Conditions: Acute Heart Failure
Keywords: acute heart failure, AHF, multi-center, randomized, double-blind
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6600
Healthy volunteers: no

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

Detailed description:
This Phase IIIb outcome study in AHF patients was designed as a multicenter, randomized, double-blind, placebo-controlled, event-driven study in order to assess the efficacy, safety and tolerability of intravenous infusion of serelaxin or placebo. The AHF patients randomized to either serelaxin or placebo in the study were followed for a period of 180 days, and were required to receive standard-of-care background HF management during both the index hospitalization and post discharge according to regional or local guidelines/institutional standards.

Arms:
arm 1: Participants received continuous intravenous infusion of serelaxin 30 ug/kg/day for 48 hours. arm 2: Participants received continuous intravenous infusion of matching placebo to serelaxin for 48 hours.

Interventions: intervention 1: RLX030 intervention 2: Placebo
Intervention descriptions: intervention 1: 1 mg/mL solution in 6 mL vials intervention 2: Matching placebo solution to serelaxin

Protocol document:
Prot_001.pdf: 
Clinical Development 
RLX030A 
Clinical Trial Protocol CRLX030A2301 / NCT01870778
A multicenter, randomized, double-blind, placebo-
controlled phase IIIb study to evaluate the efficacy, safety 
and tolerability of Serelaxin when added to standard 
therapy in acute heart failure patients 
Authors: 
 
 
Principal or Coordinating 
Investigator 
 for the RLX030A2301 
Executive Committee 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2013-001498-25 
Version number: 
v05 Clean 
Development phase: 
IIIb 
Release date: 
18Feb2015 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Protocol synopsis ................................................................................................................. 9 
Amendment 5 ........................................................................................................................... 15 
Amendment 4 ........................................................................................................................... 17 
Amendment 3 ........................................................................................................................... 20 
Amendment 2 ........................................................................................................................... 21 
Amendment 1 ........................................................................................................................... 21 
1 
Introduction ....................................................................................................................... 23 
1.1 
Background ............................................................................................................ 23 
1.2 
Purpose .................................................................................................................. 25 
2 
Study objectives ................................................................................................................. 25 
2.1 
Primary objectives ................................................................................................. 25 
2.2 
Key and other secondary objectives ...................................................................... 25 
 
 25 
3 
Investigational plan ........................................................................................................... 26 
3.1 
Study design........................................................................................................... 26 
3.2 
Rationale of study design ....................................................................................... 28 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 28 
3.4 
Rationale for choice of comparator ....................................................................... 29 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 29 
3.6 
Risks and benefits .................................................................................................. 29 
4 
Population .......................................................................................................................... 30 
4.1 
Inclusion criteria .................................................................................................... 30 
4.2 
Exclusion criteria ................................................................................................... 31 
5 
Treatment ........................................................................................................................... 33 
5.1 
Protocol requested treatment ................................................................................. 33 
5.1.1 
Investigational treatment ....................................................................... 33 
5.1.2 
Additional study treatment .................................................................... 33 
5.2 
Treatment arms ...................................................................................................... 33 
5.3 
Treatment assignment, randomization ................................................................... 34 
5.4 
Treatment blinding ................................................................................................. 34 
5.5 
Treating the patient ................................................................................................ 35 
5.5.1 
Patient numbering ................................................................................. 35 


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5.5.2 
Dispensing the investigational treatment .............................................. 35 
5.5.3 
Handling of study treatment .................................................................. 35 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 36 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 38 
5.5.6 
Rescue medication ................................................................................ 39 
5.5.7 
Concomitant treatment .......................................................................... 39 
5.5.8 
Prohibited Treatment ............................................................................. 39 
5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 40 
5.5.10 
Emergency breaking of treatment assignment ...................................... 41 
5.5.11 
Study completion and post-study treatment .......................................... 41 
5.5.12 
Early study termination ......................................................................... 41 
6 
Visit schedule and assessments ......................................................................................... 42 
6.1 
Information to be collected on screening failures .................................................. 47 
6.2 
Patient demographics/other baseline characteristics ............................................. 47 
6.3 
Treatment exposure and compliance ..................................................................... 47 
6.4 
Efficacy .................................................................................................................. 47 
6.4.1 
Efficacy assessment 1 ........................................................................... 47 
6.4.2 
Efficacy assessment 2 ........................................................................... 48 
6.4.3 
Appropriateness of efficacy assessments .............................................. 48 
6.4.4 
Other efficacy assessments ................................................................... 48 
6.5 
Safety ..................................................................................................................... 49 
6.5.1 
Physical examination ............................................................................ 49 
6.5.2 
Vital signs.............................................................................................. 49 
6.5.3 
Height and weight ................................................................................. 50 
6.5.4 
Laboratory evaluations .......................................................................... 50 
6.5.5 
Electrocardiogram ................................................................................. 51 
6.5.6 
Pregnancy and assessments of fertility ................................................. 52 
6.5.7 
Appropriateness of safety measurements .............................................. 52 
6.6 
Other assessments .................................................................................................. 52 
6.6.1 
Echocardiogram .................................................................................... 52 
6.6.2 
Resource utilization ............................................................................... 52 
6.6.3 
Health-related Quality of Life ............................................................... 52 
6.6.4 
Pharmacokinetics .................................................................................. 52 
6.6.5 
Pharmacogenetics/pharmacogenomics ................................................. 53 
6.6.6 
Other biomarkers ................................................................................... 53 
7 
Safety monitoring .............................................................................................................. 53 
7.1 
Adverse events ....................................................................................................... 53 


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7.2 
Serious adverse event reporting ............................................................................. 55 
7.3 
Liver safety monitoring ......................................................................................... 58 
8 
Pregnancy reporting ........................................................................................................... 59 
9 
Data review and database management ............................................................................. 59 
9.1 
Site monitoring ...................................................................................................... 59 
9.2 
Data collection ....................................................................................................... 60 
9.3 
Database management and quality control ............................................................ 60 
9.4 
Data Monitoring Committee .................................................................................. 61 
9.5 
Adjudication Committee ........................................................................................ 61 
10 Data analysis ...................................................................................................................... 61 
10.1 
Analysis sets .......................................................................................................... 61 
10.2 
Patient demographics and other baseline characteristics ....................................... 62 
10.3 
Treatments ............................................................................................................. 62 
10.4 
Analysis of the primary and key secondary variable(s) ......................................... 63 
10.4.1 
Variable(s) ............................................................................................. 63 
10.4.2 
Statistical model, hypothesis, and method of analysis .......................... 63 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 64 
10.4.4 
Supportive analyses ............................................................................... 64 
10.5 
Analysis of secondary variables ............................................................................ 64 
10.5.1 
Efficacy variables .................................................................................. 64 
10.5.2 
Safety variables ..................................................................................... 66 
10.5.3 
Resource utilization ............................................................................... 67 
10.5.4 
Health-related Quality of Life ............................................................... 67 
10.5.5 
Pharmacokinetics .................................................................................. 67 
10.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 67 
10.5.7 
Biomarkers ............................................................................................ 67 
10.5.8 
PK/PD ................................................................................................... 67 
10.6 
Interim analyses ..................................................................................................... 68 
10.7 
Sample size calculation .......................................................................................... 68 
11 Ethical considerations ........................................................................................................ 71 
11.1 
Regulatory and ethical compliance ........................................................................ 71 
11.2 
Informed consent procedures ................................................................................. 71 
11.3 
Responsibilities of the investigator and IRB/IEC .................................................. 71 
11.4 
Publication of study protocol and results............................................................... 72 
12 Protocol adherence ............................................................................................................ 72 
12.1 
Protocol Amendments ........................................................................................... 72 
13 References ......................................................................................................................... 72 


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14 Appendix 1: Clinically notable laboratory values  ............................................................ 75 
15 Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ...................................................................................................................... 76 
16 Appendix 3: Physician assessment of signs and symptoms .............................................. 79 
 
List of tables 
 
 37 
 
 37 
Table 5-3 
Weight-range adjusted dosing regimen of serelaxin (or placebo) ........ 38 
Table 5-4 
Dosing adjustment of study drug administration in the event of 
systolic BP decrease .............................................................................. 38 
Table 6-1 
Assessment schedule ............................................................................. 43 
Table 10-1 
Assumed effect sizes for worsening heart failure and the key 
secondary efficacy variables on power calculation ............................... 69 
Table 10-2 
Powers (unconditional) of primary and key secondary variables on 
selected scenarios .................................................................................. 69 
Table 15-1 
Definitions of liver events, which cannot be solely explained by 
apparent cardiac decompensation as the underlying cause (i.e., 
another etiology is suspected to cause or contribute to this event) ....... 76 
Table 15-2 
Follow Up Requirements for liver events and laboratory triggers, 
which cannot be solely explained by apparent cardiac 
decompensation as the underlying cause (i.e., another etiology is 
suspected to cause or contribute to this event) ...................................... 77 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 26 
Figure 10-1 
Sequentially rejective multiple testing procedure for two key 
secondary efficacy variables ................................................................. 65 
 


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List of abbreviations 
AE 
Adverse event 
AHF 
Acute heart failure 
Alb 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
b.i.d. 
twice a day 
CCU 
Coronary care unit 
CRF 
Case Report/Record Form (paper or electronic) 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CV 
Cardiovascular 
DS&E 
Drug Safety & Epidemiology 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ER 
Emergency Room 
ED 
Emergency Department 
HF 
Heart failure 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
ICU 
Intensive Care Unit 
LFT 
Liver function test 
LOS 
Length of stay 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 


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Protocol No. CRLX030A2301 
MedDRA 
Medical dictionary for regulatory activities 
o.d. 
once a day 
p.o. 
oral 
PT 
Preferred Term  
RF 
Renal failure 
SAE 
Serious adverse event 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
Upper limit of normal 
WHF 
Worsening heart failure 
γGT 
Gamma-glutamyltransferase 
 


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


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Protocol No. CRLX030A2301 
Protocol synopsis 
 
Protocol number 
CRLX030A2301 
Title 
A multicenter, randomized, double-blind, placebo-controlled phase IIIb 
study to evaluate the efficacy, safety and tolerability of Serelaxin when 
added to standard therapy in acute heart failure patients 
Brief title 
 
Efficacy, safety and tolerability of Serelaxin when added to standard 
therapy in acute heart failure 
Sponsor and Clinical 
Phase 
Novartis/3b 
 
Investigation type 
Biologic/Vaccine 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to evaluate the efficacy, safety and 
tolerability of intravenous infusion of 30 µg/kg/day serelaxin administered 
by body weight category (Table 5-3) for 48 hours, when added to 
standard therapy, in approximately 6,800 acute heart failure (AHF) 
patients. Efficacy will be determined based on the relative reduction in 
CV death, worsening heart failure and other clinical outcomes through a 
follow-up period of 180 days, as compared to placebo.  
The rate of mortality in AHF remains high despite contemporary 
standard-of-care management, which has not changed significantly in 
the last 10 years, and represents a key unmet need for AHF patients. In 
the RELAX AHF trial a clinically and statistically significant 37% 
reduction in both CV and all-cause mortality through Day 180 were seen.  
Data from this study is intended to replicate the reduction in mortality in 
AHF patients observed in the RELAX AHF trial. The reduction in 
worsening heart failure through Day 5 is a potential efficacy benefit 
which is evolving among the scientific community as an increasingly 
clinically relevant treatment goal of AHF.  Following initial stabilization, 
in-hospital WHF occurs in 10- 30% of hospitalized patients reflecting a 
severe manifestation of the AHF disease continuum requiring immediate 
intensification of rescue therapy (Torre-Amione et al 2009, Cotter et al 
2010, Metra et al 2010a, Teerlink et al 2013) and represents another key 
unmet need for AHF patients.   
Primary Objective(s) 
and Key Secondary 
Objective 
Primary Objectives 
• To demonstrate that serelaxin is superior to placebo in reducing CV 
death in AHF patients during a follow-up period of 180 days 
• To demonstrate that serelaxin is superior to placebo in reducing WHF 
through Day 5. 
Key secondary objectives 
• To demonstrate that serelaxin is superior to placebo in reducing all-
cause mortality during a follow-up period of 180 days 
• To demonstrate that serelaxin is superior to placebo in reducing the 
length of total hospital stay during the index AHF hospitalization 
• To demonstrate that serelaxin is superior to placebo in reducing the 
composite endpoint of CV death or rehospitalization due to heart 
failure/renal failure, during a follow-up period of 180 days 
Secondary Objectives 
Efficacy 


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• To demonstrate that serelaxin is superior to placebo in reducing the 
length of ICU and/or CCU stay during the index AHF hospitalization 
• To demonstrate that serelaxin is superior to placebo in relieving signs 
and symptoms of congestion  through Day 5 
• To compare serelaxin to placebo in the changes of selected 
biomarkers  in a subset of randomized patients 
Safety 
• To evaluate the safety and tolerability of intravenous serelaxin in AHF 
patients 
Study design 
This is a multicenter, randomized, double-blind, placebo-controlled study 
Population 
The study population will consist of male and female patients (≥18 years 
old) admitted to the hospital for AHF, with systolic BP ≥125 mmHg, and 
mild-to-moderate renal impairment. 
Inclusion criteria 
1. Male or female ≥18 years of age who sign the informed consent, 
with body weight ≤160 kg 
2. Hospitalized for AHF with the anticipated requirement of 
intravenous therapy (including IV diuretics) for at least 48 hours; 
AHF is defined as including all of the following measured at any 
time between presentation (including the emergency department) 
and the end of screening: 
• 
Persistent dyspnea at rest or with minimal exertion at 
screening and at the time of randomization, despite standard 
background therapy for acute heart failure including the 
protocol required intravenous furosemide of at least 40 mg 
total (or equivalent).   
• 
Pulmonary congestion on chest radiograph 
• 
BNP ≥ 500 pg/mL or NT-proBNP ≥2,000 pg/mL;  for patients 
≥ 75 years of age or with current atrial fibrillation (at the time 
of randomization), BNP ≥ 750 pg/mL or NT-proBNP ≥ 3,000 
pg/mL*** 
3. Systolic BP ≥125 mmHg at the start and at the end of screening 
and impaired renal function defined as an eGFR*** between 
presentation and randomization of ≥ 25 and ≤75mL/min/1.73m2, 
calculated using the sMDRD equation 
4. Able to be randomized within 16 hours from presentation to the 
hospital, including the emergency department** 
5. Received intravenous furosemide of at least 40 mg total (or 
equivalent) at any time between presentation (this includes 
outpatient clinic, ambulance, or hospital including emergency 
department) and the start of screening for the study for the 
treatment of the current acute HF episode. Time from 
presentation to start of furosemide administration must be less 
than 6 hours. 
** Presentation starts as the earliest of (1) time of presentation at either the 
ER/ED, ICU/CCU or ward, (excludes EMS or other pre-hospital care); or (2) 
time of first IV loop diuretic prior to arrival at the hospital (this includes 
outpatient clinic, ambulance, or hospital including emergency department) for 
the current acute HF episode. 
***Assessed based on local laboratory 


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Exclusion criteria 
1. Dyspnea due to non-cardiac causes such as acute or chronic 
respiratory disorders or infections (i.e., severe chronic obstructive 
pulmonary disease, bronchitis, pneumonia), which may interfere 
with the ability to interpret the primary cause of dyspnea.  
2. Known history of respiratory disorders requiring the daily use of 
IV or oral steroids (does not include inhaled steroids); need for 
intubation or the current use of IV or oral steroids for COPD  
3. Patients with blood pressure > 180 mmHg at the time of 
randomization or persistent heart rate >130 bpm. 
4. Temperature >38.5°C (oral or equivalent) or sepsis or active 
infection requiring IV anti-microbial treatment 
5. Clinical evidence of acute coronary syndrome currently or within 
30 days prior to enrollment. (Note: the diagnosis of acute 
coronary syndrome is a clinical diagnosis and that the sole 
presence of elevated troponin concentrations is not sufficient for 
a diagnosis of acute coronary syndrome, given that troponin 
concentrations may be significantly increased in the setting of 
AHF.)  
6. AHF due to significant arrhythmias, which include any of the 
following: sustained ventricular tachycardia, bradycardia with 
sustained ventricular rate <45 beats per minute, or atrial 
fibrillation/flutter with sustained ventricular response of >130 
beats per minute 
7. Patients with severe renal impairment defined as pre-
randomization eGFR < 25 mL/min/1.73m2 calculated using the 
sMDRD equation, and/or those receiving current or planned 
dialysis or ultrafiltration 
8. Patients with hematocrit  <25%, or a history of blood transfusion 
within the 14 days prior to screening, or active life-threatening GI 
bleeding. 
9. Known hepatic impairment (as evidenced by total bilirubin > 3 
mg/dL, or increased ammonia levels, if performed) or history of 
cirrhosis with evidence of portal hypertension such as varices. 
10. Significant, uncorrected, left ventricular outflow obstruction, such 
as obstructive hypertrophic cardiomyopathy or severe aortic 
stenosis (i.e., aortic valve area <1.0 cm2 or mean gradient >40 
mmHg on prior or current echocardiogram), and severe mitral 
stenosis 
11. Severe aortic insufficiency or severe mitral regurgitation for which 
surgical or percutaneous intervention is indicated. 
12. Documented, prior to or at the time of randomization, restrictive 
amyloid myocardiopathy, OR acute myocarditis or hypertrophic 
obstructive, restrictive, or constrictive cardiomyopathy (does NOT 
include restrictive mitral filling patterns seen on Doppler 
echocardiographic assessments of diastolic function). 


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13. Current (within 2 hours prior to  randomization) or planned 
(through the completion of study drug infusion) treatment with 
any IV vasoactive therapies, including vasodilators (including 
nesiritide), positive inotropic agents and vasopressors, or 
mechanical support (endotracheal intubation, mechanical 
ventilation; intra-aortic balloon pump or any ventricular assist 
device; hemofiltration, ultrafiltration or dialysis), with the 
exception of IV furosemide (or equivalent), or IV nitrates at a 
dose of ≤ 0.1 mg/kg/hour if the patient has a systolic BP >150 
mmHg at the start of screening. 
14. Any major solid organ transplant recipient or planned/ anticipated 
organ transplant within 1 year or Major surgery, including 
implantable devices (e.g. ICD, CRT), or major neurologic event 
including cerebrovascular events, within 30 days prior to 
screening 
15. 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  
16. Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are 
using highly effective methods of contraception during dosing of 
study treatment plus 5 days after cessation of study drug.  
Pregnant or nursing (lactating) women, where pregnancy is 
defined as the state of a female after conception and until the 
termination of gestation, confirmed by a positive hCG laboratory 
test. .  Highly effective contraception methods total abstinence, 
male/female sterilization and a combination of the following a+b 
or a+c or b+c). Refer to Section 4.2 Exclusion Criteria #18. 
17. Any other medical condition(s) that may put the patient at risk or 
influence study results in the investigator’s opinion, or that the 
investigator deems unsuitable for the study, including drug or 
alcohol abuse or psychiatric, behavioral or cognitive disorders, 
sufficient to interfere with the patient’s ability to understand and 
comply with the protocol instructions or follow-up procedures. 
Investigational and 
reference therapy 
• Serelaxin (30 µg/kg/day) administered by body weight category 
(Table 5-3) infused over 48 hours 
• Placebo 
Efficacy assessments 
Primary efficacy assessments: 
• Time to confirmed CV death during a follow-up period of 180 days 
• 
Time to first occurrence of worsening heart failure* through Day 
5 (considering death in the 5-day period as WHF event) 
Key secondary efficacy assessments: 
• 
Time to all-cause death during a follow-up period of 180 days 
• 
Length of total hospital stay for the index AHF hospitalization  
• 
Time to first occurrence of the composite endpoint of CV death 
or rehospitalization due to heart failure/renal failure, during a 
follow-up period of 180 days. 


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* Worsening heart failure through Day 5 post randomization, includes 
worsening signs and/or symptoms of heart failure that require an 
intensification of intravenous therapy for heart failure or mechanical 
ventilatory, renal or circulatory support. Such treatment can include the 
institution or up-titration of IV diuretic, IV nitrates or any other IV medication 
for heart failure, or institution of mechanical support such as mechanical 
ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or 
ventricular assist device, etc.  WHF can occur either during the index 
admission, or after discharge as an unplanned rehospitalization or 
unscheduled physician office/emergency department visit due to a primary 
diagnosis of HF. This endpoint also includes patients who die in this 5-day 
period of any cause before experiencing episode(s) of WHF. 
Other secondary efficacy assessments: 
• 
Length of ICU and/or CCU stay for the index AHF hospitalization 
• 
Change from baseline in congestive signs and symptoms of HF 
through Day 5  
• 
Change from baseline in selected biomarkers from baseline 
through Day 14 in a subset of randomized patients 
Safety assessments 
• 
Physical examination 
• 
Vital signs 
• 
Height and weight 
• 
Laboratory evaluations 
• 
Electrocardiogram 
Other assessments 
• 
Echocardiogram 
• 
Healthcare resource utilization (RU parameters) 
Data analysis 
The primary efficacy variables will be the time to confirmed CV death 
during the follow-up period of 180 days and time to worsening heart 
failure through Day 5.   
For CV death, time-to-event is computed as the number of days from 
randomization to CV death. Patients without an event will be censored at 
the earlier of the last date at which the vital status was known or Day 
180.  Patients who die from a non-cardiovascular cause before Day 180 
will be censored at the time of death. 
The statistical hypothesis is:  H0: λ2/λ1 ≥ 1, i.e., the rate of primary event 
of CV death is greater or equal in the serelaxin group relative to the 
placebo group versus the one-sided alternative HA: λ2/λ1 < 1, i.e., the 
rate of CV death is smaller in the serelaxin group relative to the placebo 
group, where λ1 and λ2 are the hazard rates for CV death in the placebo 
group and serelaxin group, respectively. The ratio λ2/λ1 is also called the 
hazard ratio of serelaxin to placebo. 
The hypothesis will be tested based on the FAS with a logrank test at an 
initial significance level of (4/5)α within a sequentially rejective multiple 
testing procedure.  (See Section 10.5.1). Note that the significance level 
for the final test will be adjusted to account for, the planned interim 
analysis. 
Time to worsening heart failure through Day 5 will be analyzed using 
Gehan’s generalized Wilcoxon test at an initial significance level of 
(1/5)α within a sequentially rejective multiple testing procedure. (See  
Section 10.5.1).  


