverse events 
(number and percent) will be presented by system organ class and MedDRA preferred term. 
In addition, a summary of AEs by preferred term and severity, using the worst reported 
severity grade for each event for the subject, will be provided. The number and percentage of 
patients with AEs possibly related to study medication will be summarized by age cohort and 
dose group and for all patients as well. These summaries will be presented for the entire study 
period, during each of the 16 hour dose escalation periods and over the post infusion period, 
respectively.
Death (if any) will be summarized by system organ class and MedDRA preferred term as well.
AEs, SAEs and death will be also presented in data listings at individual patient level.
Laboratory, vital signs, body weight and decreased blood pressure events
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 
 


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from baseline (mean, confidence interval, median, standard deviation, 1st and 3rd quartiles Q1 
and Q3) at each assessment time point by age cohort and dose group and for all subjects. 
Notably abnormal values for individual subjects will be flagged in data listings.
Vital sign data and clinical assessments (including HR, SBP and DBP, ventilation parameters
etc. as described in Section 6.5.2 excluding the efficacy variables specified in Section 6.4.1) 
will be descriptively summarized as appropriate by presenting absolute values and change 
from baseline at each assessment time point for each age cohort and dose group and for all 
patients.
In addition, respiratory parameters including FiO2, and oxygenation index 
(FiO2xMAP)/PaO2 (for patients on mechanical ventilation only), and PaO2/FiO2 ratio, will 
also be summarized by presenting absolute values and change from baseline at each 
assessment time point by age cohort, dose group and ventilation mode.
The absolute values and change from baseline at each visit in body weight will be 
summarized descriptively by age cohort and dose group and for all patients.
The number and proportion of patients who experience a confirmed blood pressure decrease 
event during study drug administration will be provided by dose level within each dose group 
and age cohort. Further details on confirmed blood pressure decrease events (including 
whether they result in study drug dose reduction or discontinuation) will be provided as well.
ECG
The ECG findings and central ECG data will be summarized as appropriate by age cohort and 
dose group and for all subjects in the SAF population.
9.5.3
Resource utilization
Not applicable
9.5.4
Pharmacokinetics
The pharmacokinetics data analysis is described in Section 9.4.
9.5.5
Pharmacogenetics/pharmacogenomics
Not applicable
9.5.6
Biomarkers
 
 
 
9.5.7
PK/PD
 
 
 


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9.6
Interim analyses
There will be no interim analysis for this study. However, there will be interim PK and safety 
data reviews by the PSRC. See Section 3.1 for study design details.
9.7
Sample size calculation
Sample size is guided by feasibility in pediatric patient studies for assessment of safety, 
tolerability and pharmacokinetics. 
The sample size planned for the high-dose group (10/30/100 µg/kg/day) per age cohort will be 
6 subjects. With a sample size of 6 subjects per age cohort, receiving RLX030 at various 
doses, there is ~80% probability to observe an adverse event with an underlying occurrence 
rate of 24% at least once for each cohort and dose combination during the study. With a 
sample size of 3 subjects per age cohort, receiving RLX030 at various doses, there is ~56% 
probability to observe an adverse event with an underlying occurrence rate of 24% at least 
once for each cohort and dose combination during the study.
Data from 6 subjects will also provide ~80% probability for the 95% confidence intervals (CI) 
of geometric means of RLX030 Css to fall within the range of  (68%U, 146%U), data from 3 
subjects will provide ~80% probability for the 95% confidence intervals (CI) of geometric 
means of RLX030 Css to fall within the range of  (39%U, 257%U), where U is the observed 
geometric mean, assuming a coefficient of variation of 30% 
 
.
 an additional 3 subjects will be enrolled into a low-dose group (3/10/30 
µg/kg/day) in each age cohort. The purpose of this low-dose group is to further enhance the 
safety by collecting safety data at a starting dose of 3 µg/kg/day up to the ad ult efficacious 
dose of 30 µg/kg/day, before enrolling patients in the high-dose group.
These calculations were performed using nQuery.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 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
 
 
 
 


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10.3
Responsibilities of the investigator and IRB/IEC
 
 
 