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The key secondary efficacy endpoint of all-cause mortality through Day 
180 will not be formally incorporated in a multiple testing procedure.  It 
will be tested with a full α (two-sided) by itself if one of the primary 
endpoints is statistically significant.  
A sequentially rejective multiple testing procedure (Bretz, F et al 2009) is 
used in order to control the overall α across the primary variables and 
the other two key secondary variables, length of hospital stay (LOS) and 
composite of CV death or rehospitalization due to HF/RF (CVDR).   
Although there are two primary endpoints in this trial, the sample size is 
calculated based on CV death only. This is an event-driven trial with 
fixed maximum duration of 180 day follow-up period for each patient. 
The 180-day CV death rate is assumed to be 9.0% in the placebo group. 
 
 
Using the proposed multiple testing 
procedure, the power for WHF is at least 80% with this sample size 
assuming at least 20% RRR and 12.2% placebo event rate for WHF. 
Key words 
Acute Heart Failure (AHF), Renal Impairment, Worsening Heart Failure,  


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Amendment 5 
Prevention of in-hospital WHF events is increasingly being recognized as a clinically relevant 
treatment goal of AHF.  Following initial stabilization, in-hospital WHF occurs in 10-30% of 
hospitalized patients reflecting a severe manifestation of the AHF disease continuum requiring 
immediate intensification of rescue therapy (Torre-Amione et al 2009, Cotter et al 2010, Metra 
et al 2010a, Teerlink et al 2013) and represents a key unmet need for AHF patients.  Thus after 
further consideration, the Executive Committee has recommended including the reduction of 
WHF events through day 5 as an additional primary endpoint.  The following changes were 
made: 
Sections 2.1 and 2.2 were updated to add reduction in worsening heart failure through Day 5 as 
a primary objective and delete it from the key secondary objectives. 
Section 3.1 was updated to change the target number of CV deaths and the sample size needed 
to adjust for the alpha-split required to accommodate the additional primary objective.    
Section 3.2 was updated to add WHF to the primary objective and include the WHF rationale. 
Section 4 was changed to update the target number of CV deaths and the sample size needed to 
adjust for the alpha-split required to accommodate the additional primary objective. 
Section 6.4.1 and 6.4.2 were updated to add the reduction in worsening heart failure through 
Day 5 as a primary objective and delete it from the key secondary objectives. 
Sections 10.4.1, 10.4.2, 10.4.3, 10.4.4, and 10.5.1 were updated to define the statistical analysis 
of the new additional primary endpoint. 
Section 10.6 was revised to update the type 1 error for the interim analysis.   
Section 10.7 was revised to define the alpha-split for the two primary endpoints.  The sample 
size calculation was also revised to define the additional patients needed to accommodate the 
additional primary endpoint. 
In addition to the changes related to elevating WHF to an additional primary endpoint, changes 
were made to Sections 6, 6.4.4, 6.5.1, 6.5.2, 6.5.3, 6.5.4, 6.6.6 and Table 6-1 to provide some 
clarity and flexibility around the conduct and timing the study visits and visit procedures. 
The following additional minor changes were also made: 
• Throughout the document, worsening of heart failure was changed to worsening heart 
failure. 
• Section 1.1 minor grammatical changes were made.   
• Section 4.1 was changed to clarify that the time from presentation to start of furosemide 
must be less than 6 hours. 
• Section 4.2 was updated to clarify the following exclusion criteria: 
• Criteria 2: …. use of IV or oral steroids (does not include inhaled steroids); 
• Criteria 10: mean gradient for the aortic valve area was changed to >40mmHg 
• Criteria 13: diuretic was added to the description of equivalent for IV furosemide 


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• Criteria 16 current and due to the malignancy was added to life expectancy less than 1 
year 
• Section 5.3 was updated to clarify that the misrandomized patients should have been 
considered screen failures.  
• Section 5.5.9 was updated to clarify patient withdrawals and continued patient follow-up.  
• Additional references were added to the reference list. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.  In addition, if the changes herein affect the 
Informed Consent, sites are required to update and submit for approval a revised Informed 
Consent that takes into account the changes described in this amended protocol. 


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Amendment 4 
Acute Heart Failure is a complex and subjective clinical diagnosis.  Since the diagnosis of AHF 
is primarily based on clinical observations that are interpreted bedside, in an urgent care 
environment, based on the clinical judgment of the investigator, the diagnosis is sometimes 
difficult to qualify.  Therefore, to improve the overall clarity of the study inclusion and 
exclusion criteria, the study Executive Committee recommended the following changes: 
Inclusion criteria: 
• The criteria for hospitalization due to AHF was enhanced to read: hospitalized for AHF with 
the anticipated requirement of intravenous therapy (including IV diuretics) for at least 48 
hours; 
• The dyspnea at rest criteria was enhanced to read: persistent dyspnea at rest or with minimal 
exertion at screening and at the time of randomization, despite standard background therapy 
for acute heart failure including the protocol required intravenous furosemide of at least 40 
mg total (or equivalent).   
• The BNP and NT proBNP criteria were increased to BNP ≥ 500 pg/mL or NT-proBNP 
≥2,000 pg/mL.  The following BNP and NT proBNP criteria were also added:  for patients 
≥ 75 years of age or with current atrial fibrillation (at the time of randomization), BNP ≥ 
750 pg/mL or NT-proBNP ≥ 3,000 pg/mL 
• The inclusion criteria for intravenous furosemide was updated to add the following criteria:  
Time from presentation to start of furosemide administration should be less than 6 hours. 
Exclusion criteria:  
The following exclusion criteria were updated: 
• The dyspnea primarily due to non-cardiac causes was enhanced to read: Dyspnea due to 
non-cardiac causes such as acute or chronic respiratory disorders or infections (i.e., severe 
chronic obstructive pulmonary disease, bronchitis, pneumonia), which may interfere with 
the ability to interpret the primary cause of dyspnea.  
• “Uncorrected” was added to the significant, left ventricular outflow obstruction, criteria. 
• The criteria for current or planned treatment with IV vasoactive therapies was updated to 
clarify that the use of IV nitrates is permitted if the patient has systolic BP > 150 mmHg at 
“the start of “ screening.  
• The criteria for other medical conditions that put the patient at risk or influence study results 
was updated to include drug or alcohol abuse or psychiatric, behavioral or cognitive 
disorders sufficient to interfere with the patient’s ability to understand and comply with the 
protocol instructions or follow up procedures. 
The following exclusion criteria were added: 
• Known history of respiratory disorders requiring the daily use of IV or oral steroids; need 
for intubation or the current use of IV or oral steroids for COPD  
• Patients with blood pressure > 180 mmHg at the time of randomization or persistent heart 
rate >130 bpm. 


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•
Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased
ammonia levels, if performed) or history of cirrhosis with evidence of portal hypertension
such as varices.
•
Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous
intervention is indicated.
•
Documented, prior to or at the time of randomization, restrictive amyloid myocardiopathy,
OR acute myocarditis or hypertrophic obstructive, restrictive, or constrictive
cardiomyopathy (does NOT include restrictive mitral filling patterns seen on Doppler
echocardiographic assessments of diastolic function).
The following exclusion criteria were also updated and added to comply with the most recent 
Novartis standard guidelines for managing patients of child-bearing potential:  
Updated: 
•
The criteria for women of child-bearing potential, was updated to require the use of highly
effective methods of contraception during dosing of study treatment plus 5 days after
cessation of study drug.  The methods for effective contraception were also updated to
define a combination of criteria required.
Added: 
•
Women are considered post-menopausal and not of child bearing potential if they have had
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.
age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment is she considered not of child bearing
potential.
Section 5.3 was updated to clarify the management of misrandomized patients. 
Section 5.5.4 was modified to remove the requirement for infusion bags containing similar 
polymeric materials.  There is no restriction for use of any other 250 mL infusion bag with 5% 
dextrose. 
Minor modifications were made to the assessment of AHF signs and symptoms to clarify who 
besides the PI can perform the assessment of signs and symptoms (Section 6.4.4), and to the 
vital signs section to clarify what assessments are performed at all timepoints (Section 6.5.2).   
Section 7.2 was updated to define the process for managing local SUSAR reporting. 
Section 7.3 Liver safety monitoring, and Section 15 Appendix 2 Liver event definitions, were 
amended to update the guidelines for liver safety monitoring to conform to the updated Novartis 
standard liver monitoring guidelines.  
As per feedback from the FDA, Amendment 2 was issued to change Section 10.5 of the protocol 
to include all four key secondary efficacy variables in the multiple testing procedure so the 
overall type I error including all-cause death and other three key efficacy variables is controlled 
at 5% alpha level.  Subsequent to the change, the FDA indicated that this change to the protocol 
was not required.  So Section 10.5 has been amended again to return to the initial testing 
procedure where all-cause death through Day 180 is not included in the multiple testing 


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procedure of the key secondary efficacy variables, i.e, only the other three key secondary 
efficacy variables are included in the multiple testing procedure.   
Section 10.5 was further updated to include sensitivity analyses of WHF using a modified 
definition of WHF, for example where both signs and symptoms are present. 
Section 10.7 Table 10-2 was also update to reflect the powers of the key secondary variables 
on the selected scenarios.   
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.  In addition, if the changes herein affect the 
Informed Consent, sites are required to update and submit for approval a revised Informed 
Consent that takes into account the changes described in this amended protocol.  


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Amendment 3 
Amendment rationale and major changes 
In the original protocol, exclusion criteria #8 states: 
current (within 2 hours prior to screening) or planned (through completion of study drug 
infusion) treatment with any IV vasoactive therapies, including vasodilators (including 
nesiritide), positive inotropic agents and vasopressors, or mechanical support 
(endotracheal intubation, mechanical ventilation; intro-aortic balloon pump or any 
ventricular assist device; hemofiltration, ultrafiltration or dialysis), with the exception 
of IV furosemide (or equivalent), or IV nitrates at a dose of ≤ 0.1 mg/kg/hour if the 
patient has a systolic BP > 150 mmHg at screening.  
To improve patient recruitment, the study Executive Committee has recommended to  amend 
this exclusion criteria to exclude current treatment within 2 hours prior to randomization (and 
not at screening).  In addition, a few minor updates have been made to the protocol in the 
following areas: 
• Section 5.5.4 has been updated to include additional information about 5% dextrose 
infusion bags and materials which can be used during preparation of study treatment 
• Table 5-2 filter name has been updated based on the  availability of a new brand name 
• Section 6.5.1, the timing of the physical exam was clarified due to inconsistency with 
table 6-1 (schedule of assessments). 
• Amendment 2 summary of amendment was updated to remove the requirement for 
IRB/EC protocol approval prior to implementation since this is not valid in select 
countries 
• Table 6-1 schedule of assessments table has been updated to clarify the intervals for 
collection of worsening heart failure assessment (at hours 24, 48, 72, 96 and 120) as part 
of the physician assessment of HF signs and symptoms 
• Section 10.1 safety set definition has been updated to clarify a statement that any patient 
who has received serelaxin will be included as part of the serelaxin treatment group 
• Section 10.5.1 time-to-event has been changed to be defined as randomization to the 
event   
• Section 10.5.1 length of stay definition has been changed to index hospitalization 
discharge date and time minus the randomization date and time 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.   
 


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Amendment 2 
Short summary of the amendment rationale and major changes 
In the current protocol, all-cause death through Day 180 is not included in the multiple testing 
procedure of the key secondary efficacy variables, i.e, only the other three key secondary 
efficacy variables are included in the multiple testing procedure.  As per feedback from FDA, 
Section 10.5 of the protocol has been amended to include all four key secondary efficacy 
variables in the multiple testing procedure, so the overall type I error including all-cause death 
and other three key efficacy variables is controlled at 5% alpha level.   
In addition a minor change was made to the Physician assessment of signs and symptoms 
criteria located in Section 16, Appendix 3.  NA, not evaluable, was removed from the 
assessments for exertional dyspnea and orthopnea.  This was done to avoid confusion during 
data collection between when the evaluation was not evaluable (subject was immobile) and 
when the evaluation was simply not done. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.  In addition, if the changes herein affect the 
Informed Consent, sites are required to update and submit for approval a revised Informed 
Consent that takes into account the changes described in this amended protocol.  
Summary of previous amendments 
Amendment 1 
Amendment rationale 
In order to comply with Health Authority requests stemming from the Volunteer Harmonization 
Procedure (VHP), the following changes have been made throughout the protocol.  
• A criteria was added excluding patients with hematocrit <25%, or a history of blood 
transfusion within the 14 days prior to screening, or active life-threatening GI bleeding 
• The protocol was updated to include ECG assessments at screening and at Day 5 or 
discharge, whichever occurs first. ECGs will be performed and interpreted locally, and the 
interpretation and person interpreting the ECG will be recorded in the source documents. 
• The protocol was updated to include an echocardiogram.  The echo will be performed 
during the index hospitalization, to determine a patient’s ejection fraction which will be 
used to classify the type of heart failure for subgroup analysis.  The echocardiogram 
should be performed as soon as possible post randomization, but prior to discharge.  If an 
echocardiogram is performed during the screening period (i.e. within the 16 hours 
window) and the patient is subsequently randomized, the screening echocardiogram will 
qualify as the index hospitalization echocardiogram and a repeat echocardiogram post 
randomization will not be necessary.   
• The protocol was updated to change the follow up period, if following the interim analysis 
the trial is concluded early for efficacy, from a minimum of 14 days to 180 days.   


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• A minor clarification was made to the timing of the ECG substudy in the Assessment 
Schedule and substudy description.  The first substudy ECG should be performed at 
baseline, not at screening.   
• A minor clarification was made to the Laboratory substudy urine assessment in the 
Assessment Schedule to reflect that the data is to be maintained in the source documents 
only and not in the database (X was changed to S). 


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1 
Introduction 
1.1 
Background 
Acute heart failure (AHF) is a major public health problem associated with high mortality, 
morbidity, and financial costs. It is already the most common and most expensive cause of 
hospitalization and rehospitalization in patients 65 years and older (Hunt et al 2009, Jencks S 
NEJM). With the aging of the population, the prevalence of HF is projected to increase by 25% 
over the next 20 years (Heidenreich et al 2011). As such, the burden of HF for health care 
systems will also increase.  
AHF is defined as the rapid onset of, or change in, signs and symptoms of HF requiring urgent 
therapy, which usually results in hospitalization (McMurray et al 2012). Recent HF registries 
demonstrate that more than 80% of AHF patients present with dyspnea, 60-80% with renal 
impairment, and >50-75% with normal to elevated systolic BP (Adams et al 2005, Gheorghiade 
et al 2006a, Gheorghiade et al 2006b, Gheorghiade et al 2009). Although there are multiple 
precipitants of AHF, ultimately AHF results in (1) pulmonary, central and/or peripheral venous 
congestion and (2) hypoperfusion, both of which can induce end organ damage and metabolic 
abnormalities. The pathophysiology of AHF is complex, including processes such as abnormal 
ventricular systolic and/or diastolic function, myocardial injury as manifested by elevation of 
circulating cardiac troponin, vascular changes such as endothelial dysfunction, increased aortic 
impedance and left ventricular afterload, renal dysfunction precipitating sodium and fluid 
retention, as well as neurohormonal and inflammatory activations (Metra et al 2010a; Metra et 
al 2012). 
Although symptomatic improvement occurs in most patients following currently available AHF 
therapy within a few days of admission, such improvement is usually incomplete. Persistent or 
recurrent HF symptoms both during and after hospitalization likely contribute to the downward-
spiral of disease progression with poor clinical outcomes. In the IMPACT-HF trial, 60% of 
patients were discharged with continuing symptoms of dyspnea or fatigue, and after 60 days, 
45% had worsening of HF symptoms with 25% of patients rehospitalized (Gheorghiade, 2006). 
The presence of worsening HF symptoms confers a worse prognosis for AHF patients (Damman 
et al 2007; Metra et al 2008). Overall, the mortality in AHF patients remains very high, e.g. 30 
day, 1 year and 5 year mortalities are reportedly 10.4%, 22% and 42.3% (Lloyd-Jones 2010).  
Post-discharge rehospitalization afflicts up to 1/3 of patients (Gheorghiade, 2006). Despite a 
decade of efforts, outcome from AHF remain dismal. 
The main clinical challenges in AHF management are to achieve optimal and sustained 
resolution of congestion to improve symptoms, prevent in-hospital worsening heart failure  and 
end organ dysfunction or damage, prevent rehospitalization, and most importantly, reduce both 
short- and intermediate-term mortality. However, current standard-of-care for AHF offers few 
options, if any to meet these challenges.  Therapies used 4 decades ago are the same therapies 
used today: oxygen, loop diuretics, vasodilators, inotropes and opiates, with diuretics as the 
cornerstone of AHF therapy. These pharmacological treatments are focused on achieving short-
term symptom relief and decongestion; none have definitively shown a beneficial impact on 
either short- or intermediate-term mortality underscoring the significant unmet medical need in 
the AHF patient population (Hunt et al 2009).  At present, there are no Class 1, Level A 
pharmacologic guideline recommendations for the treatment of AHF. 


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Serelaxin (H2) is a naturally occurring peptide hormone associated with many of the maternal 
hemodynamic and renovascular changes that occur in response to pregnancy, such as systemic 
and renal vasodilation and increases in global arterial compliance (Conrad 2010, Conrad 2011a, 
Conrad 2011b, Conrad and Shroff 2011). Serelaxin’s activity is initiated by binding to its 
cognate receptor, serelaxin family peptide receptor 1 (RXFP1), which is present in the systemic 
and renal vasculature as well as in the human heart (Hsu et al 2002). Nitric oxide, endothelial 
endothelin type B receptor, vascular endothelial growth factor (VEGF) and cAMP act as 
mediators for the vasodilatory as well as anti-fibrotic and anti-inflammatory effects of serelaxin 
(Bani et al 1998; Danielson et al 1999; Dschietzig et al 2003). With these pleiotropic effects, 
serelaxin may benefit HF patients not only through its favorable hemodynamic effects but also 
via its protective effects on the heart and kidney, leading to potential mortality benefits. 
Serelaxin is a recombinant protein identical in structure to the naturally occurring H2 serelaxin. 
Its efficacy and safety in AHF patients as a continuous intravenous (IV) infusion for up to 48 
hours was evaluated in two multicenter, randomized, double-blind, placebo-controlled trials, 
including the dose-finding phase II study Pre-RELAX-AHF (Teerlink et al 2009) and the phase 
III pivotal study RELAX-AHF (Teerlink et al 2013). 
In the RELAX-AHF study, which enrolled 1,161 AHF patients randomized to receive either 
serelaxin (N=581) or matching placebo (N=580), both in addition to standard-of-care AHF 
treatment, the 48-hour intravenous infusion of serelaxin produced dyspnea relief as 
demonstrated by a 19.4% treatment improvement compared to placebo measured over 5 days 
by visual analogue scale (VAS), representing one of the two primary efficacy endpoints in the 
study. Serelaxin was administered according to a weight range adjusted dosing regimen at the 
nominal dose of 30 µg/kg/day. In addition, serelaxin treatment significantly reduced the 
incidence of WHF episodes through Day 5 and the overall length of index hospital stay, 
associated with a range of other in-hospital clinical benefits. These clinical improvements were 
associated with significant improvements in biomarkers with evidence of less end organ 
damage in serelaxin treated patients (Metra et al 2013). Analysis of all-cause mortality through 
Day 180 showed fewer deaths with serelaxin, compared to placebo, with a total of 42 (K-M 
estimate 7.3%) deaths in the serelaxin group compared to 65 (K-M estimate 11.3%) in the 
placebo group (hazard ratio 0.63, p=0.020).  The mortality difference  was largely driven by 
CV death through Day 180 (K-M estimates 9.6% and 6.1%) in placebo and serelaxin groups, 
respectively, hazard ratio 0.63, p=0.028. These findings support the sustained benefits of 
serelaxin observed beyond the initial 48 hours of therapy, in which a clinically and statistically 
significant 37% reduction in both CV and all-cause mortality through Day 180 were seen 
(Teerlink et al 2013).   
Hence, a replicate phase III study with randomization to intravenous administration of serelaxin 
or placebo within 16 hours of clinical presentation in AHF patients similar to RELAX-AHF 
trial is proposed to further assess its effect on CV death and other clinical outcomes including 
all-cause mortality during a follow-up period of 180 days. The CRLX030A2301 protocol 
describes a multi-center, randomized, double-blind, placebo-controlled, event-driven study 
which aims to evaluate the efficacy and safety/tolerability of intravenous serelaxin, when added 
to standard therapy, in AHF patients who present with dyspnea, normal-to-elevated systolic BP 
and mild-to-moderate renal impairment. 


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1.2 
Purpose  
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy, safety and tolerability of intravenous infusion of 30 µg/kg/day serelaxin for 48 hours, 
when added to standard therapy, in approximately 6,375 AHF patients. Efficacy will be 
determined based on the relative reduction in CV death and other clinical outcomes including 
all-cause mortality through a follow-up period of 180 days, as compared to placebo. Data from 
this study is intended to replicate the reduction in mortality in AHF patients observed in the 
RELAX-AHF trial. 
2 
Study objectives 
2.1 
Primary objectives 
• To demonstrate that serelaxin is superior to placebo in reducing CV death in AHF patients 
during a follow-up period of 180 days  
• To demonstrate that serelaxin is superior to placebo in reducing worsening heart failure 
through Day 5. 
2.2 
Key and other secondary objectives 
Key secondary objectives 
• To demonstrate that serelaxin is superior to placebo in reducing all-cause mortality during 
a follow-up period of 180 days 
• To demonstrate that serelaxin is superior to placebo in reducing the length of total hospital 
stay during the index AHF hospitalization 
• To demonstrate that serelaxin is superior to placebo in reducing the composite endpoint of 
CV death or rehospitalization due to heart failure/renal failure, during a follow-up period 
of 180 days 
Other secondary objectives 
Efficacy 
• To demonstrate that serelaxin is superior to placebo in reducing the length of ICU and/or 
CCU stay during the index AHF hospitalization 
• To demonstrate that serelaxin is superior to placebo in relieving signs and symptoms of 
congestion  through Day 5 
• To compare serelaxin to placebo in the changes of selected biomarkers in a subset of 
randomized patients 
Safety 
• To evaluate the safety and tolerability of intravenous serelaxin in AHF patients 


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3 
Investigational plan 
3.1 
Study design 
Figure 3-1 
Study design 
 
• 
† Weight-range based dosing regimen for serelaxin and matching placebo (see Table 5-3) 
• *If Discharge Visit coincides with a scheduled visit, only the Discharge Visit will be 
performed. 
• Presentation starts as the earliest of (1) time of presentation either at the ER/ED, 
ICU/CCU or ward, (excludes EMS or other pre-hospital care); or (2) time of first IV loop 
diuretic prior to arrival at the hospital (this includes outpatient clinic, ambulance, or 
hospital including emergency department) for the treatment of the current AHF episode. 
This study is a multicenter, randomized, double-blind, placebo-controlled, event-driven phase 
IIIb clinical trial designed to evaluate the efficacy and safety of an intravenous infusion of 
serelaxin when added to standard therapy in AHF patients. After assessing eligibility during the 
screening period, patients who meet the study inclusion and exclusion criteria will be 
randomized 1:1 to receive an intravenous infusion of either serelaxin or matching placebo in a 
double-blind manner for up to 48 hours (Figure 3-1). Potential study candidates are those 
patients hospitalized for AHF, who have received at least 40 mg intravenous furosemide (or 
equivalent) prior to screening, with dyspnea at rest or minimal exertion, systolic BP ≥125 
mmHg at the time of screening, and mild to moderate renal impairment measured as an 
estimated eGFR of ≥ 25 and ≤ 75 mL/min/1.73m2 by sMDRD formula (Levey et al, 2003). 
These patients must be randomized within 16 hours of presentation, (presentation starts as the 


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earliest of (1) time of presentation at either the ER/ED, ICU/CCU or ward, (excludes EMS or 
other pre-hospital care); or (2) time of first IV loop diuretic for treatment of the current AHF 
episode prior to arrival at the hospital (this includes outpatient clinic, ambulance, or hospital 
including emergency department). 
Serelaxin (and/or matching placebo) will be administered as a continuous intravenous infusion 
for 48 hours according to a weight-range adjusted dosing regimen at the nominal dose of 
30µg/kg/day. Due to the potential risk of hypotension, blood pressure will be monitored 
regularly during the administration of study drug. If at any time during dosing, the patient’s 
systolic BP is decreased by >40 mmHg from baseline but the absolute systolic BP is ≥100 
mmHg in two consecutive measurements 15 minutes apart, the study drug infusion rate should 
be decreased by 50% for the remainder of the infusion period. If the patient’s systolic BP falls 
to <100 mmHg in two consecutive measurements 15 min apart, study drug must be permanently 
discontinued.  Measures may be taken by the investigator to address the decrease in blood 
pressure during the intervening 15 minutes, if clinically indicated.  Should the study drug dose 
be decreased or the study drug be discontinued prematurely due to blood pressure decrease, 
then measurements should be taken every half hour through 2 hours following the blood 
pressure decrease event, and then hourly through 5 hours after event onset.  Upon completion 
of the 5 hour post event onset time point, heart rate and blood pressure measurements should 
be resumed as outlined in Section 6.5.2.  If hypotension persists beyond the 5 hours post event 
onset, continued hourly blood pressure monitoring should be considered by the investigator, if 
clinically indicated.  Additional blood pressure data collected beyond the 5 hours post event 
should be captured in the source documents; only heart rate and blood pressure outlined in 
Section 6.5.2 will be entered into the eCRFs. 
All randomized patients will be assessed daily while hospitalized up to Day 5, at Discharge, 
and then followed up at scheduled visits for a period of 180 days. Patients discharged prior to 
Day 5 will return to the hospital/clinic for Day 5 procedures. They are required to receive 
standard-of-care treatment for HF during both the index hospitalization and post discharge per 
local and institutional practice guidelines. Visits to assess efficacy are scheduled through Day 
5, at Discharge, and Days 14, 60, 120 (telephone contact) and 180. For the safety evaluation, 
all adverse events (AEs) will be collected from signing of the informed consent form through 
Day 5 for non-serious AEs and through Day 14 for serious AEs. 
In addition to the core study, ECG, laboratory and biomarker substudies will be conducted.   
• At least 500 patients from selected centers will participate in an ECG substudy.  ECGs 
will be performed at Baseline and at the end of study drug infusion.  
• At least 1600 patients from selected centers will participate in a laboratory substudy.  
Safety laboratories will be collected at Baseline, daily while hospitalized up to Day 5, 
Discharge and Day 14.  Patients discharged prior to Day 5 will return to the hospital/clinic 
for Day 5 procedures. 
• At least 1600 patients from selected centers participating in the laboratory substudy will 
also participate in the biomarker substudy.  Biomarkers will be collected at Baseline, Days 
2, and 5, Discharge, and Day 14. Patients discharged prior to Day 5 will return to the 
hospital/clinic for Day 5 procedures. 
  
Based on sample size calculations based on RELAX-AHF, approximately 6,800 randomized 
AHF patients will be required to accrue the number of events during the 180-day follow-up 


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period necessary to reach the primary efficacy endpoint. Once randomized, all randomized 
patients will be followed to 180-day.  
There will be one interim analysis at 60% of the accrued numbers of confirmed CV deaths (see 
details in Section 10.6 and Section 10.7).  If following the interim analysis, the trial is concluded 
early for efficacy, all ongoing randomized patients will be followed for 180 days. 
3.2 
Rationale of study design 
This replicate Phase IIIb outcome study in AHF patients is designed as a multicenter, 
randomized, double-blind, placebo-controlled, event-driven study in order to assess the 
efficacy, safety and tolerability of intravenous infusion of serelaxin for 48 hours with a weight-
range adjusted regimen targeted at approximately 30 µg/kg/day. The AHF patients randomized 
to either serelaxin or placebo in the study will be followed for a period of 180 days, and are 
required to receive standard-of-care background HF management during both the index 
hospitalization and post discharge according to regional or local guidelines/institutional 
standards. 
The primary objective of this study is to further establish that serelaxin is superior to placebo 
in reducing CV death in AHF patients during the follow-up period of 180 days and in reducing 
worsening heart failure through Day 5.  The reduction in CV death is an efficacy benefit 
suggested by the Pre-RELAX-AHF study and observed in the completed RELAX-AHF trial. 
The rate of mortality in AHF remains high despite contemporary standard-of-care management, 
which has not changed significantly in the last 10 years, and represents a key unmet need for 
AHF patients.  
The reduction in worsening heart failure through Day 5 is a potential efficacy benefit which is 
evolving among the scientific community as an increasingly clinically relevant treatment goal 
of AHF.  Following initial stabilization, in-hospital WHF occurs in 10- 30% of hospitalized 
patients reflecting a severe manifestation of the AHF disease continuum requiring immediate 
intensification of rescue therapy (Torre-Amione et al 2009, Cotter et al 2010, Metra et al 2010a, 
Teerlink et al 2013) and represents another key unmet need for AHF patients.       
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The weight-range adjusted dose regimen of serelaxin (see Table 5-1 in Section 5.5.4) at the 
nominal dose of 30 µg/kg/day studied in RELAX-AHF study will be evaluated in this phase 
IIIb outcome study, and serelaxin will be administrated via continuous intravenous infusion for 
48 hours during the most critical early period of AHF patient management to achieve 
decongestion, hemodynamic improvement and end organ protection. For patients who 
experience significant systolic BP decrease during the 48-hour study drug infusion, protocol-
specified dosing adjustment and/or discontinuation rules must be followed to ensure patient 
safety (refer details in Section 5.5.5). In the completed RELAX-AHF study, serelaxin treatment 
significantly improved early signs and symptoms of congestion, reduced WHF through Day 5 
and the length of index hospital stay in addition to a range of other in-hospital clinical benefits; 
it also demonstrated overall safety and tolerability. Importantly, serelaxin provided sustained 
benefits beyond the initial 48 hours of therapy leading to a clinically and statistically significant 
37% reduction in both CV and all-cause mortality through Day 180 (Teerlink et al 2013). The 


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favorable efficacy and safety observed in the RELAX-AHF study support the adoption of the 
same dosing regimen of serelaxin administration in this study. 
3.4 
Rationale for choice of comparator 
This placebo-controlled study has been designed to demonstrate the superiority of serelaxin 
treatment over placebo in the reduction of CV death and other clinical outcomes in AHF 
patients. There is no evidence based therapy that has been shown to provide a mortality benefit 
in AHF and thus an active comparator is not available. All patients in this study, however, will 
be required to receive standard-of-care background HF management during both hospitalization 
and the follow-up period of 180 days. 
3.5 
Purpose and timing of interim analyses/design adaptations 
There will be one interim analysis at 60% of the accrued numbers of CV deaths using Lan-
DeMets spending function of O’Brien-Fleming (OF) stopping boundary which allows early 
stopping in case of overwhelming evidence of treatment benefit. (See details in Section 10.6 
and Section 10.7).  
3.6 
Risks and benefits  
Dyspnea and congestion are the cardinal presenting features of AHF. The rapid onset or change 
in signs and symptoms of HF requires urgent care. Hospitalization and worsening heart failure 
with accompanying end organ damage, namely, worsening renal function and myocardial wall 
stress and injury, are both associated with increased mortality. Although therapies are available 
to improve dyspnea and congestion in AHF, a substantial number of patients remain 
symptomatic prior to discharge.  Importantly, no AHF therapy to date has demonstrated a 
mortality benefit. 
Serelaxin infused for 48 hours in both the pre-RELAX-AHF (Teerlink et al, 2011) and RELAX-
AHF study (Teerlink et al, 2013) demonstrated significant improvement in dyspnea and signs 
and symptoms of congestion.  It was also associated with significant reductions in early 
worsening heart failure events and length of stay during the index hospitalization including 
duration of intensive care. Reductions in both cardiovascular and all-cause mortality were 
observed in the serelaxin-treated patients in RELAX-AHF. Pre-specified biomarker changes 
suggest serelaxin therapy has a protective effect on both the heart and kidney, supporting the 
mortality benefit. Serelaxin was generally well-tolerated with no notable differences in the 
overall adverse event profile compared to placebo. Although blood pressure can decrease in a 
portion of patients due to the vascular mechanism of action of the drug, worse outcomes were 
not observed in these patients. The current instructions for the management of systolic blood 
pressure (SBP), including close and careful monitoring as well as mandatory dose adjustment 
or stopping rules, which were utilized during RELAX-AHF, support that current safety rules 
and management of SBP are both robust and sufficient.   
The risk to patients participating in study will be minimized by compliance with the 
inclusion/exclusion criteria and close clinical monitoring, which proved effective during the 
RELAX-AHF trial. Since the potential of immunogenicity as a result of repeated intravenous 
dosing has not yet been fully characterized, those patients who participated in prior serelaxin 
clinical studies will be excluded.  It is also important to note that all patients in this study will 


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be required to receive standard-of-care background HF management during hospitalization as 
well as the follow-up period of 180 days. 
Women 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.  Such participants are 
required to sign informed consent that outlines the risks as well as protocol specific safety rules 
to adhere to the contraception requirements for the duration of the study. If there is any question 
regarding compliance, the patient should not be enrolled.   
Refer to the Investigator’s Brochure (IB) for additional information regarding the safety profile 
of serelaxin. 
4 
Population 
The study population will consist of male and female patients (≥18 years old) admitted to the 
hospital for AHF, with systolic BP ≥125 mmHg, and mild-to-moderate renal impairment. It is 
aimed to randomize approximately 6,800 patients
 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any study-specific assessment is 
performed* 
2. Male or female ≥18 years of age, with body weight ≤160 kg 
3. Hospitalized for AHF with the anticipated requirement of intravenous therapy (including 
IV diuretics) for at least 48 hours; AHF is defined as including all of the following 
measured at any time between presentation (including the emergency department) and the 
end of screening: 
• Persistent dyspnea at rest or with minimal exertion at screening and at the time of 
randomization, despite standard background therapy for acute heart failure including 
the protocol required intravenous furosemide of at least 40 mg total (or equivalent). 
• Pulmonary congestion on chest radiograph 
• BNP ≥ 500 pg/mL or NT-proBNP ≥2,000 pg/mL;  for patients ≥ 75 years of age or 
with current atrial fibrillation (at the time of randomization), BNP ≥ 750 pg/mL or NT-
proBNP ≥ 3,000 pg/mL *** 
4. Systolic BP ≥125 mmHg at the start and at the end of screening 
5. Able to be randomized within 16 hours from presentation to the hospital, including the 
emergency department** 
6. Received intravenous furosemide of at least 40 mg total (or equivalent) at any time 
between presentation (this includes outpatient clinic, ambulance, or hospital including 
emergency department) and the start of screening for the study for the treatment of the 
current acute HF episode.  Time from presentation to start of furosemide administration 
must be less than 6 hours.   
7. Impaired renal function defined as an eGFR*** between presentation and randomization 
of ≥ 25 and ≤75mL/min/1.73m2, calculated using the sMDRD equation 


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* Patient assessments of AHF that are per current local institutional/hospital standard protocol 
or part of routine clinical care are allowed before signing informed consent, and can be used 
to support patient screening. 
** Presentation starts as the earliest of (1) time of presentation at either the ER/ED, ICU/CCU 
or ward, (excludes EMS or other pre-hospital care); or (2) time of first IV loop diuretic prior 
to arrival at the hospital (this includes outpatient clinic, ambulance, or hospital including 
emergency department) for the current acute HF episode. 
***Assessed based on local laboratory 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Dyspnea due to non-cardiac causes, such as acute or chronic respiratory disorders or 
infections (i.e., severe chronic obstructive pulmonary disease, bronchitis, pneumonia), 
which may interfere with the ability to interpret the primary cause of dyspnea.    
2. Known history of respiratory disorders requiring the daily use of IV or oral steroids (does 
not include inhaled steroids); need for intubation or the current use of IV or oral steroids 
for COPD. 
3. Patients with blood pressure > 180 mmHg at the time of randomization or persistent heart 
rate > 130 bpm. 
4. Temperature >38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-
microbial treatment 
5. Clinical evidence of acute coronary syndrome currently or within 30 days prior to 
enrollment. (Note: the diagnosis of acute coronary syndrome is a clinical diagnosis and 
that the sole presence of elevated troponin concentrations is not sufficient for a diagnosis 
of acute coronary syndrome, given that troponin concentrations may be significantly 
increased in the setting of AHF.)  
6. AHF due to significant arrhythmias, which include any of the following: sustained 
ventricular tachycardia, bradycardia with sustained ventricular rate <45 beats per minute, 
or atrial fibrillation/flutter with sustained ventricular response of >130 beats per minute 
7. Patients with severe renal impairment defined as pre-randomization eGFR < 25 
mL/min/1.73m2 calculated using the sMDRD equation, and/or those receiving current or 
planned dialysis or ultrafiltration 
8. Patients with hematocrit  <25%, or a history of blood transfusion within the 14 days prior 
to screening, or active life-threatening GI bleeding. 
9. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased 
ammonia levels, if performed) or history of cirrhosis with evidence of portal hypertension 
such as varices. 
10. Significant, uncorrected, left ventricular outflow obstruction, such as obstructive 
hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <1.0 cm2 or 
mean gradient >40 mmHg on prior or current echocardiogram), and severe mitral stenosis 
11. Severe aortic insufficiency or severe mitral regurgitation for which surgical or 
percutaneous intervention is indicated. 


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12. Documented, prior to or at the time of randomization, restrictive amyloid myocardiopathy, 
OR acute myocarditis or hypertrophic obstructive, restrictive, or constrictive 
cardiomyopathy (does NOT include restrictive mitral filling patterns seen on Doppler 
echocardiographic assessments of diastolic function). 
13. Current (within 2 hours prior to randomization) or planned (through the completion of 
study drug infusion) treatment with any IV vasoactive therapies, including vasodilators 
(including nesiritide), positive inotropic agents and vasopressors, or mechanical support 
(endotracheal intubation, mechanical ventilation; intra-aortic balloon pump or any 
ventricular assist device; hemofiltration, ultrafiltration or dialysis), with the exception of 
IV furosemide (or equivalent diuretic), or IV nitrates at a dose of ≤ 0.1 mg/kg/hour if the 
patient has a systolic BP >150 mmHg at the start of screening. 
14. Any major solid organ transplant recipient or planned/ anticipated organ transplant within 
1 year 
15. Major surgery, including implantable devices (e.g. ICD, CRT), or major neurologic event 
including cerebrovascular events, within 30 days prior to screening 
16. 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 current life expectancy less than 
1 year due to the malignancy.  
17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test 
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of study treatment plus 5 days after cessation of study drug. 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 patients on the study, 
the vasectomized male partner should be the sole partner for that subject 
• Combination of any two of the following (a+b or a+c, or b+c): 
a. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository  
b. Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception 
c. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 


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Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential. 
19. Use of other investigational drugs within 30 days prior to screening 
20. History of hypersensitivity to serelaxin 
21. History of participating in serelaxin clinical studies  
22. Inability to follow instructions or comply with follow-up procedures 
23. Any other medical condition(s) that may put the patient at risk or influence study results in 
the investigator’s opinion, or that the investigator deems unsuitable for the study, 
including drug or alcohol abuse or psychiatric, behavioral or cognitive disorders, sufficient 
to interfere with the patient’s ability to understand and comply with the protocol 
instructions or follow-up procedures. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Serelaxin (and/or matching placebo) will be administered according to a weight-range adjusted 
dosing regimen at a nominal dose of 30 µg/kg/day (refer to the details in Section 5.5.4), as a 
continuous intravenous infusion for 48 hours. The study drug is provided as a 1 mg/mL solution 
in 6 mL vials (with 3.5 mL fill). For the randomized patients to receive the study drug infusion, 
it can be withdrawn from the vials contained in the blinded kits, injected into a 250 mL 
intravenous bag of 5% dextrose solution, and then infused through a dedicated IV line or port, 
using compatible tubing, infusion filters, and IV bags according to instructions in the Pharmacy 
Manual. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is required for this trial. Nevertheless, 
patients randomized to either serelaxin or placebo in this study will all be required to receive 
standard-of-care background HF management during both the index hospitalization and post 
discharge according to the regional or local guidelines/institutional standard.  This treatment 
can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin 
receptor antagonists, β blockers, and aldosterone receptor antagonists, etc. 
5.2 
Treatment arms 
Patients will be randomized in a 1:1 ratio to receive continuous intravenous infusion of one of 
the following treatment assignments for 48 hours: 
• Placebo  
• Serelaxin (30 µg/kg/day) 


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5.3 
Treatment assignment, randomization  
At baseline, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria.  The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of investigational treatment 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).  
The randomization scheme for patients will be reviewed and approved by a member of the IIS 
Randomization Group. 
Misrandomized patients are those who have not been qualified for randomization, have been 
inadvertently randomized into the study and who did not take study drug. Misrandomized 
patients are defined as cases where IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the patient’s final randomization eligibility and double-
blind medication was not administered to the patient. These patients should have been 
considered screen failures as they did not meet eligibility criteria and should subsequently be 
discontinued from the study.  Sites should notify IRT and contact their Novartis monitor as soon 
as possible if a patient is misrandomized into the study. 
5.4 
Treatment blinding  
This will be a double-blind study.  Patients, investigator staff, persons performing the 
assessments, and data analysts will remain blind to the identity of the treatment from the time 
of randomization until database lock, using the following methods: 
• Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the exception of the independent 
unblinded statistician, programmer and data manager/data coordinator (and assistant as 
required) from an external and independent Data Analysis Center, who need to have 
access to prepare safety and/or efficacy interim analysis reports for the Data Monitoring 
Committee (DMC). These personnel will not be involved in any other trial activities. 
• The identity of the treatments will be concealed by the use of study drugs that are identical 
in packaging, labeling, schedule of administration and appearance. 
• Unblinding should only occur in the case of patient emergencies (see Section 5.5.10), at 
the time of interim analysis and at the conclusion of the study. In the event a patient 
becomes unblinded for any reason other than safety concerns they should continue study 
treatment and assessments according to the protocol.   


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• In the event a patient becomes unblinded for safety reasons, they should discontinue study 
drug and continue study assessments according to protocol. 
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Patient Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. A center number is 
also assigned by Novartis to the investigative site. Once assigned to a patient, the Subject 
Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the requested 
identifying information for the patient to register them into the IRT. In the electronic data 
capture (EDC) system, there will be blank CRF books available labeled with a Patient Number. 
The site should select the CRF book with a matching Patient Number from the EDC system to 
enter data.  
If the patient was inadvertently randomized in the IRT (ie. prematurely randomized even though 
the patient failed to meet the inclusion/exclusion criteria), and the patient was subsequently not 
treated, the IRT must be notified immediately that the patient was not treated. The reason for 
discontinuing from the screening epoch will be entered on the Screening Epoch Study 
Disposition CRF.   
If the patient was correctly randomized in the IRT, but treatment was not administered for any 
reason, that patient must be followed until Day 180, and all information entered into the 
appropriate eCRFs.   
5.5.2 
Dispensing the investigational treatment  
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance.  Blinded kits will contain 1 vial of serelaxin or placebo, enough study 
drug for 24 hours of infusion. To receive the second 24 hours of study drug, the investigator’s 
staff will contact the IRT again and request a second kit. 
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to one of the 2 treatment arms. On the first 
day of the infusion, the investigator’s staff will identify the investigational treatment package(s) 
to dispense to the patient by contacting the IRT and obtaining the medication number(s). 
Immediately before dispensing the medication to the patient, investigator staff will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label Form) 
for that patient’s unique patient number.   
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment  
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all investigational treatment should be stored in a 


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refrigerator according to the instructions specified on the labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and no information about the patient. 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.10), at the time 
of the predefined interim efficacy analyses, and at the conclusion of the study. The investigator 
must maintain an accurate record of the shipment and dispensing of investigational treatment 
in a drug accountability log. Monitoring of drug accountability will be performed by the field 
monitor during site visits and at the completion of the trial. At the conclusion of the study, and 
as appropriate during the course of the study, the investigator will return all unused 
investigational treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
5.5.4 
Instructions for prescribing and taking study treatment  
The study drug infusion will begin after the signing the ICF and the completion of all screening 
procedures, and continue for 48 hours. Study drug should be administered in a dedicated IV 
line or port, as soon as possible, but no more than 4 hours after randomization. Serelaxin 
infusion solution must be prepared in infusion bags containing 5% dextrose as a diluent. 
Recommended infusion bags, which have been tested and qualified for use with serelaxin, are 
listed in Table 5-1. 
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Compatible infusion filters, which have been tested and qualified for use with serelaxin, must 
be used to administer the study drug. Table 5-2 lists the infusion filters that can be used for this 
study. 
 