 
 
 
 
 
 
10.4
Publication of study protocol and results
 
 
 
11
Protocol adherence
 
 
 
 


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11.1
Protocol Amendments
 
 
 
 
 
 


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12
References
References are available upon request.
Bani D, Failli P, Bello MG, Thiemermann C, Bani Sacchi T, Bigazzi M, Masini E (1998) 
Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in 
culture. Hypertension. 31(6):1240-7
Barry P, Morris K, Ali T (2010) Congestive Heart Failure: Pediatric Intensive Care; Oxford 
University Press; p. 356-7
Conrad KP (2010) Unveiling the vasodilatory actions and mechanisms of relaxin.
Hypertension 56(1):2-9
Conrad KP (2011) Emerging role of relaxin in the maternal adaptations to normal pregnancy: 
implications for preeclampsia. Semin Nephrol 31(1):15-32
Conrad KP (2011) Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J 
Physiol Regul Integr Comp Physiol 301(2):R267-75
Conrad KP, Shroff SG (2011) Effects of relaxin on arterial dilation, remodeling, and 
mechanical properties. Curr Hypertens Rep 13(6):409-20
Danielson LA, Sherwood OD, Conrad KP (1999) Relaxin is a potent renal vasodilator in 
conscious rats. J Clin Invest. 103(4):525-33
Davidson J, Tong S, Hancock H, Hauck A, da Cruz E, Kaufman J (2012) Prospective 
validation of the vasoactive inotropic score and correlation to short term outcomes in neonates 
and infants after cardiothoracic surgery. Intensive Care Med 38:1184-1190
Dschietzig T, Bartsch C, Richter C, Laule M, Baumann G, Stangl K (2003) Relaxin, a 
pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-
mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-
1/2 and nuclear factor-kappaB. Circ Res. 10;92(1):32-40
Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ (2010) Cardiovascular effects of 
relaxin: from basic science to clinical therapy. Nat Rev Cardiol. 7(1):48-58
Epstein D, Wetzel RC (2006) Cardiovascular Physiology and Shock. Congestive Failure. In: 
Nichols DG, Ungerleider RM, Spevak PJ, Greeley WJ, Cameron DE, Lappe DG, Wetzel RC 
(eds.) Critical Heart Disease in Infants and Children. 2nd ed; Mosby Elsevier, p. 42-5
Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, Balk E, Lau J, Levin A, 
Kausz AT, Eknoyan G, Levey AS (2003) National Kidney Foundation’s Kidney Disease 
Outcomes Quality Initiative Clinical Practice Guidelines for Chronic Kidney Disease in 
Children and Adolescents: Evaluation, Classification, and Stratification. Pediatrics 111:1416
Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ (2002) 
Activation of orphan receptors by the hormone relaxin. Science. 295(5555):671-4
Kantor PF, Mertens LL (2010) Clinical practice: heart failure in children. Part I: clinical 
evaluation, diagnostic testing, and initial medical management. Eur J Pediatr 169(3):269-79
Kantor PF, Mertens LL (2010) Clinical practice: heart failure in children. Part II: current 
maintenance therapy and new therapeutic approaches. Eur J Pediatr. 169(4):403-10
 