For each randomized patient to receive the study drug according to a weight-range adjusted 
dosing regimen over a period of 24 hours (Table 5-3), the required amount of study drug will 
be withdrawn from the 6-mL vials (with 3.5 mL fill) contained in the blinded kits, taking care 
not to shake the vial, injected into a 250 mL intravenous bag of 5% dextrose solution 
recommended above, and then infused at a constant rate of 10 mL/hour. Details of study drug 
preparation and infusion can be found in the Pharmacy Manual. 


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Study drug will be dispensed only by study staff qualified to perform that function under 
applicable local laws and regulations for the study site(s), according to the protocol and 
Schedule of Events (see Table 6-1). The blinded study drug kits, allocated to each randomized 
patient via IRT, containing one 6-mL vial of serelaxin or placebo (with 3.5 mL fill), will be 
used to compound study drug for the first 24 hour of infusion for all patients <115 kg in weight; 
in cases when the subject is ≥115 kg, two study drug kits will be assigned via IRT for the first 
24 hour of infusion. The body weight determined between presentation and randomization, 
rounded up to the nearest 0.5 kg, will be used for the calculation of the dose for each patient, 
for the entire 48 hour infusion period.  Study drug from a second kit or pair of kits, also assigned 
via IRT depending on the patient’s body weight as assessed between presentation and 
randomization, will be used to continue the infusion for the second 24 hours.  
Table 5-3 
Weight-range adjusted dosing regimen of serelaxin (or placebo) 
All kits of investigational treatment assigned by the IRT will be recorded/databased in the IRT. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Table 5-4 describes the actions required for a systolic BP decrease during the period of study 
drug infusion, which must be strictly followed.  
Table 5-4 
Dosing adjustment of study drug administration in the event of 
systolic BP decrease 
Changes in systolic BP during 
infusion* 
Adjustments of study drug administration 
Decrease >40 mmHg from pre-
treatment at baseline, but systolic 
BP remains >100 mmHg 
Reduce the infusion rate by half for the remainder of the study 
drug administration, i.e., reduce infusion rate from 10 mL/hour 
to 5 mL/hour for the remainder of 48-hour infusion 
Decrease in absolute systolic BP to 
<100 mmHg 
Permanently terminate study drug infusion 
* These systolic BP values should be confirmed by two measurements taken 15 minutes apart 
In addition, dosing may be discontinued at any time at the discretion of the investigator. Reasons 
the investigator may discontinue study drug administration include, but are not limited to, 
serious or intolerable AEs suspected to be related to study drug. If dosing is discontinued for 
systolic BP decreases, or any safety reasons, it should not be restarted.  Re-administration of 
study drug once terminated for safety reasons is not allowed. The total time from initiation of 
study drug infusion to completion must not exceed 48 hours. In the event that study drug 
administration is discontinued, regardless of the reason, the patient will continue to be followed 
at all study visits defined in the protocol. 
Changes in study drug dose must be recorded on the Dosage Administration Record CRF. 
Body weight (kg) 
Serelaxin or 
placebo (mg) 
Volume of serelaxin or placebo to be added to 250 mL 
IV bag of sterile 5% dextrose for intravenous infusion 
over a period of 24 hours 
40-59 kg 
2.0 mg 
2.0 mL 
60-74 kg 
3.0 mg 
3.0 mL 
75-114 kg 
3.5 mg 
3.5 mL 
115-160 kg 
5.5 mg 
5.5 mL (2 vials needed) 


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5.5.6 
Rescue medication  
The investigator may prescribe any medications and/or supportive care during the study based 
on clinical needs. Any medication and/or supportive care administered must be recorded on the 
appropriate Concomitant Medications or Tests/Procedures/Treatments CRFs.  
5.5.7 
Concomitant treatment  
To be eligible for the study, all patients must have received IV furosemide of at least 40 mg (or 
equivalent) at any time between presentation to emergency services (this includes outpatient 
clinic, ambulance, or hospital including emergency department) or hospital and screening for 
the study. 
Patients will not be enrolled in the study if concomitant therapy for AHF includes current 
(within 2 hours prior to randomization) or planned (through the completion of study drug 
infusion) treatment with any cardiovascular IV therapies, including vasodilators (including 
nesiritide), positive inotropic agents and vasopressors, or mechanical support (intra-aortic 
balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist 
device), with the exception of  IV furosemide (or equivalent), or IV nitrates at a dose of < 0.1 
mg/kg/hr if the patient has a systolic BP > 150 mmHg at screening.  Use of IV furosemide (40 
mg or equivalent) is an inclusion criterion; further doses of IV furosemide can be administered 
at any time after enrollment.   
Major cardiovascular and non-cardiovascular classes of medication taken by a subject 
approximately 30 days prior to study drug initiation and on a daily basis while hospitalized 
through Day 5, at Discharge, and at Days 14, 60, 120 and 180 will be recorded.  Only those 
medications currently being taken or that were taken within 24 hours prior to the visit will be 
collected.  These include but are not limited to: loop diuretics, other diuretics, ACE inhibitors, 
angiotensin receptor antagonists, beta-blocker, hydralazine, nitrates, calcium channel blockers, 
digoxin, non-steroidal anti-inflammatory agents, COX-2 inhibitors, aminoglycoside antibiotics, 
inotropes, vasodilators and others (e.g. insulin, oral antidiabetics, statins, anticoagulants etc.). 
The investigator may prescribe any additional medications during the study as dictated by the 
patients’ condition. Administration of standard treatment should in no instance be delayed or 
withheld due to patient’s participation in the study. Standard treatment includes, but is not 
limited to, administration of the major classes of medications, as described above, as well as 
administration of oxygen, analgesics, anxiolytics and sedatives, as needed.   
Heart failure medications, procedures and significant non-drug therapies  administered after the 
patient was enrolled into the study must be recorded.  The investigator should instruct the patient 
to notify the investigator or associated study personnel about any new medications he/she takes 
after the patient was enrolled into the study. 
5.5.8 
Prohibited Treatment  
Use of IV vasoactive therapies within 2 hours prior to randomization is an exclusion criterion 
with the exception of IV loop diuretics, or IV nitrates at a dose of ≤ 0.1 mg/kg/hour if the patient 
has a systolic BP >150 mmHg at screening. Thus, study drug should be started concomitantly 
with IV nitrates only if at a low dose (≤ 0.1 mg/kg/hour) in a patient with high systolic BP (>150 
mmHg).   


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Post-randomization, the investigator may prescribe any additional medication as dictated by the 
patients’ condition.  Administration of standard treatment should never be delayed or withheld 
due to patient’s participation in the study.   The investigator should exercise caution when up-
titrating or adding concomitant standard therapies that might decrease BP during study drug 
infusion.  Investigator may consider not administering all BP lowering medication 
simultaneously.  Changes to these medications during the index hospitalization should be 
recorded on the CRF.  
5.5.9 
Discontinuation of study treatment and premature patient withdrawal  
Discontinuation of study treatment: The investigator should discontinue the study drug 
infusion for a patient if, on balance, he/she believes that continuation would be detrimental to 
the patient’s well-being. In particular, the study drug administration must be discontinued under 
the following circumstances: 
• If the patient’s systolic BP falls to <100 mmHg in two consecutive measurements 15 min 
apart, study drug must be permanently discontinued.  Measures may be taken by the 
investigator to address the decrease in blood pressure during the intervening 15 minutes, if 
clinically indicated. (see details in Table 5-4) 
• Pregnancy 
• Any significant risk to the patient’s safety 
Patients who discontinue study treatment should NOT be considered withdrawn from the study.  
They should be followed per the visit/assessment schedule illustrated in Table 6-1 until the 
study is complete. If they fail to return for these assessments for unknown reasons, every effort 
should be made to contact them as specified in Section 5.5.11. 
For any patient(s) whose treatment code has been broken inadvertently for any reason, study 
drug treatment should be continued. 
Patient withdrawal: Patients may voluntarily withdraw consent to participate in the study for 
any reason at any time.  
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and, does not want any further visits or assessments and, does not want any further 
study related contacts and does not allow analysis of already obtained biologic material. 
If a patient withdraws consent, the investigator must make every effort to determine the primary 
reason for this decision and record this information. Study treatment must be discontinued and 
no further assessments conducted. All biological material that has not been analyzed at the time 
of withdrawal must not be used. Further attempts to contact the patient are not allowed unless 
safety findings require communicating or follow-up.  However, if local regulations permit, sites 
will be asked to check public registries on a regular basis to try and obtain a health status on 
their patients, so that the Survival Information eCRF page can be completed. 
Patients can also refuse to participate in specific aspects of the study and/or take study 
medication at any time without withdrawing consent and permission should be requested of the 
patient to conduct follow-up visits or calls.  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.  This includes performing telephone visits to obtain health 
status and/or mortality information for patients who are unable to or refuse to return for clinic 
visits.   


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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, 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 just prior 
to database lock, after every effort to contact the patient has been exhausted. 
5.5.10 
Emergency breaking of treatment assignment  
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation and knowledge of 
the possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Currently, there is no known treatment available to reverse the effect of 
seralaxin.  Consequently, in case of an emergency, management of the emergency condition 
will be independent from the knowledge of study treatment. If the knowledge of study treatment 
is deemed absolutely necessary, emergency treatment code breaks will be performed using the 
IRT. When the investigator contacts the system to break a treatment code for a patient, he/she 
must provide the requested patient identifying information and confirm the necessity to break 
the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Global Trial Leader (GTL) that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact his/her 
backup in cases of emergency when he/she is unavailable. The investigator will provide 
protocol number, study treatment name, patient number, and instructions for contacting the 
local Novartis CPO (or any entity to which it has delegated responsibility for emergency code 
breaks) to the patient in case an emergency treatment code break is  required at a time when the 
investigator and backup are unavailable. 
Any patient who is unblinded will continue in the study and complete all study assessments 
according to the protocol. 
5.5.11 
Study completion and post-study treatment  
Patient participation will be completed 180 days after the start of the study drug infusion.   
The investigator also must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.12 
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 IRBs and/or ECs of the early termination of the trial. 
It is planned to have one formal interim efficacy analyses. The cut-off for this interim analysis 
is planned when 60% of the targeted total number of CV deaths is achieved. The trial may be 


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concluded early for efficacy, at the recommendation of the DMC, if a significant difference 
between two treatment arms for the number of CV deaths is achieved by crossing the pre-
specified boundary at interim analysis.   
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “X” or “S” when the required 
assessments and/or procedures are performed at a scheduled study visit. Patients should be seen 
for all visits on the designated day or timepoint, or as close to it as possible.  Patients are 
expected to return to the clinic for all scheduled outpatient study visits.  Patients unable or 
unwilling to return to the hospital/clinic for scheduled outpatient visits will be contacted by 
telephone as close as possible to the expected visit to obtain information about endpoints and 
survival status. 
Patients who prematurely discontinue the investigational treatment remain in the study and 
should undergo all the assessments illustrated in Table 6-1. If a patient withdraws from 
participation in the study, refuses to return for study assessments or is unable to do so, every 
effort should be made to contact them or a knowledgeable informant by telephone and/or other 
measures to determine the patient’s survival status during the follow-up period. 
Patients eligible to participate in this study must be randomized within 16 hours of presentation.  
Presentation starts at the earliest of (1) time of presentation either at the ER/ED, ICU/CCU or 
ward, (excludes EMS or other pre-hospital care); or (2) time of first IV loop diuretic prior to 
arrival at the hospital (this includes outpatient clinic, ambulance, or hospital including 
emergency department) for the current AHF episode.  
Prospective study candidates will be identified either enroute to or upon arriving at the 
ED/ER/hospital.  After identifying a potential subject, an ICF must be signed before performing 
study-related screening procedures that are not considered standard of care for AHF patients at 
that site.  Procedures that are part of a site’s standard of care for an individual with AHF may 
pre-date the signed ICF.  The AE and SAE reporting period will begin at the time the ICF is 
signed. 
Screening will continue until the patient has been deemed eligible for enrollment and 
randomized into the study via the IRT. 


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Table 6-1 
Assessment schedule 
Epoch 
Screening 
Randomized Treatment 
Screen d Baseline Study drug infusiona 
Post-treatment daily assessments 
Follow-upc 
Time points  
Hour -16  Hour 0 
(Day 1) 
Hour 6 
(Day 1) 
Hour 12 
(Day 1) 
Hour 24 
(Day 1) 
Hour 48 
(Day 2) 
Hour 72 
(Day 3) 
Hour 96 
(Day 4) 
Hour 120 
(Day 5)b  
Dischargee Day 14 Day 60 Day 120 Day 180 
/PSW 
Visits 
1 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
199 
Visit Date 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demography 
X 
Screening disposition 
X 
BNP or NT-pro-BNP for study 
entry  
X 
 
Estimated GFR (sMDRD) for 
study entry  
X 
 
Chest X-Ray g 
S 
ECGq 
S 
S 
S 
ECG Substudy n 
X 
X 
Medical History – Protocol 
Solicited Events 
X 
 
Medical History 
X 
Heart Failure and Diabetes 
History 
X 
 
Alcohol History 
X 
Drug Abuse History 
X 
 
Smoking History 
X 
Pregnancy Test (CHBP 
females only) f 
X 
 
Body Weightt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Epoch 
Screening 
Randomized Treatment 
Screen d Baseline Study drug infusiona 
Post-treatment daily assessments 
Follow-upc 
Time points  
Hour -16  Hour 0 
(Day 1) 
Hour 6 
(Day 1) 
Hour 12 
(Day 1) 
Hour 24 
(Day 1) 
Hour 48 
(Day 2) 
Hour 72 
(Day 3) 
Hour 96 
(Day 4) 
Hour 120 
(Day 5)b  
Dischargee Day 14 Day 60 Day 120 Day 180 
/PSW 
Visits 
1 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
199 
Height  
X 
Echocardiogramr 
X 
Physical Examination with 
Vital Signs h 
S/X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP and HR measurements i X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Systolic blood pressure 
decrease event 
X 
X 
X 
X 
X 
 
Index Heart Failure 
Hospitalization 
X 
 
Index Heart Failure Summary 
X 
Health Economics – 
Tests/Procedures/Treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician assessment of HF 
signs and symptomss  
X 
X 
Xs 
Xs 
Xs 
Xs 
Xs 
X 
X 
X 
 
Chemistryj 
X 
X 
X 
X 
X 
X 
X 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
Laboratory Substudy – 
Chemistryk 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Substudy – 
Hematologyk  
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Substudy – Urine 
DipstickK 
S 
 
Biomarker Substudy l 
X 
X 
X 
X 
X 
Concomitant Medicationso 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital status and clinical 
outcome assessments  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Epoch 
Screening 
Randomized Treatment 
Screen d Baseline Study drug infusiona 
Post-treatment daily assessments 
Follow-upc 
Time points  
Hour -16  Hour 0 
(Day 1) 
Hour 6 
(Day 1) 
Hour 12 
(Day 1) 
Hour 24 
(Day 1) 
Hour 48 
(Day 2) 
Hour 72 
(Day 3) 
Hour 96 
(Day 4) 
Hour 120 
(Day 5)b  
Dischargee Day 14 Day 60 Day 120 Day 180 
/PSW 
Visits 
1 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
199 
Assessment of readmission 
X 
X 
X 
X 
Administer study medication 
X 
Contact IRT/IWRS 
X 
X 
Adverse and serious adverse 
events m 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Follow up completion form 
X 
Withdrawal of Informed 
Consent Formp 
X 
X 
PSW = premature patient withdrawal; X= assessment to be recorded on clinical database; S= assessment to be recorded on source documentation 
a Study drug treatment will be administered as continuous intravenous infusion for up to 48 hours. Dosage can be adjusted under specific circumstances as described in 
Section 5.5.5 
b Patients discharged prior to Day 5 will return to the hospital/clinic for Day 5 procedures.  Patients unable or unwilling to return to the hospital/clinic will be contacted on or 
after Day 5 by telephone to obtain information about AEs/SAEs, potential endpoints and survival status. 
c Patients discharged prior to Day 14 will return to the hospital/clinic for Day 14 procedures. Patients unable or unwilling to return to the hospital/clinic will be contacted on 
or after Day 14 by telephone to obtain information about SAEs, potential endpoints and survival status.  The Day 60 and Day 180 assessments will be conducted as 
outpatient visits if the patient is discharged prior. The Day 180 assessments can be performed as early as - 7 days from the timepoint.  The Day 120 assessment will be 
conducted by telephone. Patients unable or unwilling to return to the hospital/clinic for scheduled outpatient visits will be contacted by telephone as close as possible to 
the expected visit to obtain information about endpoints and survival status. If a patient fails to return for the remaining outpatient visit(s) the investigator should show “due 
diligence” by contacting the patient, family or family physician up to the time of database lock.  
d Procedures performed as part of a site’s standard of care for an individual with AHF can  be done during the pre-screening interval and may pre-date the signed ICF. 
e If Discharge Visit coincides with a scheduled visit, only the Discharge Visit will be performed. 
f At screening, a locally-analyzed sample will be obtained for female patients of child-bearing potential to qualify the patient for study entry.  
g Chest X-ray may be interpreted by the study physicians or physicians attending to the patient. Interpretation and the person interpreting the radiograph must be recorded 
in the source documentation. A radiologist’s interpretation is not necessary for the purposes of the study. 
h A complete physical will be performed at screening; an abbreviated physical examination will be performed at all other specified timepoints. Following randomization, all 
physical examinations should be performed daily at approximately the same time of day. Daily vital signs measurements may be made and recorded by trained study 
personnel as well as trained healthcare personnel as part of their routine clinical duties.  The first recorded measurement per day will be used as the daily measurement 
for that day.   Refer to Section 6.5.1.  


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i BP and HR measurements are to be performed at 30 & 60 minutes and then every hour for the first 6 hours of study drug infusion, and then every 3 hours during study 
drug infusion, including night time hours. Post-infusion, BP and HR are to be measured every 3 hours until 12 hours following end of infusion, then every 6 hours for 48 
hours and then every 24 hours until the earlier of Day 5 or Discharge. All measurements should be performed as close as possible to specified timepoints. BP and HR are 
to be measured with the patient in the same position and with the same equipment using the same arm, throughout study drug infusion. These measurements may be 
made and recorded by trained healthcare personnel as part of their routine clinical duties, as well as trained study personnel. Refer to Section 6.5.2. 
j Blood will be locally collected and analyzed daily during hospitalization.  If discharge occurs prior to Day 5, local blood collection will not be required at the Day 5 
hospital/clinic visit.  Following randomization, local laboratory collections can be adjusted to conform to the hospital’s routine laboratory collection schedule and can be 
collected at any time of day. Refer to Section 6.5.4.  
k Blood will be collected in a subset of randomized patients participating in the laboratory substudy for measurement of biochemistry, hematology, and  plasma HbA1C by 
the central laboratory.  Following randomization, central laboratory collections can be adjusted to conform to the hospital’s routine laboratory collection schedule and can 
be collected at any time of day. Baseline collection can be done at screening at the same time as the local laboratory collections.  Urine dipstick will be measured locally 
at screening to rule out any conditions requiring further diagnostic evaluation or treatment.  Refer to Section 6.5.4.3  
l Blood will be collected in a subset of randomized patients participating in the biomarker substudy to be performed by the central laboratory. Following randomization, 
biomarker substudy laboratory collections can be adjusted to conform to the hospital’s routine laboratory collection schedule and can be collected at any time of day.   
 Refer to Section 6.6.6   
m Non-serious AEs and SAEs will be reported from the signing of the ICF through Day 5 and 14, respectively. 
n ECGs will be collected in a subset of randomized patients participating in the ECG substudy and sent to a central ECG vendor for evaluation. ECGs will be collected at 
Baseline and at the end of study drug infusion.  Refer to Section 6.5.5. 
o Major cardiovascular and non-cardiovascular classes of medication taken by a subject approximately 30 days prior to study drug initiation and on a daily basis while 
hospitalized through Day 5, at Discharge, and at Days 14, 60, 120 and 180 will be recorded.  Only those medications currently being taken or that were taken within 24 
hours prior to the visit will be collected. 
p Withdrawal of consent form is only completed when a patient does not want to participate in the study any more 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.. 
q ECGs will be performed and interpreted locally at screening and at Day 5 or discharge, whichever occurs first.  The ECG interpretation and person interpreting the ECG 
must be recorded in the source documents 
r The echocardiogram should be performed as soon as possible post randomization, but prior to discharge.  If an echocardiogram is performed during the screening 
period (i.e. within the 16 hours window) and the patient is subsequently randomized, the screening echocardiogram will qualify as the index hospitalization 
echocardiogram and a repeat echocardiogram post randomization will not be necessary. 
s At hours 24, 48, 72, 96 and 120, physician assessment of HF signs and symptoms will include an assessment of the occurrence of worsening heart failure in the interval 
preceding the visit. These evaluations should be done at approximately the same time of day, each day, in the same position, and hospital/clinic setting, preferably by the 
same assessor. Refer to Section 6.4.4. 
t Body weight measurements performed during hospitalization can be performed anytime 
   
 


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6.1 
Information to be collected on screening failures  
All patients who have signed informed consent but not entered into the next epoch (study phase) 
will have the study completion page for the screening epoch, visit date, demographics, 
inclusion/exclusion, and SAE data collected. Adverse events that are not SAEs will be followed 
by the investigator and collected only in the source data. 
For all patients who have signed informed consent and are entered into the next epoch of the 
study, all adverse events occurring after informed consent is signed will be recorded on the 
Adverse Event CRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
6.2 
Patient demographics/other baseline characteristics  
Patient demographic and baseline characteristic data to be collected on all patients include: date 
of birth, age, sex, race, ethnicity, weight and height. Relevant medical history/current medical 
condition data includes data until the start of study drug. Where possible, diagnoses and not 
symptoms will be recorded. Baseline HF medications and other CV medications will be 
recorded in eCRFs separately from other medications. Likewise, detailed HF history and other 
relevant CV medical history will be recorded on eCRFs separately from other medical history. 
6.3 
Treatment exposure and compliance  
Study drug will be given IV under medical supervision.  Infusions times and rates will be 
recorded in the CRF.  Study drug and supplies must be made available for inspection by the 
clinical trial monitor for accountability. 
6.4 
Efficacy 
6.4.1 
Efficacy assessment 1 
• The primary efficacy endpoint is defined as the time to confirmed CV death during a follow-
up period of 180 days. 
• Time to first occurrence of worsening heart failure* through Day 5 (considering death in 
the 5-day period as WHF event) 
* Worsening heart failure through Day 5 post randomization, includes worsening signs and/or 
symptoms of heart failure that require an intensification of intravenous therapy for heart failure 
or mechanical ventilatory, renal or circulatory support. Such treatment can include the 
institution or up-titration of IV diuretic, IV nitrates or any other IV medication for heart failure, 
or institution of mechanical support such as mechanical ventilation, ultrafiltration, 
hemodialysis, intra-aortic balloon pump or ventricular assist device, etc.  WHF can occur 
either during the index admission, or after discharge as an unplanned rehospitalization or 
unscheduled physician office/emergency department visit due to a primary diagnosis of HF. 


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This endpoint also includes patients who die in this 5-day period of any cause before 
experiencing episode(s) of WHF. 
6.4.2 
Efficacy assessment 2 
Key secondary efficacy endpoints will comprise: 
• Time to all-cause death during a follow-up period of 180 days 
• Length of total hospital stay for the index AHF hospitalization  
• Time to first occurrence of the composite endpoint of CV death or rehospitalization due to 
heart failure/renal failure, during a follow-up period of 180 days. 
Other secondary efficacy endpoints will comprise: 
• Length of ICU and/or CCU stay for the index AHF hospitalization 
• Change from baseline in congestive signs and symptoms of HF through Day 5  
• Change from baseline in selected biomarkers from baseline through Day 14 in a subset of 
randomized patients 
6.4.3 
Appropriateness of efficacy assessments  
The primary efficacy endpoint is defined as the time to confirmed CV death during a follow-up 
period of 180 days. Mortality in AHF patients remains high despite contemporary standard-of-
care HF management, and CV death is a well-established efficacy endpoint to assess the effect 
of pharmacologic interventions on clinical outcomes of HF patients. The follow-up period of 
180 days is selected here based on the finding in completed RELAX-AHF study that sustained 
benefits beyond the initial 48 hours of serelaxin therapy were associated with a clinically and 
statistically significant 37% (95% CI 4-59%) reduction in CV death through Day 180. 
6.4.4 
Other efficacy assessments 
6.4.4.1 
Assessment of AHF signs and symptoms 
The investigator or appropriately qualified designee will evaluate the signs and symptoms of 
heart failure, including patient’s dyspnea on exertion or at rest, orthopnea, rales, jugular venous 
pulse (JVP), peripheral edema, and the patient’s assessment of dyspnea (Refer to Section 16 
Appendix 3).  These evaluations will be done at baseline, 6, 24 and 48 hours from start of study 
drug infusion, and then daily while hospitalized through Day 5, at Discharge, and Days 14 and 
60.  These evaluations should be done at approximately the same time of day, each day, in the 
same position, and hospital/clinic setting, preferably by the same assessor.  To ensure 
consistency, if the same assessor cannot perform the daily assessments, the second assessor 
should evaluate the patient together with the first assessor at least once prior to performing the 
assessments independently.  
6.4.4.2 
Rehospitalization 
Rehospitalization will be defined as all unplanned hospitalization (including admission to a 
hospital or any attendance in an acute care setting e.g. ED, or in another health care facility) of 
24 hours or greater, regardless of whether the patient was admitted to the hospital.   


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6.5 
Safety  
6.5.1 
Physical examination  
An overall physical examination will be performed by the investigational staff at screening and 
include the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. An 
abbreviated physical examination will be performed at all other visits and include the 
examination of general appearance and vital signs (SBP/DBP and pulse). 
Following randomization, all physical examinations should be performed daily at 
approximately the same time of day.  Information for all physical examinations must be 
included in the source documentation at the study site. Significant findings that are present prior 
to signing informed consent must be included in the Medical History part of the eCRF. 
Significant findings made after signing the informed consent, up to and including Day 5, which 
meet the definition of an adverse event (AE) must be recorded on the Adverse Event section of 
the eCRF (Section 7.1). Significant findings made after signing the informed consent, up to and 
including Day 14, which meet the definition of a serious adverse event (SAE) must be recorded 
on the Serious Adverse Event section of the eCRF (Section 7.2), and a completed signed Serious 
Adverse Event form must be faxed to the local Novartis Drug Safety and Epidemiology 
Department (DS&E) faxed within 24 hours after awareness of the SAE. 
6.5.2 
Vital signs  
Body temperature, blood pressure, heart rate and respiration rate will be measured at Screening, 
Baseline, daily while hospitalized up to Day 5 and at Discharge, and Days 14, 60 and 180. Daily 
measurements may be made and recorded by trained study personnel as well as trained 
healthcare personnel as part of their routine clinical duties.  The first recorded measurement per 
day will be used as the daily measurement for that day.  
Patients discharged prior to Day 5 will return to the hospital/clinic for Day 5 procedures.  
Patients unable or unwilling to return to the hospital/clinical for the Day 5 procedures will be 
contacted by telephone. 
Continuous BP and HR measurements will also be performed at Screening, Baseline, 
throughout study drug infusion at 30 & 60 minutes, then every hour for the first 6 hours, and 
then every 3 hours, including night time hours. Post-infusion, BP and HR are to be measured 
every 3 hours until 12 hours following end of infusion, then every 6 hours for 48 hours and then 
every 24 hours until the earlier of Day 5 or discharge. All measurements should be performed 
as close as possible to specified timepoint.  BP and HR are to be measured with the patient in 
the same position and with the same equipment using the same arm throughout study drug 
infusion. These measurements may be made and recorded by trained healthcare personnel as 
part of their routine clinical duties, as well as trained study personnel.   
Should the study drug dose be decreased or the study drug be discontinued prematurely due to 
blood pressure decrease, then measurements should be taken every half hour through 2 hours 
following the blood pressure decrease event, and then hourly through 5 hours after event onset.  
Upon completion of the 5 hour post event onset time point, heart rate and blood pressure 
measurements should be resumed as outlined above. 


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6.5.3 
Height and weight  
Height in centimeters (cm) or inches (inch) will be measured at Screening.  
Body weight (to the nearest 0.1 kilogram [kg] or 0.1 pounds [lbs] in indoor clothing, but without 
shoes) will be measured at Screening, Days 1-5, Discharge, and Days 14, 60 and 180.  
Measurements performed during hospitalization can be performed anytime.   
If patient’s body weight cannot be measured at Screening because of the patient physical 
condition, a verbal weight will be acceptable.  Weight should be obtained as soon as the patient 
is physically able.   
6.5.4 
Laboratory evaluations  
A local laboratory will be used for analysis of all specimens collected.  The laboratory name 
and value must be entered into the eCRF page.  Local laboratory specimens will be collected at 
Screening, daily while hospitalized up to Day 5 and at discharge.   Following randomization, 
local laboratory collections can be adjusted to conform to the hospital’s routine laboratory 
collection schedule and can be collected at any time of day.   
Laboratory values that exceed the boundaries of a notable laboratory abnormality should be 
assessed for AEs and additional evaluations should be performed, as judged appropriate by the 
investigator. If the laboratory abnormality induces clinical signs and symptoms, or requires 
therapeutic intervention, then the diagnosis or medical condition must be entered on the AE 
screen of the patient’s eCRF. If the laboratory abnormality is the primary reason for an 
unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then the 
procedure for immediate notification of SAEs must be followed. Likewise, if the laboratory 
abnormality leads to discontinuation from the study, then the patient must be followed until the 
abnormality resolves or is judged to be permanent. 
In addition to the local laboratory collections outlined above, at least 1600 patients from 
selected centers will participate in a laboratory substudy.  A central laboratory will be used for 
the analysis of all baseline and post-baseline specimens collected in the subset of patients 
participating in the laboratory substudy.  Central laboratory specimens will be collected at 
baseline (can be collected at screening), daily while hospitalized up to Day 5, at Discharge, Day 
5 if discharged prior to Day 5, and Day 14. Following randomization, central laboratory 
collections can be adjusted to conform to the hospital’s routine laboratory collection schedule 
and can be performed at any time of day. Details of the substudy are described in Section 
6.5.4.3.   
6.5.4.1 
Hematology 
The following hematology tests will be measured locally at screening and daily during 
hospitalization: hemoglobin, hematocrit, and white blood cell count, including differential.     
6.5.4.2 
Clinical chemistry 
The following serum chemistry tests will be measured locally at screening and daily during 
hospitalization: sodium, potassium, glucose, blood urea nitrogen (BUN) or urea, AST, ALT, 


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alkaline phosphatase, total bilirubin, and creatinine. In addition, BNP/NT pro-BNP and 
hemoglobinA1c will be measured at screening only. 
6.5.4.3 
Laboratory substudy 
At least 1600 patients from selected centers will participate in a laboratory substudy.  All 
patients at a selected center will be asked to participate in the substudy until all 1600 patients 
have been enrolled.  All patients enrolled in the laboratory substudy will have the substudy 
blood samples collected in addition to the local laboratory blood samples outlined in Sections 
6.5.4.1 and 6.5.4.2 and biomarker blood samples outlined in Section 6.6.6.  A central laboratory 
will be used for the analysis of all baseline and post-baseline specimens collected in the subset 
of patients participating in the laboratory substudy. All laboratory results (excluding biomarker 
results) will be communicated by the central lab to the investigators and the sponsor. Details on 
the collections, shipment of samples and reporting of results by the central laboratory for the 
patients in the aforementioned substudy are provided to investigators in the laboratory manual. 
The following tests will be measured by the central laboratory in the subset of at least 1600 
patients participating in the laboratory substudy: 
• Hematology: hemoglobin, hematocrit, red blood cell count, mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), white blood cell count with differential, 
and platelet count  
• Chemistry: serum creatinine, blood urea nitrogen, total bilirubin, AST, ALT, alkaline 
phosphatase, lactate dehydrogenase (LDH) sodium, potassium, chloride, calcium, 
phosphorous, glucose, total protein, albumin, cholesterol, triglycerides and uric acid.   
Hemoglobin A1c will be performed at baseline only on whole blood.  
• Urine dipstick will be measured locally at screening to rule out any conditions requiring 
further diagnostic evaluation or treatment.  Results are to be recorded in the patient’s 
chart. 
Since results of substudy related laboratory assessments will be delayed because of sample 
transit times, local laboratory evaluations will also be performed by the investigators at the site 
and used to guide patient management (refer to Sections 6.5.4.1 and 6.5.4.2).   
6.5.5 
Electrocardiogram  
6.5.5.1 
Local ECGs 
ECGs will be performed and interpreted locally at screening and at Day 5 or discharge, 
whichever occurs first.  The ECG interpretation and the person interpreting the ECG must be 
recorded in the source documents. 
6.5.5.2 
ECG substudy 
At least 500 patients from selected centers will participate in a substudy to evaluate the impact 
of serelaxin on ECGs values.  All patients at a selected center will be asked to participate in the 
substudy until all 500 patients have been enrolled.  A standard triplicate 12-lead ECG will be 
performed at baseline and at the end of study infusion and sent to a central ECG vendor for 
interpretation. Each ECG tracing should be labeled with the study and patient number, patient 


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initials (if applicable), date, and kept in the source documents at the study site. Clinically 
significant abnormalities should also be recorded on the Medical History/Adverse event CRF 
page. 
6.5.6 
Pregnancy and assessments of fertility  
At screening, a locally-analyzed urine pregnancy test will be performed for all females of 
childbearing potential.  Any subject with a positive pregnancy test at Screening will be excluded 
from participating in the study.    
6.5.7 
Appropriateness of safety measurements  
The safety assessments selected for this trial are standard assessments for demonstrating safety 
in this patient population. 
6.6 
Other assessments  
6.6.1 
Echocardiogram 
An echocardiogram will be performed during the index hospitalization.  The echocardiogram 
should be performed as soon as possible post randomization, but prior to discharge.  If an 
echocardiogram is performed during the screening period (i.e. within the 16 hours window) and 
the patient is subsequently randomized, the screening echocardiogram will qualify as the index 
hospitalization echocardiogram and a repeat echocardiogram post randomization will not be 
necessary.   
6.6.2 
Resource utilization  
Analyses will be undertaken, as appropriate, to assess the effects of treatments on healthcare 
resource utilization (RU) parameters.  
At Visit 1 (screening), prior heart failure hospitalizations, relevant medical conditions and 
therapies, and prior procedures will be collected. Throughout the index hospitalization, the level 
of health care resource utilization will be assessed by the overall length of stay, length of time 
in specific inpatient care units, and procedures rendered during hospital stay. The frequency 
and duration of subsequent inpatient hospitalization will be recorded along with the primary 
reason for the hospital admission and discharge, length of time in specific inpatient care units, 
and procedures rendered. The frequency of urgent care for AHF lasting more than 24 hours and 
the procedures rendered will also be recorded.   
All attempts will be made to collect RU variables in all patients throughout the duration of the 
study in order to avoid selection bias. There may also be circumstances when the collection of 
such data after completion of the study may be warranted.   
6.6.3 
Health-related Quality of Life  
Health related quality of life assessments will not be collected in this study. 
6.6.4 
Pharmacokinetics  
No formal pharmacokinetic analyses will be performed.   


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6.6.5 
Pharmacogenetics/pharmacogenomics  
Pharmacogenetics will not be performed in this study. 
6.6.6 
Other biomarkers  
At least 1600 patients from selected centers participating in the laboratory substudy will also 
participate in the biomarker substudy.  All patients at a selected center will be asked to 
participate in the substudy until all 1600 patients have been enrolled.  All patients enrolled in 
the biomarker substudy will have biomarker blood samples collected in addition to the local 
laboratory blood samples outlined Sections 6.5.4.1 and 6.5.4.2 and substudy laboratory blood 
samples outlined in Section 6.5.4.3.  Following randomization, biomarker substudy laboratory 
collections can be adjusted to conform to the hospital’s routine laboratory collection schedule 
and can be collected at any time of day.  Biomarkers related to cardiac and renal function/injury 
will be obtained from blood in the subset of patients participating in the biomarker 
substudy. Biomarkers will be used to elucidate the effect of serelaxin and to explore drug effect 
versus baseline biomarkers of risk. Biomarkers of potential interest are high sensitivity troponin 
T, NT-proBNP, Galectin 3, ST2, Cystatin C and NGAL.  This list of potential biomarkers may 
be changed or expanded further as it is recognized that more relevant or novel biomarkers may 
be discovered. Biomarkers may be measured during the process of this study or after its 
completion. Detailed sample handling instructions will be provided in a separate laboratory 
manual. 
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.  In this study, non-serious AEs will be collected through 
Day 5, serious adverse events (SAEs) will be collected through Day 14.  
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events 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 adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  
Unexpected, 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 


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patient with underlying disease.  Investigators have the responsibility for managing the safety 
of individual patient and identifying adverse events. Alert ranges for labs and other test 
abnormalities are included in Section 14 Appendix 1. 
Adverse events with an onset up to and including Day 5 should be recorded in the Adverse 
Events CRF under the signs, symptoms or diagnosis associated with them accompanied by the 
following information. 
• the severity grade  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• its relationship to the study treatment (no/yes),  
• 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 study  treatment  
• whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any adverse event (appearance of or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria  
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• 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. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously through Day 14 and 
have special reporting requirements; see Section 7.2. 


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All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications (IN). 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 event reporting  
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and through Day 14 must be reported to Novartis within 24 hours 
of learning of its occurrence. Any SAEs experienced after Day 14 should only be reported to 
Novartis if the investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the relationship 
to study treatment, complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department. The telephone and fax number of the contact persons in the local 
department of Drug Safety and Epidemiology, specific to the site, are listed in the investigator 
folder provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a follow-
up to a previously reported SAE. 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or 


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progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is unexpected, i.e., the event is not previously documented as ‘expected’ in the 
Investigator’s Brochure or Package Insert (new occurrence) and is thought to be related to the 
study drug, this event is considered a Suspected Unexpected Serious Adverse Reaction 
(SUSAR). A DS&E Department associate may then urgently require further information from 
the investigator for Health Authority reporting. In general, it is Novartis policy to unblind 
SUSARs for regulatory reporting. If the unblinding shows that the Novartis drug is involved, 
Novartis will report this SUSAR in an expedited timeframe (7 or 15 days) to the competent 
authorities and relevant Ethics Committees (ECs) in accordance with Directive 2001/20/EC or 
as per national regulatory requirements in participating countries. In addition, an IN will be 
issued to inform all investigators involved in any study with the same investigational treatment 
that this SAE has been reported. 
Study-specific unblinding rules for SUSARs that are also efficacy endpoints 
In studies such as this one, where the efficacy endpoints potentially meet the requirements for 
SUSAR reporting, the integrity of the study may be compromised if the endpoints are 
systematically unblinded for expedited reporting to competent authorities/relevant ECs and 
investigators. In such cases, regulations allow an exemption from SUSAR unblinding and 
expediting aimed at ensuring the validity of an outcome study (European Commission 
ENTR/CT13 Guideline 2006; FDA Guidance 2012). Therefore, the rules for unblinding 
SUSARs during the 14-day SAE collection period will be applied as follows. 
1. Endpoint events that will not be unblinded 
A SUSAR will not be unblinded, if the event is considered consistent with one of the efficacy 
endpoints: Non-CV death, CV death, WHF, rehospitalization due to HF and/or RF. 
In addition, Novartis will not expedite a report to competent authorities/relevant ECs and will 
not issue an IN.  
If specifically requested by a local Health Authority, pre-specified endpoints (see above) that 
also meet the criteria for SUSARs will be expedited to this Health Authority as blinded reports. 
INs will not be issued for these events.   
2. Endpoint events that will be unblinded  
There is a subset of SAEs, which will require unblinding and expedited reporting to competent 
authorities/relevant ECs and investigators, if these meet SUSAR and/or endpoint criteria and 
are indicative of one of the following events: 
• Fatal events, which are often associated with drug toxicity and which include SAEs 
indicative of anaphylaxis, angioedema, blood dyscrasias (including agranulocytosis, 
aplastic anemia, bone marrow failure, pancytopenia and bicytopenia), hepatic injury, 
inflammatory lung disorders (including allergic, fibrosing, necrotizing alveolitis, 
eosinophilic pneumonia and interstitial lung disease), rhabdomyolysis,  and serious 


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


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Monitoring of safety data by the Data Monitoring Committee  
An external independent Data Monitoring Committee (DMC) (Section 9.4) will be appointed 
to monitor the safety of study participants and to ensure that the program is being conducted 
with highest scientific and ethical standards. This DMC will review the endpoint and SAE data 
throughout the trial in a semi-unblinded manner. Should the DMC make recommendations on 
the conduct of the trial that are considered to have significant bearing on the benefit-risk of the 
trial, these will be communicated by Novartis to HAs, ECs and investigators within an 
appropriate timeframe. 
7.3 
Liver safety monitoring 
Hepatotoxicity clinical safety standard guideline 
Hepatic dysfunction as sequelae of HF, even with modest cardiac compromise, has long been 
recognized. Passive hepatic congestion due to increased central venous pressure and low hepatic 
perfusion, reflecting impaired hemodynamics due to decreased cardiac output and profound 
hypotension, are considered causative mechanisms. Subsequent atrophy of liver cells and 
edema of the peripheral hepatic parenchyma are both leading to hepatocellular hypoxia; 
additionally PaO2 alterations can add to the hepatic injury. These events present both acutely 
with cardiac decompensation events and chronically with low-grade hepatic compromise 
resulting in fibrosis or cirrhosis (Alvarez and Mukherjee 2011; Nikolau et al 2013). 
Since cardiac induced hepatic injury can mask hepatotoxic events, it is important to clearly 
determine the underlying cause of elevations of liver function tests (LFTs) that may occur 
during the course of this study. Therefore, to ensure patient safety and enhance reliability in 
determining the hepatotoxic potential of an investigational drug, a standardized process for 
identification, monitoring and evaluation of liver events has to be followed.  
Liver events, which cannot be solely explained by apparent cardiac decompensation as the 
underlying cause (i.e., another etiology is suspected to cause or contribute to this event), 
are divided into two categories: 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter  
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Table 15-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.  
Every liver laboratory trigger of liver event without apparent cardiac decompensation as the 
underlying cause and as defined in Table 15-1 of Appendix 2 should be followed up by the 
investigator or designated personal at the trial site as summarized below. Detailed information 
is outlined in Table 15-2 in Appendix 2. 
For the liver laboratory trigger:  
• Repeating the LFT within the next week to confirm elevation. 


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Repeat laboratory tests should be entered on the appropriate unscheduled local laboratory CRF 
page.  
• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption is deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution.  
It is the investigator’s responsibility to investigate the potential occurrence of these events.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 
8 
Pregnancy reporting  
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment  
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
9 
Data review and database management  
9.1 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study 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. 


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed. 
9.2 
Data collection  
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
9.3 
Database management and quality control  
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will make 
the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples, from the laboratory substudy, will be processed centrally and the results 
will be sent electronically to Novartis (or a designated CRO). 
ECG tracing, from the ECG substudy, will be processed centrally and the results will be sent 
electronically to Novartis. 