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Kay JD, Colan SD, Graham TP Jr (2001) Congestive heart failure in pediatric patients. Am 
Heart J 142(5):923-8
Kim JJ, Rossano JW, Nelson DP, Price JF, Dreyer WJ (2008) Heart Failure in infants and 
children: Etiology, Pathophysiology, and Diagnosis of heart failure. In: Nichols DG (ed. In 
chief) Roger’s Textbook of Pediatric Intensive Care. 4th ed; p. 1064-74
Kleinman ME, Chameides L, Schexnayder SM, Samson RA, Hazinski MF, Atkins DL, Berg 
MD, de Caen AR, Fink EL, Freid EB, Hickey RW, Bradley S. Marino BS, Nadkarni VM, 
Lester T, Proctor LT, Faiqa A, Qureshi FQ, Sartorelli K, Topjian A, van der Jagt EW and 
Zaritsky AL (2010) Part 14: PALS (Pediatric Advanced Life Support): 2010 American Heart 
Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular 
Care. Circulation;122:S876-S908
Lipshultz SE, Sleeper LA, Towbin JA, Lowe AM, Orav EJ, Cox GF, Lurie PR, McCoy KL, 
McDonald MA, Messere JE, Colan SD (2003) The incidence of pediatric cardiomyopathy in 
two regions of the United States. N Engl J Med 348(17):1647-55
Madriago E, Silberbach M (2010) Heart Failure in Infants and Children. Pediatric Review  
31:4-12
Massin MM, Astadicko I, Dessy H (2008) Epidemiology of heart failure in a tertiary pediatric 
center. Clin Cardiol 31(8):388-91
Neumann T, Biermann J, Erbel R, Neumann A, Wasem J, Ertl G, Dietz R (2009) Heart failure: 
the commonest reason for hospital admission in Germany: medical and economic perspectives.
Dtsch Arztebl Int 106(16):269-75
NHLBI (2004) The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents:  National High Blood Pressure Program Working 
Group on High Blood Pressure in Children and Adolescents.  Pediatrics 114:555–576
Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, Davis AM, 
Kahler SG, Chow CW, Wilkinson JL, Weintraub RG (2003) The epidemiology of childhood 
cardiomyopathy in Australia. N Engl J Med 348(17):1639-46
Pettersen MD, Du W, Skeens, ME, Humes RA (2008) Regression Equations for Calculation 
of Z Scores of Cardiac Structures in a Large Cohort of Healthy Infants, Children, and 
Adolescents: An Echocardiographic Study. Journal of the American Society of 
Echocardiography 21(8):923-934
Ricci Z, Ronco C (2013) Neonatal RIFLE. Nephrology Dialysis Transplantation 0:1–3
Schwartz GJ, Work DF (2009) Measurement and Estimation of GFR in Children and 
Adolescents. Clin J Am Soc Nephrol 4: 1832–1843
Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Davison Weatherley B, Marmor 
A, Katz A, Grzybowski J, Unemori E, Teichman SL, Cotter G (2009) Relaxin for the 
treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, 
placebo-controlled, parallel-group, dose-ﬁnding phase IIb study. Lancet 373: 1429–39
Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, 
Unemori E, Voors AA, Adams Jr KF, Dorobantu DI, Grinfeld LR, Jondeau G, Marmor A, 
Masip J, Pang PS, Werdan K, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, 
 


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Severin TM, Metra M (2013) Serelaxin, recombinant human relaxin-2, for treatment of acute 
heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 381: 29–39
Tseng CH (2010) Clinical features of heart failure hospitalization in younger and elderly 
patients in Taiwan. Eur J Clin Invest 41(6):597-604
 


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15
Appendix 3: 25th Percentile Systolic Blood Pressure Table
Table 15-1
25th Percentile Systolic Blood Pressure Table*
SBP (mmHg)
SBP (mmHg)
Age
BP percentile
Boys, 50th percentile in height
Girls, 50th percentile in height
<1 month
25th estimate**
70
70
<1 year
25th estimate**
75
75
1 year
25th
78
80
2 years
25th
82
81
3 years
25th
84
83
4 years
25th
86
84
5 years
25th
88
86
6 years
25th
89
88
7 years
25th
90
89
8 years
25th
92
91
9 years
25th
93
93
10 years
25th
95
95
11 years
25th
97
97
12 years
25th
99
99
13 years
25th
102
101
14 years
25th
104
102
15 years
25th
107
103
16 years
25th
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17 years
25th
112
105
*Calculated 25th percentile SBP values, based on data provided in the NHLBI (2004): The Fourth 
Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and 
Adolescents:  National High Blood Pressure Program Working Group on High Blood Pressure in 
Children and Adolescents
** Estimate based on calculated 25th percentile SBP values for 1 yr + and AHA PALS Guidelines for 
the 5th percentile SBP (Kleinman 2010)
 


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Appendix 4: 5th Percentile Systolic Blood Pressure Table
Table 16-1
5th Percentile Systolic Blood Pressure Table (AHA PALS Guidelines)
Age
SBP 
percentile
SBP (mmHg)
<1 month
5th
60
<1 year
5th
70
1 year
5th
72
2 years
5th
74
3 years
5th
76
4 years
5th
78
5 years
5th
80
6 years
5th
82
7 years
5th
84
8 years
5th
86
9 years
5th
88
10 years
5th
90
11 years
5th
90
12 years
5th
90
13 years
5th
90
14 years
5th
90
15 years
5th
90
16 years
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17 years
5th
90
* AHA PALS guidelines 2010 (Kleinman 2010) are widely used criteria for hypotension in AHF patients. 
The formula (for 1 y/o and older: 70 mmHg + 2 x Age, up to age 10) is understood to provide the 5th 
BP percentile up to 10 y/o. For children >10 y/o, the AHA PALS guidelines 2010 5th percentile is set at 
90 mmHg. . NOTE: This formula approximates the population-based 5th percentile BP data; however, 
the margin of error increases with increasing age, with the PALS formula value generally providing a 
lower value.
 


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19
Appendix 7: Oxygen delivery devices and FiO2
Table 19-1
Oxygen delivery devices and FiO2
Oxygen Device
FiO2 to be captured
Comment
Nasal Prongs/cannulas
1-2 l/min 
25%
3-4 l/min 
30%
5-6 l/min 
35%
O2 delivery depends on the flow
Indicated FiO2 is approximate, 
actual FiO2 depends on the 
patients breathing pattern and 
device positioning 
Simple O2 mask
6-8 l/min 
35%
8-10 l/min
45%
O2 delivery depends on the flow
Indicated FiO2 is approximate, 
actual FiO2 depends on the 
patients breathing pattern and 
device positioning
Non-rebreathing mask
10-15 l/min
90%
O2 delivery depends on the flow
Indicated FiO2 is approximate, 
actual FiO2 depends on the 
patients breathing pattern and 
device positioning
Venturi mask
24 – 50% depending on the 
connector used
Record what is indicated on the 
connector
Mask or helmet non-invasive 
ventilation
21-100%
Record ventilator reading
Invasive ventilation
21-100%
Record ventilator reading
 


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Amended Protocol Version v04 Clean
Protocol No. CRLX030A2208
 


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Amended Protocol Version v04 Clean
Protocol No. CRLX030A2208
 

SAP_001.pdf: 
Clinical Development
RLX030/Serelaxin
Study No. CRLX030A2208/ NCT02151383
Multicenter, open-label, dose escalation study to evaluate safety, 
tolerability and pharmacokinetics of RLX030 in addition to standard 
of care in pediatric patients from birth to <18 years of age, 
hospitalized with acute heart failure
Statistical Analysis Plan (SAP)
Addendum 1
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
09-Aug-2018
Number of pages:
5
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of M3 (SAP)
amendment 1
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
09-
Aug-
2018
Post 
DB 
lock
CSR 
addendum 
1
Added additional analyses required for 
CSR addendum 1
NA


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................4
1
Introduction .........................................................................................................................5
2
Statistical methods...............................................................................................................5
2.1
Analysis of the Pharmacokinetics (PK) data ...........................................................5
2.2
Analysis of the secondary efficacy endpoints .........................................................5


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List of abbreviations
CSR
Clinical Study Report
CV
Coefficient of variation
CVP
Central venous pressure
LAP
Left atrial pressure
PAP
Pulmonary artery pressure
PK
Pharmacokinetics
RAP
Report and Analysis Process
SAP
Statistical Analysis Plan