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Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The database will be sent electronically to Novartis (or a 
designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
9.4 
Data Monitoring Committee  
An external and independent Data Monitoring Committee (DMC) will be formed for this study 
to primarily evaluate the unblinded results of pre-specified safety interim analyses of the data 
during the course of study, which will be provided by an independent and external Statistical 
Data Analysis Center. This includes interim analyses from entire study population as well as 
subgroups of interest. In addition, DMC will review efficacy data from one pre-specified 
interim efficacy analysis when approximately 60% of confirmed CV deaths occurred. 
Pending the outcome of the DMC’s review from each of the interim analyses, modifications of 
the study may be made to patient inclusion/exclusion criteria, assessment schedule, etc.   Any 
major recommendation from the DMC will be provided in writing to the Executive Committee 
and must be reviewed and ratified by the Executive Committee prior to its enactment.   
The membership of the DMC and the responsibilities of the DMC and Novartis will be defined 
in a separate document entitled the ‘Data Monitoring Committee Charter’. The DMC Charter 
will include information about data flow, purpose and timing of DMC meetings, guidance in 
the decision making process, communication strategy, procedures for ensuring confidentiality, 
procedures to address conflicts of interest and statistical monitoring guidelines. 
9.5 
Adjudication Committee 
An external and independent Clinical Event Committee (CEC) will review and adjudicate all 
deaths and rehospitalizations that occur through Day 180 for endpoint determination.  The CEC 
will be responsible for classifying all death events (e.g., CV and non-CV death) and for 
determining whether pre-specified endpoint criteria were met for rehospitalization due to heart 
failure or renal failure. The detailed definitions of the endpoints, required documentation, and 
the adjudication process will be provided to all sites in a separate CEC Manual. 
10 
Data analysis  
10.1 
Analysis sets  
The following analysis populations will be defined for statistical analysis: 
• Randomized (RAN) set - All patients who received a randomization number, regardless 
of receiving trial medication.  
• Safety set (SAF) - All patients who received any amount of study drug and have at least 
one post-baseline safety assessment. Of note, the statement that a patient had no adverse 
events also constitutes a safety assessment. Patients will be analyzed according to 


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treatment received.  Patients who receive any amount of serelaxin will be included in the 
serelaxin treatment group.  
• Full analysis set (FAS) - All patients in the RAN population who were not 
misrandomized patients*. Following the intent-to-treat (ITT) principle, patients are 
analyzed according to the treatment they have been assigned to at the randomization.  
• Misrandomized patients are those who have not been qualified for randomization, have 
been inadvertently randomized into the study and who did not take study drug. 
Misrandomized patients are defined as cases where IRT calls were made by the site either 
prematurely or inappropriately prior to confirmation of the patient’s final randomization 
eligibility and double-blind medication was not administered to the patient. These patients 
should subsequently be discontinued from the study.  
• Per protocol set (PPS) – all patients in the FAS who received any amount of study 
medication and have no major protocol deviations (as defined in VAP module 3). 
10.2 
Patient demographics and other baseline characteristics  
Subject demographics (age, sex, ethnicity, race, weight and height) and baseline characteristics 
will be summarized for the RAN and FAS. Screening BNP, NT pro-BNP and estimated eGFR, 
laboratory values as reported by the investigator will be summarized with standard descriptive 
statistics.  The number and percentages of patients meeting all eligibility criteria at screening 
will also be provided.  The number and percentage of patients who were hospitalized for heart 
failure in the past year and patients on IV nitrates at the time of randomization will both be 
presented.  Inclusion and exclusion criteria violations will be listed. Medical history data will 
be summarized by treatment group.  Continuous variables will be summarized using n, mean, 
median, standard deviation, minimum, maximum, and categorical variables will be summarized 
using frequency and percentage. 
Treatment groups will be compared using the Chi-square test for categorical variables or using 
t-test for continuous variables. The p-values will be provided for descriptive purpose and will 
not be considered to define any formal basis for determining factors to be included in statistical 
models. If an imbalance of treatment groups with respect to some variables does occur, 
supplemental analyses with addition of these variables in model may be performed to assess the 
potential impact on efficacy as appropriate. 
10.3 
Treatments  
Overall study drug administration details will be summarized for the RAN population. This will 
include time from presentation to randomization (hrs), time from randomization to study drug 
administration (hrs), study drug administered (yes/no), reason study drug not administered, 
actual study drug received, and the number of days infused (one or two). Study drug 
administration will also be summarized in the Safety Set. The duration of study drug 
administration (in hours) and the total volume of study drug administered (estimated from the 
total time and rate of infusion) will be summarized. In addition, the number of patients whose 
study medication dose was lowered or discontinued prematurely, and the reasons for 
discontinuation, will be summarized by treatment group.  


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Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date, respectively, will be summarized by therapeutic class, preferred term, and 
treatment group for the randomized population. 
10.4 
Analysis of the primary and key secondary variable(s) 
The primary analysis and the analyses of all secondary and exploratory efficacy variables will 
be based on the FAS, following the intention-to-treat principle. 
10.4.1 
Variable(s) 
The primary efficacy variables will be the time to confirmed CV death during the follow-up 
period of 180 days and time to worsening heart failure through Day 5 (considering death in the 
5-day period as WHF event). 
10.4.2 
Statistical model, hypothesis, and method of analysis 
CV death 
Time-to-event is computed as the number of days from randomization to CV death. Patients 
without an event will be censored at the earlier of the last date at which the vital status was 
known or Day 180.  Patients who die from a non-cardiovascular cause before Day 180 will be 
censored at the time of death. 
The statistical hypothesis is: 
H0: λ2/λ1 ≥ 1, i.e., the rate of primary event of CV death is greater or equal in the serelaxin 
group relative to the placebo group versus the one-sided alternative HA: λ2/λ1 < 1, i.e., the rate 
of CV death is smaller in the serelaxin group relative to the placebo group, where λ1 and λ2 are 
the hazard rates for CV death in the placebo group and serelaxin group, respectively. The ratio 
λ2/λ1 is also called the hazard ratio of serelaxin to placebo. 
The hypothesis will be tested based on the FAS with a logrank test at an initial significance 
level of (4/5)α within a sequentially rejective multiple testing procedure described in detail in  
Section 10.5.1. Note that the significance level for the final test will be adjusted to account for 
the planned interim analysis.  
Number and percentage of patients who died from cardiovascular reasons based on the number 
of patients in the population as denominator will be provided by treatment group. The hazard 
ratio (relative risk) and its associated two-sided 95% confidence interval will be estimated based 
on a Cox proportional hazards model with treatment assignment as a factor.  
The Kaplan-Meier estimates of the survival functions for each treatment group will be plotted. 
The Kaplan-Meier estimates of the cumulative event rate will also be presented in tables by 
treatment group for each day and also by time interval.  
The SAS procedures PHREG and LIFETEST will be used to conduct the analyses [SAS/STAT 
User’s Guide, version 9.3]. 


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WHF 
Time to worsening heart failure through Day 5 will be analyzed using Gehan’s generalized 
Wilcoxon test at an initial significance level of (1/5)α within a sequentially rejective multiple 
testing procedure described in detail in  Section 10.5.1.  
Number and percentage of patients who experienced WHF based on the number of patients in 
the population as denominator will be provided by treatment group. The hazard ratio (relative 
risk) and its associated two-sided 95% confidence interval will be estimated based on a Cox 
proportional hazards model with treatment assignment as a factor. 
Kaplan-Meier curves will be presented graphically by treatment group and Kaplan-Meier 
estimates for selected time points with 95% confidence intervals will be tabulated.  
The SAS procedures PHREG and LIFETEST will be used to conduct the analyses [SAS/STAT 
User’s Guide, version 9.3].  
10.4.3 
Handling of missing values/censoring/discontinuations 
A patient without an event will be censored for CV death at the earlier of: 
• Date of death for non-CV related causes 
• The last date at which the vital status was known 
• Day 180 
A patient without a WHF event will be censored at the earlier of the last contact date, 
withdrawal of consent date or 120 hours after randomization. 
10.4.4 
Supportive analyses  
In addition to the primary analyses, the primary efficacy variable, CV death and WHF will also 
be analyzed using the same primary analysis model on the Per Protocol set as supportive 
information. Subgroup (age [65 and 75 cut off], gender, race, region, PEF/REF, naïve vs prior 
history of HF) analyses will be analyzed for both primary endpoints for FAS. 
The survival function for each treatment arm will be estimated by the Kaplan-Meier-technique 
and the Kaplan-Meier curves will be presented for both FAS and PP. The proportion of patients 
with a primary endpoint will be estimated from the Kaplan-Meier curve for each treatment. 
Sensitivity analyses will also be performed using a modified definition of WHF, for example 
where both signs and symptoms are present. 
10.5 
Analysis of secondary variables 
10.5.1 
Efficacy variables  
There are three key secondary efficacy variables defined in this study: 
• Time to all-cause death through Day 180 
• Length of total hospital stay (LOS) during the index AHF hospitalization 
• Time to first occurrence of the composite endpoint of CV death or rehospitalization due to 
heart failure (HF)/renal failure (RF) through Day 180 


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The key secondary efficacy endpoint of all-cause mortality through Day 180 will not be 
formally incorporated in a multiple testing procedure.  It will be tested with a full α (two-
sided) by itself if one or both of the primary endpoints, CV death or WHF is statistically 
significant.   
The other two key secondary variables will be tested using a sequentially rejective multiple 
testing procedure in testing LOS and composite of CV death or rehospitalization due to HF/RF 
(CVDR) in controlling overall α (Bretz, et al 2009).  Figure 10-1 illustrates this multiple testing 
procedure for two primary and two key secondary variables with strong control of overall α 
level of 5%. Note: although CV death will be tested initially at 0.02 (one-sided) significance 
level and WHF at 0.005 (one-sided) significance level, the final significance level for CV death 
and WHF will be updated according to the graphical testing strategy incorporating two 
secondary variables, LOS and CVDR, as depicted in Figure 10-1. 
Figure 10-1 
Sequentially rejective multiple testing procedure for two key 
secondary efficacy variables  
 
 
 
 


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Where CVD is CV death, WHF is worsening heart failure, LOS is length of hospital stay, and 
CVDR is CV death or rehospitalization due to heart failure or renal failure. 
The time-to-event (from randomization to the event) analysis similar to the primary analysis of 
CV death will be used for the analyses of all-cause death at Day 180, and composite of CV 
death or rehospitalization due to HF or renal failure at Day 180. Patients without an event will 
be censored at the earlier of the last contact date or Day 180.  
Length of stay will be defined as the index hospitalization discharge date and time minus the 
randomization date and time. Patients still in the hospital at Day 60 will be censored at Day 60. 
Patients who die during the initial hospitalization will be assigned the maximum length of stay 
(including those censored at Day 60) + 1 day. Treatment groups will be compared using a 
Wilcoxon rank sum test. 
Other secondary efficacy variables will comprise: 
• Length of ICU and/or CCU stay for the index AHF hospitalization 
• Change from baseline in congestive signs and symptoms of HF through Day 5 
• Change from baseline in selected biomarkers from baseline through Day 14 in a subset of 
randomized patients 
The length of ICU and/or CCU stay for the index AHF hospitalization will be analyzed similarly 
to the length of hospital stay.  Change from baseline in congestive signs and symptoms of HF 
through Day 5 (Section 16 Appendix 3) will be analyzed by displaying the percentage of 
patients (with asymptotic 95% CIs) by treatment and time points for each of the signs and 
symptoms variables.  A time-to-event (response defined as >=1 point improvement from 
baseline) analysis will be applied to provide treatment comparisons.  Hazard ratios 
(serelaxin/placebo) of being a responder for each of the signs and symptoms variables will be 
estimated using a Cox regression model stratified by region with treatment as a factor.  Detailed 
biomarker analyses will be included in the biomarker substudy protocol. 
10.5.2 
Safety variables  
The incidence of AEs recorded through Day 5 and the incidence of SAEs recorded through Day 
14 will be presented for the Safety Set.  Incident AEs will be considered those AEs with an 
onset date and time after the initiation of study drug.  Adverse events with an onset between 
informed consent and study drug initiation will be listed separately. Adverse events will be 
coded using the most current version of MedDRA. All reported AEs will be summarized by 
system organ class (SOC) and preferred term by treatment groups. Serious AEs (SAEs) will be 
summarized similarly.   
In addition, AEs will be summarized by time period of onset: from study drug initiation to Day 
5, or from Day 6 to Day 14. Additionally, a summary of AEs by preferred term and severity, 
using the worst reported severity grade for each event for the subject, will be provided. For 
analysis purposes, all AEs defined as “definite”, “probable” or “possible” will be considered as 
related. If the relationship to study drug is unknown or missing, the AE will be considered to 
be drug-related. All study-drug-related AEs, AEs with an outcome of death, AEs leading to 
discontinuation of treatment, and study-drug-related SAEs, SAEs with an outcome of death, 
and SAEs leading to study drug discontinuation will be summarized by percentages and 


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frequencies. Percentages will be based on the number of patients in the Safety Set. For the 
analysis by time period of onset, the percentages will be based on the number of patients in the 
Safety Set with the corresponding AE form completed.  
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), summary statistics of raw data and change from 
baseline (means, medians, standard deviations, 1st and 3rd quartiles, Q1 and Q3) and by flagging 
of notable values in data listings.   
For vital signs, descriptive statistics will be provided for values and change from baseline at 
each assessment time point for pulse, respiratory rate, body temperature, and weight. Treatment 
groups will be compared for changes from baseline using t-tests. 
The number and proportion of patients who experience a confirmed blood pressure decrease 
event during study drug administration will be provided.  Among patients who experience a 
confirmed blood pressure decrease event, the events will be further characterized. Summaries 
will be provided separately for those confirmed events that resulted in study drug dose 
reduction, and those that resulted in study drug discontinuation. The possible interaction 
between the effect of serelaxin and the effect of IV nitrate administration within the first 48 
hours will be examined. 
10.5.3 
Resource utilization  
Summary statistics will be provided by treatment group on hospital length of stay (total and per 
ward) for the initial and subsequent hospitalizations, as well as procedures rendered during these 
hospitalizations,.  Additional information will be provided in the Statistical Analysis Plan. 
10.5.4 
Health-related Quality of Life  
Health related quality of life assessments will not be collected in this study. 
10.5.5 
Pharmacokinetics  
Pharmacokinetics will not be collected in this study. 
10.5.6 
Pharmacogenetics/pharmacogenomics  
Not applicable. 
10.5.7 
Biomarkers  
Biological markers will be measured in a subset of patients.  Summary statistics for the baseline 
values, the post-baseline values, and the change from baseline will be provided by treatment 
group for the FAS and Safety Set. 
10.5.8 
PK/PD  
Not applicable. 


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10.6 
Interim analyses  
It is planned to establish an external and Independent Data Monitoring Committee (DMC) to 
monitor patient safety data on a regular basis during the course of the study. For this study, it is 
likely DMC will review safety data in a regular frequency, e.g., every six months. DMC may 
request additional safety data review.  Such safety analyses do not inflate the type I error for 
the primary efficacy hypothesis testing and thus require no multiplicity adjustments. 
It is planned to have one formal interim efficacy analyses. The cut-off for this interim analysis 
is planned when the information fraction (number of confirmed CV deaths relative to the 
targeted total number of confirmed CV death at the study completion) of 60% is achieved. Some 
adjustment to the time of interim analysis may be made to coincide with the regular DMC 
meetings. One-sided tests will be performed and appropriate statistical adjustments for the 
interim analysis actually performed will be made to ensure the overall one-sided type I error of 
0.02 (Lan-DeMets spending function to match an O’Brien-Fleming stopping boundary). For the 
interim analysis, the analysis dataset will comprise all patients who were randomized before the 
cut-off date.  
The trial may only be concluded early for efficacy, if a significant difference between two 
treatment arms for the number of CV deaths is achieved by crossing the pre-specified boundary 
(irrespective of WHF results) at interim analysis and the overall risk/benefit profile is 
considered positive. Interim analysis will be performed by an external independent statistician 
at an external data analysis center, who will not be involved in the study conduct. The results 
will be reviewed by the independent DMC. Investigators and others who are involved in the 
conduct of the trial and in the analysis of the final trial results, or who have contact with study 
centers, will remain blinded to the treatment codes and interim analysis results until all 
monitoring decisions have been made and the database has been locked for final analysis.  
Additional details of the interim analysis plan for efficacy and safety will be described in the 
DMC charter. 
10.7 
Sample size calculation 
The alpha (α) level of 5% is split to CV death at 4% and to WHF at 1%. The sample size 
calculation is based on the CV death endpoint. This is an event-driven trial with fixed maximum 
duration of 180 day follow-up period for each patient. In the sample size calculation, the 180-
day CV death rate is assumed to be 9.0% in the placebo group, which is about 80% of 11.3% 
of all cause death observed in the placebo group in the RELAX-AHF study.
 
 
 This sample size accounts 
for one planned efficacy interim analysis when 60% of CV deaths have been accrued, using the 
Lan-DeMets spending function and an O’Brien-Fleming (OF) stopping boundary. 
The interim analysis will be performed when 329 CV deaths are accrued. At the interim 
analysis, if Z-score of 2.786 (one-sided nominal p = 0.0027) is observed, which corresponds to 
HR of 0.735 (at least 26.5% RRR), the DMC may recommend to stop the study due to crossing 
the boundary. If there is no stopping at the formal efficacy interim analysis, the final analysis 
will need to have a Z-score of 2.072 (one-sided nominal p = 0.0192), which corresponds to HR 


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of 0.838 (at least 16.2% RRR), to declare a significant study. (East ® 5.4.2, Cytel Inc., 
Cambridge MA, 2010). 
If the observed overall event rate of the CV death endpoint during the course of the trial is much 
lower than expected based on the design assumptions (assessed on a blinded basis), adjustments 
may be made to the number of patients to be randomized in order to achieve the required number 
of events in the pre-planned timeframe (180 days) and thus to preserve the target study power. 
For the sample size of 6,800, the unconditional power for the WHF endpoint and all three key 
secondary endpoints under various HRs (mean difference for Length of Stay) are summarized 
below in Table 10-1 and Table 10-2: 
Table 10-1 
Assumed effect sizes for worsening heart failure and the key 
secondary efficacy variables on power calculation  
 
Assumed HR or mean 
difference 
Worsening Heart 
Failure (placebo rate: 
12.2%) 
0.70 
0.80 
All cause death 
(placebo rate: 
11.3%) 
0.80 
0.816 
0.83 
Length of Stay 
(mean ±SD between 
placebo and 
serelaxin: 0.9 ±9.6 
day) 
0.9 day 
0.7 day 
CV death or HF/RF 
rehospitalization 
(placebo rate: 
34.1%) 
0.85 
0.88 
 
Note:  Assumed placebo rates for all cause death and WHF and mean difference (mean + SD) in LOS 
between serelaxin and placebo were based on RELAX AHF study; placebo event rate of CV death or 
HF/RF rehospitalization was estimated to be 34.1% by assuming an exponential distribution with the 
same hazard as that observed through Day 60 in RELAX AHF study.   
Table 10-2 
Powers (unconditional) of primary and key secondary variables on 
selected scenarios 
 
A) All cause death 
Scenarios of effect sizes 
All cause 
death Day 
180* 
All-cause death (HR=0.80); WHF (HR=0.70) 
83 
All-cause death (HR=0.816); WHF (HR=0.70) 
77 


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All-cause death (HR=0.82); WHF (HR=0.70) 
70 
All-cause death (HR=0.80); WHF (HR=0.80) 
82 
All-cause death (HR=0.816); WHF (HR=0.80) 
76 
All-cause death (HR=0.82); WHF (HR=0.80) 
70 
 
Note: The true HR for CV death is assumed to be 0.78 in all scenarios. 
          *Power if one or both of the two primary variables are significant.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The true HR for CV death is assumed to be 0.78 in all scenarios. 
Note: The power for the WHF endpoint is approximated based on logrank test, but the analysis 
will be based on Gehan-Wilcoxon test. 
 
B) CVD, WHF, LOS and CVDR 
Scenarios of effect sizes 
CV 
death 
Day 180 
WHF 
Day 5 
LOS 
CV 
death or 
HF/RF 
hosp. 
Reject All 
WHF (HR=0.7) – LOS (0.9 days) – 
CVD/rehosp (HR=0.85)  
82 
99 
93 
93 
77 
WHF (HR=0.7) – LOS (0.9 days) – 
CVD/rehosp (HR=0.88)  
82 
99 
92 
79 
68 
WHF (HR=0.7) – LOS (0.7 days) – 
CVD/rehosp (HR=0.85) 
82 
99 
78 
93 
69 
WHF (HR=0.7) – LOS (0.7 days) – 
CVD/rehosp (HR=0.88) 
82 
99 
77 
77 
60 
WHF (HR=0.8) – LOS (0.9 days) – 
CVD/rehosp (HR=0.85) 
82 
82 
87 
87 
68 
WHF (HR=0.8) – LOS (0.9 days) – 
CVD/rehosp (HR=0.88) 
82 
82 
86 
73 
59 
WHF (HR=0.8) – LOS (0.7 days) – 
CVD/rehosp (HR=0.85) 
82 
81 
73 
86 
60 
WHF (HR=0.8) – LOS (0.7 days) – 
CVD/rehosp (HR=0.88) 
81 
81 
72 
72 
53 


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11 
Ethical considerations  
11.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
11.2 
Informed consent procedures  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents.  
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.3 
Responsibilities of the investigator and IRB/IEC  
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made. 


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11.4 
Publication of study protocol and results   
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
12 
Protocol adherence  
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the trial 
to request approval of a protocol deviation, as requests to approve deviations will not be granted. 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants.  Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR. 
12.1 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed within 10 
working days or less, if required by local regulations.  
13 
References  
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Bani D, Failli P, Bello MG, et al (1998) Relaxin activates the L-arginine-nitric oxide pathway 
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Bretz, F., Maurer, W., Brannath, W., and Posch, M. (2009) A graphical approach to 
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53:557–573. 
Hochberg Y (1988). A sharper Bonferroni procedure for multiple tests of significance. 
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Hunt SA, Abraham WT, Chin MH, et al (2009) 2009 focused update incorporated into the 
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report of the American College of Cardiology Foundation/American Heart Association Task 
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Levey AS, Coresh J, Balk E, et al (2003) National Kidney Foundation Practice Guidelines for 
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McMurray JJV, Adamopoulos S, Anker SD, et al (2012) ESC Guidelines for the diagnosis 
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Metra M, Teerlink JR, Felker GM, et al (2010a) Dyspnoea and worsening heart failure in 
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Nikolaou M, Parissis J, Yilmaz MB, et al (2013) Liver function abnormalities, clinical profile, 
and outcome in acute decompensated heart failure. Eur Heart J;34(10):742-9. 
Teerlink JR, Metra M, Felker GM, et al (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, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure 
(RELAX-AHF) : a randomised, placebo-controlled trial Lancet 2013;381:29-39 
Torre-Amione GJ, Milo-Cotter O, Kaluski E, et al (2009) Early worsening heart failure in 
patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome. 
J Card Fail; 15:639-44. 
 