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1
Introduction
This document provides details of the additional statistical analyses required to support the 
completion of the abbreviated Clinical Study Report (CSR) addendum 1 for the study
CRLX030A2208. 
2
Statistical methods
The following analyses will follow the general information and definitions outlined in the 
study statistical analysis plan CRLX030A2208 M3 amendment 1 (previous final version of 
SAP), including the definitions of baseline, analysis sets, age cohorts and dose groups. 
2.1
Analysis of the Pharmacokinetics (PK) data
The PK concentration will be summarized descriptively by age cohort within each dose group 
as well as in the overall group, and time point, using n, mean, standard deviation, coefficient 
of variation (CV), geometric mean, geometric CV, median, minimum, and maximum. 
The PK analysis set will be used for the above analysis. This analysis will include the PK 
concentration data at all scheduled PK sampling time points, i.e., at 0, 2, 16, 22, 32, 40, 48 hr. 
during the infusion, at 0.5, 4, 8 hours post infusion or study drug discontinuation, and on day 
14/day 28.
2.2
Analysis of the secondary efficacy endpoints
Summary statistics (n, mean, standard deviation, median, the first quartile (Q1), the third 
quartile (Q3), minimum, and maximum) will be provided by age cohort within each dose 
group as well as in the overall group for the measurement at each visit and change from 
baseline values for the following secondary efficacy variables:
o
Central venous pressure (CVP)
o
Left atrial pressure (LAP)
o
Pulmonary artery pressure (PAP- systolic and diastolic)
o
Central venous and arterial oxygen saturation
o
Urine output
o
Blood lactate levels (arterial and central venous lactate)
The safety set will be used for the above analyses. Data collected at the following assessment 
time points/visits will be included in the analyses: at baseline, prior to each dose escalation, at 
48 hours post infusion start, and at 24 hours post end of infusion.


Clinical Development
RLX030/Serelaxin
Study No. CRLX030A2208 / NCT02151383
Multicenter, open-label, dose escalation study to evaluate safety, 
tolerability and pharmacokinetics of RLX030 in addition to standard 
of care in pediatric patients from birth to <18 years of age, 
hospitalized with acute heart failure
Module 3 – Detailed Statistical Methodology
Amendment 1
Author(s):
 Trial Statistician
Document type:
RAP Documentation Amendment
Document status:
Final
Release date:
29-Jun-2017
Number of pages:


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Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
2
Analysis sets ........................................................................................................................7
3
Subgroup definitions ...........................................................................................................9
4
Baseline and post baseline definitions.................................................................................9
5
Subject Disposition, background and demographic characteristics ..................................10
5.1
Subject disposition.................................................................................................10
5.2
Protocol deviations ................................................................................................10
5.3
Background and demographic characteristics .......................................................10
5.4
Medical History .....................................................................................................11
6
Study medication...............................................................................................................11
7
Concomitant medication....................................................................................................11
8
Pharmacokinetic (PK) data................................................................................................11
9
Selected vital signs for safety (SBP, DBP, HR and RR)...................................................11
10 Adverse Events (AEs), SAEs and Deaths .........................................................................11
11 Other data ..........................................................................................................................12
12 Interim analyses.................................................................................................................13
13 Sample size and power considerations..............................................................................13
14 Appendix 1 - Reference.....................................................................................................13
 


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List of tables
Table 2-1
Rules for subject classification in the analysis sets based on 
protocol deviations and non-protocol deviation classification 
criteria .....................................................................................................8
Table 3-1
Specification of subgroups......................................................................9


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List of abbreviations
AE
Adverse Event
BP
Blood Pressure
            
SBPDE
Systolic Blood Pressure Decrease Event
CSR                            
Clinical Study Report
                            
 
DBP                            
Diastolic Blood Pressure
ECG                            
Electrocardiogram   
ES                               
Enrolled Set
FAS        
Full Analysis Set
HR    
Heart Rate
 
 
 
      
 
MedDRA
Medical Dictionary for Regulatory Affairs
                              
                                
                            
                               
PK                                
Pharmacokinetics
PT
Preferred Term
PSRC
Pediatric Safety Review Committee
Q1   
the First Quartile
Q3   
the Third Quartile
RR                                
Respiratory Rate
SAE 
Serious Adverse Event


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SAF                              
Safety Set
SBP                              
Systolic Blood Pressure
SCR                              
Screened Set
SOC
  
System Organ Class
  
                            
 
 
 
 
 
 
 
 
 
 
 
 
 