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


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15 
Appendix 2: Liver event and laboratory trigger definitions 
and follow-up requirements 
Table 15-1 
Definitions of liver events, which cannot be solely explained by 
apparent cardiac decompensation as the underlying cause (i.e., 
another etiology is suspected to cause or contribute to this event) 
 
Definition/ threshold 
Liver laboratory triggers 
• 3 x ULN < ALT/AST ≤ 5x ULN 
• 1.5 x ULN < TBL ≤ 2 x ULN 
Liver events 
• ALT or AST > 5 x ULN 
• ALP > 2 x ULN (in the absence of known bone pathology) 
• TBL > 2 x ULN (in the absence of know Gilbert syndrome) 
• Potential Hy’s Law cases (defined as ALT or AST > 3 x ULN 
and TBL > 2 x ULN (mainly conjugated fraction) without 
notable increase in ALP to > 2 x ULN 
• Any clinical event of jaundice for (or equivalent term) 
• ALT or AST > 3 x ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting or rash with 
eosinophilia 
• Any adverse event potentially indicative of liver toxicity* 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms 


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Table 15-2 
Follow Up Requirements for liver events and laboratory triggers, 
which cannot be solely explained by apparent cardiac 
decompensation as the underlying cause (i.e., another etiology is 
suspected to cause or contribute to this event) 
Criteria 
 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, fractionated 
bilirubind,  Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
ALT or AST 
> 8 x ULN 
 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, fractionated 
bilirubind,  Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 x ULN 
 
Repeat LFT within 48 hours 
If elevation persists continue 
follow-up monitoring 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
Establish causality 
Complete liver CRF 
ALT, AST, fractionated 
bilirubind,  Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 x ULN 
accompanied by 
symptomsb 
 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, fractionated 
bilirubind,  Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 x ULN  
(patient is 
asymptomatic) 
 
Repeat LFT within the next 
week 
If elevation is confirmed, initiate 
close observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
> 2 x ULN  
In the absence of 
known bone 
pathology 
 
Repeat LFT within 48 hours 
If elevation persists, establish 
causality 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBL (isolated) 


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Criteria 
 
Actions required 
Follow-up monitoring 
> 2 x ULN (in the 
absence of known 
Gilbert syndrome 
 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, fractionated 
bilirubind, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 x ULN 
(patient is 
asymptomatic) 
 
Repeat LFT once or twice in the 
week. If elevation is confirmed, 
initiate close observation of the 
patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Preferred terms 
Jaundice 
 
Discontinue the study drug 
immediately 
Hospitalize the patient 
Establish causality 
Complete liver CRF 
ALT, AST, fractionated 
bilirubind, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
“Any AE potentially 
indicative of a liver 
toxicity* 
Medically 
significant 
Consider study drug interruption 
or discontinuation  
Hospitalization if clinically 
appropriate 
 
Establish causality 
Complete liver CRF 
Investigator discretion 
* These events cover the following: hepatic failure, fibrosis and cirrhosis , and other liver damage-
related conditions: the non –infectious hepatitis: the benign, malignant and unspecified liver 
neoplasms 
a Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but without notable increase in ALP to > 2 x 
ULN  
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
c 
Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) 
stable values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated 
level after a maximum of 6 months,(4) liver transplantation, and (5) death. 
d Fractionated bilirubin includes testing for total bilirubin, direct bilirubin, and indirect bilirubin. 


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16 
Appendix 3: Physician assessment of signs and symptoms 
The following criteria are to be used to assess patient’s signs and symptoms of heart failure. 
 
Exertional Dyspnea:  The subject should be queried as to the extent of dyspnea noted over the 
preceding 1-3 hours as follows: 
 
0 
No exertional dyspnea (NYHA Class I equivalent) 
1 
Mild exertional dyspnea, occurring with moderate exertion   (climbing 
stairs or equivalent-NYHA Class II equivalent) 
2 
Moderate exertional dyspnea, occurring with only mild exertion 
(walking-NYHA Class III equivalent) 
3 
Severe exertional dyspnea, occurring at rest (NYHA Class IV) 
 
Orthopnea:  The subject should be observed after being in the lowest recumbent position for 
10-15 minutes or queried in order to determine the minimum number of “pillows” required to 
obtain/maintain comfort while supine.  This should be graded on a 0 - 4 scale as follows: 
 
0 
Comfortable with no pillow or very minimal elevation of head 
1 
Comfortable with no less than one pillow to elevate head  
(approx 10 cm elevation) 
2 
Comfortable with no less than two pillows to elevate head  
(approx 20 cm elevation) 
3 
Comfortable with head no less than at 30 degree elevation 
 
Rales:  Auscultation of the lungs applying a 4-point scale:  
 
0 
No rales heard, either moist or dry, after clearing with cough anywhere 
in the lung fields 
<1/3 
Moist or dry rales heard in the lower 1/3 of either or both lung fields 
that persist after a cough in attempt to clear 
1/3-2/3 
Moist or dry rales heard throughout the lower half to 2/3 of either or 
both lung fields 
>2/3 
Moist or dry rales heard throughout both lung fields 
 
 


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

SAP_000.pdf: 
Clinical Development 
RLX030A 
CRLX030A2301 / NCT01870778
A multicenter, randomized, double-blind, placebo-
controlled phase III study to evaluate the efficacy, safety 
and tolerability of Serelaxin when added to standard 
therapy in acute heart failure patients 
RAP Module 3 – Detailed Statistical Methodology 
Amendment 3 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Final version 1.0 
Release date: 
03-Mar-2017
Number of pages: 
36 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
1 
Introduction ......................................................................................................................... 8 
2 
Statistical methods planned in the protocol and determination of sample size ................... 8 
2.1 
Subject and treatment .............................................................................................. 8 
2.1.1 
Analysis population ................................................................................. 8 
2.1.2 
Protocol deviation (PD) ........................................................................... 9 
2.1.3 
Visit, baseline and post baseline definitions ......................................... 10 
2.1.4 
Subgroup definitions ............................................................................. 11 
2.1.5 
Subject disposition ................................................................................ 12 
2.1.6 
Background and demographic characteristics ....................................... 12 
2.1.7 
Medical history ...................................................................................... 13 
2.1.8 
Other subject history information ......................................................... 13 
2.1.9 
Study medication ................................................................................... 13 
2.1.10 
Concomitant medication ....................................................................... 13 
2.1.11 
Close-out procedure .............................................................................. 15 
2.2 
Efficacy evaluation ................................................................................................ 15 
2.2.1 
Efficacy variables .................................................................................. 15 
2.2.2 
Definition of time to CV death through Day 180 ................................. 16 
2.2.3 
Time to worsening heart failure (WHF) through Day 5 (considering 
death in the 5-day period as WHF event) .............................................. 17 
2.2.4 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.2.5 
Supportive/sensitivity analyses for primary endpoint ........................... 18 
2.2.6 
Key secondary analysis ......................................................................... 19 
2.2.7 
Other secondary analysis ....................................................................... 21 
 
 23 
2.2.9 
Handling of missing values/censoring/discontinuations in efficacy 
analyses ................................................................................................. 25 
2.3 
Safety evaluation ................................................................................................... 26 
2.3.1 
Adverse events ...................................................................................... 26 
2.3.2 
Laboratory data ..................................................................................... 29 
2.3.3 
Vital signs.............................................................................................. 29 
2.3.4 
Electrocardiogram (ECG) ..................................................................... 30 
2.3.5 
Confirmed blood pressure decreases (CBPD) ....................................... 30 
2.3.6 
Pregnancy test results ............................................................................ 31 
2.3.7 
Liver toxicity function and liver events ................................................ 31 


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2.4 
Interim analyses ..................................................................................................... 33 
2.5 
Sample size and power considerations .................................................................. 35 
3 
References ......................................................................................................................... 37 
 
List of tables 
Document History – Changes compared to previous version of RAP module 3. ...................... 5 
Table 2-1 
Protocol deviations resulting in exclusion of subjects from analysis 
populations .............................................................................................. 9 
Table 2-2 
Non-protocol deviation criteria resulting in exclusion of subjects 
from analysis populations ..................................................................... 10 
Table 2-3 
Specification of key subgroups at screening ......................................... 11 
Table 2-4 
Specification of additional subgroups at screening ............................... 11 
Table 2-5 
Primary, secondary and exploratory variables ...................................... 15 
Table 2-6 
IV loop diuretics .................................................................................... 23 
Table 2-7  
Safety risk and event of interest search specification ........................... 27 
Table 2-8 
Criteria for evaluating liver toxicity ...................................................... 31 
Table 2-9 
Nominal one-sided alpha at 70% randomized subjects accrued if 
CVD is rejected ..................................................................................... 34 
Table 2-10 
Assumed effect sizes for worsening heart failure and the key 
secondary efficacy variables on power calculation ............................... 36 
Table 2-11 
Powers (unconditional) of primary and key secondary variables on 
selected scenarios .................................................................................. 36 
 


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 Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
Amendment 1 
13-Aug-2015 
-add the testing strategy for WHF and secondary endpoints in 
case of early stopping 
-add sensitivity analysis for WHF using logistic regression  
-add substudy population definition 
Amendment 2 
06-Feb-2017 
- Clarify the method of mapping discharge visit to scheduled visits 
if scheduled visits are missing 
- Update the list of countries that recruited subjects (Table 2-3) 
- Remove subgroup category of lymphocytes and education level 
in Table 2-4 
- Use FAS in section 2.1.9 – study medication summary.  
- Align presentation of non-IV concomitant medications with 
RELAX-AHF 
-  Clarify definition of the censoring date for death endpoints 
(Adjudicated CV death, adjudicated all cause death) for patients 
who withdrew consent in countries where vital status data is 
publically available, in accordance with local laws and regulations  
- Clarify use of discharge date as the reference date for endpoint 
time to the composite endpoint of CV death or rehospitalization 
due to HF/RF during a follow-up period of 30 days post-discharge 
- Clarify the statistical method used for subgroup analysis of 
length of stay (LOS). Clarify the imputation rule for missing 
discharge information to align with RELAX-AHF 
- Clarify the imputation of signs and symptoms through Day 5 for 
subjects with WHF or died at hospital to align with RELAX-AHF 
- Addition of two new tables per ClinicalTrials.gov and EudraCT 
requirement 
-Update Safety risk and event of interest search specification 
(Table 2-7) 
- Clarify the ECG analysis population  
- Update the ECG categorical analysis,  add analysis of newly 
occurring abnormalities in ECG morphology and remove ECG 
shift table to enable comprehensive assessment 
- Update liver function categorical analysis (Table 2-8) 
Amendment 3 
03-Mar-2017 
- Add a new protocol deviation “ Site closed down for GCP 
reasons” leading to exclusion from the FAS and PPS 
-Subjects without valid written informed consent will be excluded 
from all analysis populations. 
- Remove covariate lymphocytes (%) from covariate-adjusted 
sensitivity analysis of  CV death because of a number of missing 
values at baseline 
 


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List of abbreviations 
ACE  
Angiotensin Converting Enzyme 
ACM 
All-cause mortality 
AE 
Adverse Event 
AHF  
Acute Heart Failure 
ALP 
Alanine Phosphatase 
ALT  
Alanine Aminotransferase 
ARB  
Angiotensin-II Receptor Blocker 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BNP  
Brain Natriuretic Peptide 
BPDE 
Blood pressure decrease event 
BUN 
Blood Urea Nitrogen 
CBPDE 
Confirmed blood pressure decrease event 
CCU  
Coronary care unit 
CEC  
Clinical Endpoints Committee 
CI  
Confidence interval 
CPK  
Creatine Phosphokinase 
CRF  
Case Report Form 
CSR  
Clinical Study Report 
 
  
CV 
Cardiovascular 
CVD 
CV death 
CVDR 
CV death or rehospitalization due to heart failure or renal failure 
CWHF 
Clinical Worsening Heart Failure 
dL  
Deciliter 
DMC 
Data Monitoring Committee 
DRE  
Disease-related event 
ECG 
Electrocardiogram 
EF 
Ejection fraction 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice  
HF  
Heart failure 
ICU 
Intensive Care Unit 
ITT  
Intent-to-treat 
IV  
Intravenous 
kg  
Kilogram 
LFT 
Liver Function Toxicity 
LOS 
Length of hospital stay 
LPLV 
Last Patient Last Visit 


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LSM 
Least-square Mean 
MAP 
Master Analysis Plan 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRA 
Mineralocorticoid receptor antagonist 
mg  
Milligram 
min  
Minute 
mL  
Milliliter 
mmHg  
Millimeters mercury 
NYHA 
New York Heart Association 
OF 
O’Brien-Fleming  
PASS 
Physicians Assessment of Signs and Symptoms 
PD 
Protocol Deviation 
PPS  
Per Protocol Set 
PT 
Preferred Term 
RAN 
Randomized Set 
RAP 
Report and Analysis Preparation 
RBC  
Red Blood Cell 
SAE  
Serious adverse event 
SAF 
Safety Set 
SAS  
Statistical Analysis System 
SBP  
Systolic Blood Pressure 
SCR  
Screened Set 
SGOT 
Glutamic Oxaloacetic Transaminase 
SGPT 
Glutamic Pyruvic Transaminase 
sMDRD  
Simplified Modification of Diet in Renal Disease 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TBL  
Total Bilirubin 
ULN 
Upper Limit of Normal 
WHF  
Worsening heart failure 
WHO-DD 
World Health Organization Drug Dictionary 
μg  
Microgram 
 


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1 
Introduction 
The CRLX030A2301 study (also referred to as RELAX-AHF-2) aims to evaluate the 
efficacy, safety and tolerability of intravenous infusion of 30 µg/kg/day serelaxin for 48 
hours, when added to standard therapy. Data from this study is intended to replicate the 
reduction in mortality in AHF patients observed in the RELAX-AHF study.  
The purpose of this document is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for RELAX AHF-2.  
2 
Statistical methods planned in the protocol and 
determination of sample size 
Data will be analyzed according to the data analysis section 10 of the study protocol which is 
available in Appendix 16.1.1 of the CSR. 
All nominal time points will be used for analysis; actual assessment times will not be used to 
reclassify the time point at which a measure was taken.  Time-to-event analyses will be based 
on actual dates (time) reported. 
All references to index hospitalization refer to the initial hospitalization for AHF. 
Unless specified, descriptive statistics indicates mean, median, standard deviation, minimum 
and maximum will be presented for continuous variables; the number and percentage of 
subjects in each category will be presented for categorical variables for each treatment group 
and all subjects (total).   
2.1 
Subject and treatment  
2.1.1 
Analysis population  
The following analysis populations will be defined for statistical analysis: 
• 
Screened set (SCR) – All subjects who signed the informed consent. The SCR 
includes only unique screened subjects. 
• Randomized set (RAN) - All subjects who received a randomization number, 
regardless of receiving trial medication.  
• Safety set (SAF) - All subjects who received any amount of study drug and have at 
least one post-baseline safety assessment. Of note, the statement that a subject had no 
adverse events also constitutes a safety assessment. Subjects will be analyzed 
according to treatment received. Subjects who received any amount of serelaxin will be 
included in the serelaxin treatment group. 
• Full analysis set (FAS) - All subjects in the RAN population who were not 
misrandomized subjects*. Following the intent-to-treat (ITT) principle, subjects are 
analyzed according to the treatment they have been assigned to at the randomization. 
Further exclusions from the FAS were only justified in exceptional circumstances 


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(e.g., site closed down for GCP reasons). The determination of which patients were 
excluded from the FAS is made in a blinded manner before the database lock. 
* Misrandomized subjects are those who have not been qualified for randomization, 
have been inadvertently randomized into the study and who did not take study drug. 
Misrandomized subjects are defined as cases where IRT calls were made by the site 
either prematurely or inappropriately prior to confirmation of the subject’s final 
randomization eligibility and double-blind medication was not administered to the 
subject. These subjects should subsequently be discontinued from the study.  
• Per protocol set (PPS) – all subjects in the FAS who received any amount of study 
medication and have no major protocol deviations. 
Subjects without valid written informed consent will be excluded from all analysis 
populations. 
Laboratory substudy and electrocardiogram (ECG) substudy populations will be defined for 
subjects participating laboratory or ECG substudy with informed consent.   
2.1.2 
Protocol deviation (PD) 
All cases of prospectively defined protocol deviations (PD) will be identified prior to clinical 
database lock/unblinding and entered into a dedicated data panel as part of the locked 
database. Certain deviations may stipulate that data collected from the subjects will be 
excluded from PPS. This PPS is used to assess robustness of the primary and key secondary 
analysis results. 
All exceptional cases, problems and the final decisions on the allocation of subjects to 
populations will be fully defined and documented before data base lock (in particular before 
breaking the blind where applicable) and will be fully identified and summarized in the 
clinical study report. 
Criteria defining protocol deviations are referenced in the “PD specs and edit check’ tab of 
Edit Check Specification document. Protocol deviations will be classified into 5 categories as 
appropriate: 
• Selection criteria not met 
• Subject not withdrawn as per protocol  
• Treatment deviation 
• Prohibited concomitant medication 
• Other 
The major protocol deviations resulting in exclusion of subjects from an analysis population 
are outlined in the table below:  
Table 2-1 
Protocol deviations resulting in exclusion of subjects from analysis 
populations  
PD category 
Deviation 
Excluding from analysis set 
RAN 
FAS 
SAF 
PPS 


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PD category 
Deviation 
Excluding from analysis set 
RAN 
FAS 
SAF 
PPS 
Selection criteria not 
met 
Missing informed consent (Inclusion criteria #1) 
x 
x 
x 
x 
 
Patient hospitalized for reasons of non-AHF event 
(inclusion criteria #3) 
 
 
 
x 
 
Systolic BP <125 mmHg at the start and/or at the 
end of screening (inclusion criteria #4) 
 
 
 
x 
 
Time from presentation to randomization >16 
hours (inclusion criteria #5) 
 
 
 
x 
 
Dose of IV furosemide between presentation and 
start of screening is < 40 mg (inclusion criteria #6) 
 
 
 
x 
 
eGFR is <25 or > 75 mL/min/1.73m2 at screening 
(inclusion criteria #7) 
 
 
 
x 
 
Dyspnea is primarily due to non-cardiac causes 
(exclusion criteria #1) 
 
 
 
x 
 
Sepsis or active infection requiring IV anti-
microbial treatment reported at screening 
(exclusion criteria #4) 
 
 
 
x 
 
AHF is due to significant arrhythmias (exclusion 
criteria #6) 
 
 
 
x 
 
Pre-randomization eGFR < 25 mL/min/1.73m2 or 
ongoing or planned dialysis or ultrafiltration at 
screening (exclusion criteria #7) 
 
 
 
x 
Treatment derivation 
Serelaxin infusion administered in diluent other 
than the recommended 5% dextrose bags 
 
 
 
x 
 
Wrong study drug kit administered or wrong dose 
administered 
 
 
 
x 
 
Subject misrandomized 
 
x 
x 
x 
Other 
Site closed down for GCP reasons 
 
x 
 
x 
 
In addition, deviations not defined in the protocol resulting in exclusion of subjects from an 
analysis population are outlined in the table below.  
Table 2-2 
Non-protocol deviation criteria resulting in exclusion of subjects from 
analysis populations 
Criterion 
Excluding from analysis set 
RAN 
FAS 
SAF 
PPS 
Subject randomized but not receiving any dose of double-blind 
study medication 
 
 
x 
x 
2.1.3 
Visit, baseline and post baseline definitions 
Except for biomarkers (described in Section 2.2.7.3), discharge visit will be mapped to Day 1, 
2, 3, 4, 5, 14 (with +/- 3 day window), 60 (with +/- 7 days window), 120 (with +/- 7 days 
window), 180 (with +/- 7 day window) if the scheduled visits are missing.  
Screening phase: The screening phase is defined as the period prior to randomization. After 
obtaining written informed consent, the subject will be evaluated for eligibility to participate 
in to the study.  


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Baseline definition for efficacy/safety measurements: Baseline is defined as Hour 0/Day 1 
assessment. The baseline date and time will be considered the date and time of initiation of 
study drug, or randomization if the subject was not treated with study drug. If missing, the 
value at screening visit will be used. 
Post-baseline phase for efficacy/safety measurements: The post-baseline phase begins at 
the time when study drug administration starts (Hour 0/Day 1) and ends with the last study 
assessment/last follow-up or the death of subject. For subjects who did not receive study drug, 
the phase begins at time of randomization.      
2.1.4 
Subgroup definitions 
If not otherwise specified, the following subgroups will be defined for the study using the data 
collected at screening.  
The key subgroups will be used in primary and key secondary endpoints.  
Table 2-3 
Specification of key subgroups at screening 
Subgroup  
Method of Derivation   
Age groups (<65, ≥65; <75, ≥75 years) 
Derived 
Gender 
eCRF 
Race (White/Caucasian, Other)   
Derived 
Region * 
Derived 
Ejection fractions (<50%, ≥50%;<40%,≥40%) 
Derived 
Prior history of heart failure (yes/no)  
eCRF 
* North America: USA, Canada 
Latin America (including Central America): Argentina, Brazil, Chile, Colombia, Peru, Mexico 
Western Europe: Austria, Belgium, Denmark,  France, Germany, Greece, Ireland, Italy, Netherlands, 
Norway, Portugal, Spain, Sweden, Switzerland, UK, Turkey, Israel 
Of note, Turkey and Israel are classified in Western Europe based on medical practice.  
Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Slovakia, Romania, Russia 
Other: Australia, South Africa  
Additional exploratory subgroups analysis (as defined in Table 2-4, based on Metra et al 
2013of primary and key secondary time to event endpoints will be presented in Appendix 
16.1.9 only. 
Table 2-4 
Specification of additional subgroups at screening 
Subgroup  
Method of Derivation   
NT-proBNP ≥ 3000 pg/ml or BNP ≥ 750 pg/ml 
Local lab, Derived 
Systolic blood pressure (<140, ≥140 mmHg) 
Derived 
Heart rate (< 80, ≥ 80 bpm)  
Derived 
History of Ischemic heart disease (yes/no) 
eCRF 
History of diabetic mellitus (yes/no) 
eCRF 
History of atrial fibrillation or flutter (yes/no) 
eCRF 


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Time from presentation to randomization (<2, 2-10, >10 hours) 
Derived 
Intravenous (IV) nitrate use at randomization (yes/no) 
eCRF 
eGFR (<30, ≥30; <50, ≥50; <60, ≥60  mL/min/1.73 m2 ) 
Local Lab, Derived 
 
2.1.5 
Subject disposition 
The number of subjects randomized and included in the full analysis set (FAS) will be 
presented by treatment group. The number of subjects screened only (SCR) will be presented. 
In addition, the reasons for screen failures will be provided. The number and percentage of 
subjects in the FAS who completed the study, who discontinued the study and the reason for 
discontinuation will be presented for each treatment group and all subjects.  
A completer will be defined as either has died with adjudicated cause (including those 
adjudicated as having unknown cause), or whose actual follow up is greater or equal to 165 
days (last known vital status – baseline date).  
The frequency (%) of subjects with protocol deviations as well as the criteria leading to 
exclusion from analysis sets will be presented for RAN.  
The number of subjects enrolled and randomized per region and country will be presented for 
FAS. 
For each subject, the length of follow-up (days) will be computed by subtracting the study 
drug initiation date (or the randomization date for subjects not treated with study drug) from 
the end of study date (the last known vital status).   
Descriptive statistics will be presented for length of follow-up by treatment group and overall.  
Categorical summaries will also be presented for the number and percent of subjects within 
predefined follow-up intervals as: None; >0-5 days; 6-14 days; 15-60 days; 61-120 days; 121-
180 days.  
2.1.6 
Background and demographic characteristics 
Subject demographics (age, sex, ethnicity, race, weight (continuous and <115kg, ≥ 115 kg) 
and height) and baseline characteristics (including alcohol history and smoking history) will 
be summarized for the FAS.  
For baseline comparability analysis, categorical variables will be analyzed using the Chi-
square test and continuous variables will be analyzed using the t-test and will be presented in 
Appendix 16.1.9 only.  
The p-values will be provided for descriptive purpose and will not be considered to define any 
formal basis for determining factors to be included in statistical models. If an imbalance of 
treatment groups with respect to some variables does occur, supplemental analyses with 
addition of these variables in model may be performed to assess the potential impact on 
efficacy as appropriate. 
The background and demographic characteristics analysis will be repeated for age, gender, 
race, region, PEF/REF and history of HF subgroups as defined in Table 2-2 for the FAS. The 
results will be presented as supplementary analysis in the statistical Appendix section. 