1
Introduction
This document provides details of the statistical analyses to support the completion of the 
abbreviated Clinical Study Report (CSR) for the study CRLX030A2208. Due to the early 
termination of the study, the planned analyses for a full/complete CSR (as outlined in the 
study protocol) may not provide clinically and/or statistically meaningful results. Therefore, 
an abbreviated CSR is planned for the study CRLX030A2208. No efficacy analysis will be 
performed for the abbreviated CSR: PK parameters and other derived efficacy parameters (as 
defined in the study protocol) will not be provided; Non-derived efficacy parameters (as 
outlined in the study protocol), if available, will be listed at the individual patient level. Other 
data will be listed with the following exceptions:


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Summary tables will be provided for the following non-efficacy data:

Disposition (see Section 5.1)

Demographic and background characteristics (see Section 5.3)

Safety data
o
Treatment emergent non-serious AEs (see Section 10)
o
Treatment emergent SAEs (see Section 10)
o
Treatment emergent AEs (including non-serious AEs and SAEs) (see Section 
10)
o
Treatment emergent AEs leading to discontinuation (see Section 10)
o
Deaths (see Section 10)
o
Vital signs (selected) (see Section 9)

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

Heart rate (HR)

Respiratory rate (RR)
In general, continuous variables will be summarized descriptively by n, mean, SD, median, 
minimum (min), Q1 (25th percentile), Q3 (75th percentile) and maximum (max), while 
categorical variables will be summarized by count and percentage of patients in each category. 
Unless otherwise specified, data will be summarized or listed by dose group (RLX low dose 
group: 3 µg/kg/day, 10 µg/kg/day and 30 µg/kg/day; RLX high dose group: 10 µg/kg/day, 30 
µg/kg/day and 100 µg/kg/day) and age cohort (Age cohort 1: 6 to < 18 years; Age cohort 2: 1 
to <6 years; Age cohort 3: infants 1 month to <1 year; Age cohort 4: neonates birth to <1 
month). 
Other data, including safety parameters, PK concentrations etc. will be listed at the individual 
patient level. In addition, graphical presentation of PK concentration vs. time will be provided.
 
 
2
Analysis sets 
The following analysis populations will be defined for the statistical analysis:

Screened set (SCR) – All subjects for whom valid informed consent from a parent or 
legal guardian was obtained.

Enrolled set (ES) – All subjects in the SCR to whom study treatment has been assigned, 
regardless of trial medication received.

Safety set (SAF) – All subjects in the ES who were exposed to study drug regardless of 
the exposure and have at least one post-baseline safety assessment. Of note, the statement 


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that a subject had no adverse event (AE) also constitutes a safety assessment. Subjects will 
be analyzed according to treatment received. 

The PK analysis set (PK) will include all subjects with at least one available valid (i.e. 
not noted for exclusion) PK concentration measurement, who received study drug and 
experienced no protocol deviations with relevant impact on PK data. Subjects will be 
analyzed according to treatment received.
The number and percentage of patients in each analysis set will be summarized by age cohort 
within each treatment group if applicable and for all patients. Patients excluded from any 
analysis set will be listed for the safety population. 
Table 2-1
Rules for subject classification in the analysis sets based on protocol 
deviations and non-protocol deviation classification criteria
Analysis set
Protocl Deviations (PDs) leading to the 
exclusion of a subject
Non-PD criteria leading 
to the exclusion of a 
subject
Protocol Deviation 
ID
Description of the PD
Screened set
INCL01
Written informed consent 
by parent/legal guardian 
was NOT obtained before 
any study-specific 
assessment, that is done 
specifically for the study, 
was performed.
Enrolled set
INCL01
Written informed consent 
by parent/legal guardian 
was NOT obtained before 
any study-specific 
assessment, that is done 
specifically for the study, 
was performed.
Safety set
INCL01
Written informed consent 
by parent/legal guardian 
was NOT obtained before 
any study-specific 
assessment, that is done 
specifically for the study, 
was performed.
No study medication given 
during the treatment period
PK analysis set
INCL01
Written informed consent 
by parent/legal guardian 
was NOT obtained before 
any study-specific
assessment, that is done 
specifically for the study, 
was performed.
No study medication given 
during the treatment 
period;
No valid PK concentration 
measurement


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3
Subgroup definitions
In Table 3-1, we have listed all subgroups defined for this study. In general, subgroups will be 
defined based on baseline information. Age cohort will be used throughout the analyses. 
Count and percentage of etiology subgroups will be provided as part of the patient 
demographic and background information.
 
Table 3-1
Specification of subgroups
Subgroup 
Method of 
Derivation  
Disposition 
/Backgroun
d & demo. 
/Exposures
PK analysis
Safety
Age cohort (at 
screening
): 
Age cohort 1: 6 to 
<18 years; 
Age cohort 2: 1 to <6 
years; 
Age cohort 3: 1 
month* to <1 year; 
Age cohort 4: birth to 
<1 month*
eCRF
x
x
x
Etiology subgroups 
:
Post-surgical etiology
Medical etiology
eCRF
x
*1 month = 30 days.
4
Baseline and post baseline definitions
Baseline definition
For the selected vital signs (SBP, DBP, HR and RR), baseline is defined as the measurement 
obtained on Day 1
, or the sample obtained at an earlier visit (scheduled or 


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unscheduled) which was closest to Day 1
, if the Day 1
measurement is 
missing.
5
Subject Disposition, background and demographic 
characteristics
5.1
Subject disposition
The number and percentage of patients in each analysis set, safety patients who discontinued 
from the study and the reasons for discontinuation will be summarized by age cohort within 
each treatment group and in the overall group. The screened set (SCR) will be used. 
In addition, the reasons for screen failures, based on inclusion/exclusion criteria, will be listed
at the individual patient level for the SCR.
5.2
Protocol deviations
Protocol deviations will be pre-specified and finalized for analyses prior to database lock. All 
protocol deviations will be listed at the individual patient level for the SAF.
5.3
Background and demographic characteristics
The following demographic and background characteristics data 
 
will be summarized 
descriptively (using n, mean, standard deviation, median, Q1, Q3, minimum, and maximum
for continuous variables; or number and percentage for categorical variables) for the SAF by 
age cohort within each treatment, and in the overall group (Note: Categorical variables are 
underlined. Variables without an underline are continuous variables):

Age (years)

Sex: Male; Female

Race: Caucasian; Black; Asian; Native American; Pacific Islander; Unknown; Other

Ethnicity: Hispanic or Latino; East Asian; Southeast Asian; South Asian; West Asian;
Russian; Mixed Ethnicity; Not Reported; Unknown; Other

Weight (kg)

Height (cm)

Etiology: Post-surgical; Medical

Genetic/chromosomal abnormalities: Yes; No; Unknown

Clinical syndrome without genetic diagnosis: Yes; No; Unknown

Malformation of an organ system other than the heart: Yes; No; Unknown
 


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All demographic and background characteristic data, including delivery history (only for age 
cohort 3 or 4 patients) will be listed at the individual patient level for the SAF.
5.4
Medical History
Medical history entered on the medical history CRF page at screening 
 will be coded 
using the MedDRA dictionary. Medical history and protocol solicited events (only for post-
surgical patients) will be listed at the individual patient level for the SAF. 
6
Study medication
Data entered on the Dosage Administration Record CRF page will be listed at the individual 
patient level for the SAF. This will include dose prescribed (ug/kg/day), start/end date and 
time of the infusion, concentration (ug/ml), rate of infusion (mL/h) and reason for the dosage 
administered. 
7
Concomitant medication
Prior and concomitant medications, continuous intravenous concomitant medications, surgical 
and medical procedures and use of mechanical ventilator will be listed at the individual 
patient level for the SAF. The medication name will be coded using therapeutic class (ATC 
code) and preferred term (PT).
8
Pharmacokinetic (PK) data
PK concentration data will be listed at the individual patient level for the SAF. Invalid PK 
concentration data will be noted. A graphical presentation will be employed to show 
individual serelaxin concentration-time (actual) profiles by age cohort within each dose group.
These figures will be prepared for the PK analysis set.
9
Selected vital signs for safety (SBP, DBP, HR and RR)
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be provided by age cohort within each dose group for the measurement at each visit and 
change from baseline values for the following parameters for the safety population:

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

Heart rate (HR)

Respiratory rate (RR)
10
Adverse Events (AEs), SAEs and Deaths
A treatment emergent adverse event is defined as an adverse event that occurs at or after the 
start of the study treatment. Treatment emergent adverse events including non-serious AEs, 
SAEs, AEs (including non-serious AEs and SAEs) and AEs leading to discontinuation will be 


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summarized descriptively (using number and percentage) by age cohort within each treatment 
group and in the overall group. Similarly, deaths will be summarized descriptively as 
appropriate. The number and percentage of these events will be presented by system organ 
class (SOC) and MedDRA preferred term (PT). All AEs will be listed at the individual patient 
level. These analyses will be performed for the SAF.
In addition, SAEs in screen failure patients will be listed at the individual patient level.
11
Other data
Other data will be listed at the individual patient level as appropriate. The following data will 
be listed for the SAF, and listings marked with “*” will be subject to data availability:

Local lab (including chemistry, hematology and urinalysis)

Central lab (including chemistry and hematology)

Vital signs and clinical assessment

Ventilation/respiratory parameters (if on mechanical ventilation)

* Systolic Blood Pressure Decrease Event (SBPDE)

* Vital signs – SBPDE monitoring

* Ventilation/respiratory parameters – SBPDE monitoring

* Vital signs – AE suggestive of Worsening Heart Failure (WHF) monitoring 

* Ventilation/respiratory parameters – AE suggestive of Worsening Heart Failure 
(WHF) monitoring

Echocardiography


ECG


 
 eGFR (as part of the central laboratory data) will be calculated 
using the Schwartz formula (Schwartz et al. 2009): eGFR (mL/min/1.73m2) = 0.41 x height 
(cm)/serum creatinine (mg/dL).
Mean arterial pressure, derived as [(2 x DBP) + SBP] ÷ 3 (Cywinski 1980), will be included 
in listings of the vital signs data. Notably abnormal vital signs (SBP, DBP, HR and RR)
 
 will be noted in data listings.


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12
Interim analyses
There will be no formal interim analysis for this study. However, there will be interim PK and 
safety data reviews by the Pediatric Safety Review Committee (PSRC). See Section 3.1 of the 
study protocol for study design details.
 
 
13
Sample size and power considerations
Sample size is guided by feasibility in pediatric patient studies for assessment of safety, 
tolerability and pharmacokinetics. 
The sample size planned for the high-dose group (10/30/100 µg/kg/day) per age cohort will be 
6 subjects or 3 subjects (see Section 3.1 of the study protocol v04 for the study design details). 
With a sample size of 6 subjects per age cohort, receiving RLX030 at various doses, there is 
~80% probability to observe an adverse event with an underlying occurrence rate of 24% at 
least once for each cohort and dose combination during the study. With a sample size of 3 
subjects per age cohort, receiving RLX030 at various doses, there is ~56% probability to 
observe an adverse event with an underlying occurrence rate of 24% at least once for each 
cohort and dose combination during the study.
Data from 6 subjects will also provide ~80% probability for the 95% confidence intervals (CI) 
of geometric means of RLX030 Css to fall within the range of  (68%U, 146%U), data from 3 
subjects will provide ~80% probability for the 95% confidence intervals (CI) of geometric 
means of RLX030 Css to fall within the range of  (39%U, 257%U), where U is the observed 
geometric mean, assuming a coefficient of variation of 30% 
 
.
An additional 3 subjects in each age cohort, will be enrolled into a 
low-dose group (3/10/30 µg/kg/day). The purpose of this low-dose group is to further enhance 
the safety by collecting safety data at a starting dose of 3 µg/kg/day up to the adult 
efficacious dose of 30 µg/kg/day, before enrolling patients in the high-dose group.
These calculations were performed using nQuery.
14
Appendix 1 - Reference
Schwartz GJ, Work DF (2009) Measurement and Estimation of GFR in Children and 
Adolescents. Clin J Am Soc Nephrol 4: 1832–1843
Cywinski J (1980) The essentials in pressure monitoring (Martinus Nijhoff Publishers b.v.
Boston): 23–24.


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