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Baseline characteristics of interest in vital signs and local laboratory values collected at 
screening visit will also be presented for the FAS. 
2.1.7 
Medical history 
The number and percentage of subjects including but not limited to who had history of heart 
failure, New York Heart Association (NYHA) class, primary heart failure etiology 
(ischemic/non-ischemic), who were hospitalized for heart failure, ejection fraction (<40%, 
≥40%; <50%, ≥50%), who were on heart transplant list, and who had history of diabetes 
mellitus will be presented for FAS. The number of HF hospitalization in the past year and 
ejection fraction (%) will also be presented.  
The number and percentage of subjects will also be presented for each protocol solicited event 
as pre-printed list in eCRFs for the FAS.  
Any other condition entered on the medical history not recorded on the medical history 
protocol solicited events or heart failure history eCRFs will be coded using the MedDRA 
dictionary. The number and percentage of subjects with each medical condition will be 
provided by treatment group for the FAS. 
2.1.8 
Other subject history information 
The number and percentage of subject in lifestyle history, highest level of education and home 
health care arrangement, will be presented for the FAS.  
The history drug abuse will also be presented for the FAS. 
2.1.9 
Study medication 
For the FAS population, study drug administration details will be summarized by treatment 
group and overall for the time from presentation to hospital (hours), time from first IV loop 
diuretic for the current AHF episode to randomization (hours), time from earlier of 
presentation to hospital or first IV loop diuretic to randomization (hours), time from 
randomization to study drug administration (hours), on IV nitrates at randomization (yes/no), 
dose decreased due to blood pressure decrease (yes/no), study drug administered on either day 
(yes/no), reason study drug not administered, actual study drug received, and the number of 
days infused (one or two days), study drug prematurely discontinued and reasons for 
discontinuation. 
The duration of study drug administration (in hours) and the total volume of study drug 
administered (estimated from infusion duration at each infusion rate) will also be summarized 
by treatment group and overall.   
2.1.10 
Concomitant medication 
The use of all concomitant medications will be summarized using the SAF population. 
2.1.10.1 IV loop diuretic medications 
IV loop diuretic medications include the following: 
• Bumetanide 


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• Etacrynic acid/Ethacrynic acid 
• Furosemide 
• Torasemide/Torsemide 
The number and percentage of subjects using IV loop diuretic medications will be 
summarized for each of the time periods: Hour 24/Day 1 to end of study, Hour 0/Day 1, 24 
hours/Day 1, 48 hours/Day 2, Day 3, Day 4, Day 5, and Discharge.  Each time point reflects 
medication use within the preceding 24 hours.   
The average total daily dose for each medication will also be presented at reported time point. 
In addition, cumulative use reported at 48 Hours (24 hours/Day 1 and 48 hours/Day 2), and at 
Day 5 (from 24 hours/Day 1 to Day 5) in furosemide equivalent (mg) will be summarized. 
The calculation of furosemide equivalents (mg) for Bumetanide, Ethacrynic acid/Ethacrynic 
acid and Torsemide/Torsemide acid are actual dose (mg) multiplied by constant 40, 0.8, or 2, 
respectively. For subjects who die before Day 5, the minimum of 2 times of the last recorded 
dose and 160 mg will be assumed for every day from the date of death up to and including 
Day 5. 
2.1.10.2 IV medications other than loop diuretics 
The number of subjects using other IV medications including Dopamine, Dobutamine, 
Milirinone, Enoximone, Norepinephrine, Epinephrine, Nesiritide, Levosimendan, Isosorbide 
Dinitrate, Nitroglycerin, Nitroprusside, Phenylephrine and other will be presented in the same 
way as IV loop diuretic medications.  
The average dose over the time administered of the medication will be presented separately 
for each medication at each reported time point. No equivalent dose unit among other IV 
medications will be converted.  
2.1.10.3 Other non-IV concomitant medications 
The use of other non-IV concomitant medications is reported through Day 180. The number 
and percentage of subjects using other non-IV medications will be summarized for each of the 
time periods: 30 days to 14 prior to study drug initiation, Hour 24/Day 1 to end of study, Hour 
0/Day 1, 24 hours/Day 1, 48 hours/Day 2, Day 3, Day 4, Day 5, Discharge, Day 14, Day 60, 
Day 120 and Day 180 for ACE inhibitor (ACEi), angiotensin inhibitor (ARB), ACEi or ARB, 
beta blocker, PO loop diuretics, other PO diuretics,  calcium channel blockers, aldosterone 
antagonist and cardiac glycosides.  
In addition, the number (%) of subjects who have these medications initiated during their 
index hospitalization and subjects who have these medications increased during the period 
following discharge from the index hospitalization will also be presented. 
The average daily dose administered will be summarized at each time point for each 
medication within the loop diuretics, ACEi, ARB, beta blocker, aldosterone antagonist, ARNi 
and direct renin inhibitor. .  
Other non-IV concomitant medications taken prior to, and after the start of study drug will be 
presented by the ATC and preferred terms.       


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2.1.11 
Close-out procedure 
The number of CV deaths will be predicted on an ongoing basis. 
 
Subjects who have been randomized to the study will be followed up until their final visit 
(180 days) or date of death. Attempts should be made to contact any subjects who did not 
complete the Day 180 visit.  
The aim of the close-out procedure will be to allow for all necessary activities (study 
completion visits, data cleaning, raising and resolution of all queries to the clinical sites, etc.) 
including the adjudication of all primary and secondary events that occurred during the study 
and prior to final visit.  The “adjudicated endpoint” refers to an endpoint and date of the 
endpoint that has been confirmed by an independent endpoint committee who has no access to 
the treatment code. 
Only adjudicated events will be counted in the primary analyses.  However, sensitivity 
analyses will be performed on the suspected (investigator reported) primary and secondary 
endpoints. 
2.2 
Efficacy evaluation 
The primary analysis and the analyses of all secondary efficacy endpoints will be based on the 
FAS population following the intention-to-treat principle. 
2.2.1 
Efficacy variables 
The following table gives an overview of efficacy variables.  
Table 2-5 
Primary, secondary and exploratory variables  
Variables 
Analysis set 
Analysis method 
Primary efficacy variables 
1 
Time to CV death through Day 180 
FAS/PPS 
log rank test and Kaplan-Meier 
estimates 
2 
Time to worsening heart failure (WHF) 
through Day 5 (considering death in the 5-
day period as WHF event) 
FAS/PPS 
Gehan’s generalized Wilcoxon test 
Secondary efficacy variables 
(if either primary variable is significant, follow sequential testing procedure) 
1 
Time to all-cause death through Day 180 
FAS/PPS 
log rank test and Kaplan-Meier 
estimates 
(of note: will not be formally 
incorporated in a multiple testing 
procedure) 
2 
Length of total hospital stay (LOS) during the 
index AHF hospitalization 
FAS/PPS 
Wilcoxon rank-sum test 
3 
Time to first occurrence of the composite 
endpoint of CV death or rehospitalization due 
to heart failure (HF)/renal failure (RF) through 
Day 180 
FAS/PPS 
log rank test and Kaplan-Meier 
estimates 
Other secondary efficacy endpoints (at α=0.05, no multiplicity adjustment) 


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Variables 
Analysis set 
Analysis method 
1 
Length of ICU and/or CCU stay for the index 
AHF hospitalization 
FAS 
Wilcoxon rank-sum test 
2 
Change from baseline in congestive signs 
and symptoms of HF through Day 5 
FAS 
Wilcoxon rank-sum test at each post-
baseline visit 
3 
Change from baseline in selected biomarkers 
from baseline through Day 14 in a subset of 
randomized subjects 
FAS 
Repeated measurement model 
Primary and key secondary endpoints are considered in sequential testing procedure and efficacy interim analysis 
 
For the time to confirmed CV death during the follow-up period of 180 days, the 
confirmation of primary events is based on an adjudication process through an independent 
CEC (Clinical Endpoint Committee). The CEC will also adjudicate all recurrent events of the 
unplanned hospitalizations according to the protocol. 
2.2.2 
Definition of time to CV death through Day 180 
Events that occur prior to or at the subject’s final visit date will be part of the time-to-event 
analyses. Events that occurred more than 180 days will be considered as censored from the 
analyses. The CV death will be based on adjudicated results. If the adjudicated cause of death 
is unknown, it will be considered as a CV death.   
The time-to-event for a given subject will be calculated as the difference between the subject's 
date of endpoint and the randomization date:  
• Time-to-event (days) = date of CV death – randomization date,  
For those subjects without events, the censoring date will be the earliest in the following 
dates: 
• 180 days 
• Date subject withdrew consent to all follow-up (if no subsequent vital status 
documented) 


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Note: in accordance with local laws and regulations, vital status may be publically 
available 
• Date of non-CV death 
• Date of subject’s last visit or contact or vital status 
The censoring time for the analyses will be calculated as:   
• Time-to-event censored (days) = censoring date – randomization date  
Whenever the event date or visit date needed for defining the time-to-event or censoring date 
is missing or incomplete for a given subject, an imputation rule for missing/incomplete date 
will be applied.  More details about the imputation rule are presented in Section 2.2.9. 
2.2.3 
Time to worsening heart failure (WHF) through Day 5 (considering 
death in the 5-day period as WHF event) 
WHF events occurring within 120 hours of randomization will be included in the analysis. 
WHF is defined as clinical worsening of HF during the index hospitalization or as adjudicated 
rehospitalization for HF.  A subject who dies by 120 hours without a WHF event will be 
considered to have had an event at the time of death.  
Event date and time will be used at calculating the time to event for better precision, and 
convert it back to days.  
Time-to-event (days) = (first event date/time– randomization date/time),  
For those subjects without events the censoring date will be the earliest in the following dates: 
• Hour 120 (5 days) 
• Date subject withdrew consent to all follow-up 
• Date of subject’s last visit or contact 
2.2.4 
Statistical hypothesis, model, and method of analysis 
CV death 
The statistical hypothesis is: 
H0: λ2/λ1 ≥ 1, i.e., the rate of primary event of CV death is greater or equal in the serelaxin 
group relative to the placebo group versus the one-sided alternative HA: λ2/λ1 < 1, i.e., the rate 
of CV death is smaller in the serelaxin group relative to the placebo group, where λ1 and λ2 
are the hazard rates for CV death in the placebo group and serelaxin group, respectively. The 
ratio λ2/λ1 is also called the hazard ratio of serelaxin to placebo. 
The hypothesis will be tested based on the FAS with a log rank test at an initial significance 
level of (4/5)α within a sequentially rejective multiple testing procedure described in detail in  
Section 2.2.6.4. Note that the significance level for the final test will be adjusted to account 
for the planned interim analysis.  
Number and percentage of subjects who died from cardiovascular reasons based on the 
number of subjects in the population as denominator will be provided by treatment group. The 
hazard ratio (relative risk) and its associated two-sided 95% confidence interval will be 
estimated based on a Cox proportional hazards model with treatment assignment as a factor.  


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The Kaplan-Meier estimates of the survival functions for each treatment group will be plotted. 
The Kaplan-Meier estimates of the cumulative event rate will also be presented in tables by 
treatment group for each day and also by time interval.  
WHF 
Time to worsening heart failure (WHF) through Day 5 will be analyzed using Gehan’s 
generalized Wilcoxon test at an initial significance level of (1/5)α within a sequentially 
rejective multiple testing procedure described in detail in  Section 2.2.6.4.  
Number and percentage of patients who experienced WHF based on the number of patients in 
the population as denominator will be provided by treatment group. The hazard ratio (relative 
risk) and its associated two-sided 95% confidence interval will be estimated based on a Cox 
proportional hazards model with treatment as a factor. 
Kaplan-Meier curves will be presented graphically by treatment group and Kaplan-Meier 
estimates for selected time points with 95% confidence intervals will be tabulated. 
Model assumption 
For primary efficacy variables analyzed by Cox proportional hazard model, the important 
model assumption that is made when applying a Cox proportional hazards regression model is 
the proportionality of the hazard function(s) over time. This assumption will be tested using 
the same primary Cox proportional hazards regression model and in addition a time-
dependent explanatory variable created through the interaction between log time and 
treatment. In addition, a graphical method will be used for checking the proportional hazards 
assumption. A plot of log-log survivor function vs. log time for each treatment group will be 
used. Approximate parallelism between the curves for the treatment groups will provide 
supportive evidence of the proportional hazards assumption. It should be noted that the log 
rank test remains valid even if the proportional hazards assumption is not fulfilled. 
The SAS procedures PHREG and LIFETEST will be used to conduct the analyses. 
2.2.5 
Supportive/sensitivity analyses for primary endpoint 
• Both primary efficacy variables, CV death and WHF through Day 5, will also be analyzed 
on the PPS as supportive information.  
• To explore the consistency of treatment effects across subgroups, the CV death and WHF 
will also be analysed for respective subgroups provided in Table 2.3 by adding the 
subgroup and the treatment by subgroup interaction terms to the Cox regression model of 
the primary efficacy endpoint. In all analyses a test for heterogeneity to assess for possible 
interactions between treatment and baseline variables will be applied. Results will be 
presented graphically as forest plots. The objective of the subgroup analyses is to evaluate 
the consistency of treatment effects across a wide variety of patient groups.  
• A covariate-adjusted Cox-regression model will be fitted for the CV death with baseline 
covariates (Age (continuous), history of heart failure (yes/no), cerebrovascular accident 
(yes/no), respiratory rate (continuous), systolic BP (continuous), edema (categorical), 
orthopnea (categorical), sodium (continuous), creatinine (continuous)) identified from 


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RELAX-AHF exploratory analysis (Metra, et al 2013) to account for other factors that 
might affect prognosis using likelihood ratio test for treatment effect with exact handling 
of ties. 
• Analyses will be performed using a modified definition of WHF, e.g. subjects with (1) 
worsening signs AND symptoms or (2) IV intervention and/or mechanical support. 
Another sensitivity analyses that exclude subjects whose only symptom is abdominal 
bloating/discomfort or fatigue/decreased exercise tolerance will also be provided.  
• Subjects with WHF through Day 5 (yes/no) will also be analyzed using logistic regression 
with treatment and region as factors.  
2.2.6 
Key secondary analysis 
There are three key secondary efficacy variables defined in this study.  
All key secondary variables will be analyzed using the FAS and PPS populations, and will be 
repeated for the subgroups provided in Table 2-3 by adding the subgroup and the treatment by 
subgroup interaction terms to the model for time to event endpoints.  
Whenever the event or visit time needed for defining the time-to-event or censoring date and 
time is missing or incomplete, an imputation rule for missing/incomplete time will be applied.  
More details about the imputation rule are presented in Section 2.2.9. 
2.2.6.1 
Time to all-cause death through Day 180 
Time to all-cause death will be calculated as: 
Time-to-event (days) = date of all-cause death – randomization date,  
The analysis will be performed similarly to primary endpoint.  
For those subjects without events, the censoring date will be the earliest in the following 
dates: 
• 180 days 
• Date subject withdrew consent to all follow-up (if no subsequent vital status 
documented) 
Note: in accordance with local laws and regulations, vital status may be publically 
available 
• Date of subject’s last visit or contact or vital status 
A covariate-adjusted Cox-regression model similar to the sensitivity analysis of primary 
efficacy variable will also be performed as sensitivity analysis. 
2.2.6.2 
Length of total hospital stay (LOS) during the index AHF 
hospitalization 
Length of stay will be defined as the index hospitalization discharge date and time minus the 
randomization date and time, whereas time is used for better precision and converted to days.  


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Subjects still in the hospital at Day 60 will be censored at Day 60. Subjects who die during the 
initial hospitalization will be assigned the maximum length of stay (including those censored 
at Day 60) plus 1 day.  
Subjects missing the discharge date, such that a determination of the length of stay cannot be 
calculated, will be assigned the mean length of stay over all subjects with not missing 
discharge date. 
Treatment groups will be compared using a Wilcoxon rank sum test.  
For subgroup analysis, a p-value for the test of the treatment by subgroup interaction term will 
be based on a two-way model with treatment, subgroup and treatment-by-subgroup interaction 
using rank-transformed data. 
The van Elteren extension to the Wilcoxon rank sum test will also be carried out stratifying 
for region. 
2.2.6.3 
Time to first occurrence of the composite endpoint of CV death or 
rehospitalization due to heart failure (HF)/renal failure (RF) through 
Day 180 
Time to event will be calculated as date of first event of adjudicated CV death or adjudicated 
rehospitalization due to HF/RF minus randomization date in days. If the reason for 
adjudicated rehospitalization is unknown, it will be considered as HF or RF. 
The analysis will be performed similarly to primary endpoint.  
For subjects without events the censoring date will be the earliest in the following dates: 
• 180 days 
• Date subject withdrew consent to all follow-up 
• Date of subject’s last visit or contact  
• Date of non-CV death 
In addition, the estimates with 95% CI at 30, 60, and 90 days from the Kaplan-Meier method 
will be provided. Of note estimates at 60 and 90 days are considered as exploratory analyses. 
The analysis for one of components of the composite endpoint, time to rehospitalization due 
to HF/RF through Day 180, will also be performed. The estimates with 95% CI and p-value at 
Day 180 from the Kaplan-Meier method will also be provided.  
2.2.6.4 
Multiple testing procedure 
The key secondary efficacy variables of all-cause mortality through Day 180 will not be 
formally incorporated in a multiple testing procedure.  It will be tested with a full α (two-
sided) by itself if one of the primary endpoints, CV death or WHF is statistically significant.   
The primary endpoints of CV death and WHF will be tested first. If at least one of the primary 
endpoints is significant, the other two key secondary variables will be tested using a 
sequentially rejective multiple testing procedure in testing LOS and composite of CV death or 
rehospitalization due to HF/RF (CVDR) in controlling overall α (Bretz, et al 2009).  Figure 2-
1 illustrates this multiple testing procedure for two primary and two key secondary variables 


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with strong control of overall α level of 5%. Note: although CV death will be tested initially at 
0.02 (one-sided) significance level and WHF at 0.005 (one-sided) significance level, the final 
significance level for CV death and WHF will be updated according to the graphical testing 
strategy incorporating two secondary variables, LOS and CVDH, as depicted in below figure. 
Figure 2-1 
Sequentially rejective multiple testing procedure for two key 
secondary efficacy variables  
 
 
 
 
Where CVD is CV death, WHF is worsening heart failure, LOS is length of hospital stay, and 
CVDR is a composite variable of CV death or rehospitalization due to heart failure or renal 
failure. 
2.2.7 
Other secondary analysis 
Other secondary efficacy variables comprise: 
2.2.7.1 
Length of ICU and/or CCU stay for the index AHF hospitalization 
The days stayed in ICU/CCU will be obtained from eCRF page directly. If subjects die during 
the initial hospitalization, the maximum number of days plus 1 day in the ICU/CCU over all 
subjects will be assigned. 
The length of ICU and/or CCU stay for the index AHF hospitalization will be analyzed 
similarly to the length of hospital stay, i.e., it will be compared using a Wilcoxon rank sum 


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test. As a sensitivity analysis, the van Elteren extension to the Wilcoxon rank sum test will 
also be carried out stratifying for region. 
2.2.7.2 
Change from baseline in congestive signs and symptoms of HF 
through Day 5 
Detailed criteria to assess subject’s signs and symptoms (dyspnea on exertion, orthopnea, 
edema, rales, and jugular venous pulse) of heart failure can be found in protocol Appendix 15. 
Subjects who die or have a worsening heart failure event (either during the index hospital or 
rehospitalization due to heart failure) will have their score imputed to be the worst observed 
score in any subject at any time point in the respective analysis population carried forward 
from the day of death or WHF regardless of whether their original data are missing through 
Day 5. For patients who are alive with missing values, the last preceding non-missing value 
will be used for imputation. 
A time-to-event (response defined as >=1 point improvement from baseline) analysis will be 
applied to provide treatment comparisons. Hazard ratios (serelaxin/placebo) of being a 
responder for each of the signs and symptoms variables will be estimated using a Cox 
regression model stratified by region with treatment as a factor. 
Since the assessment only occurs on the scheduled visits, the nominal scheduled day will be 
used directly to determine the time to event with exact handling of ties.   
For those subjects without events, the censoring date will be the earliest in the following 
dates: 
• 
6 days 
• 
Date subject withdrew consent to all follow-up 
• 
Date of subject’s last visit or contact  
Change from baseline in congestive signs and symptoms of HF through Day 5 will be 
analyzed by displaying the percentage of subjects in each category by treatment and time 
points for each of the signs and symptoms variables. The scores will be presented as both 
categorical and continuous statistics (i.e., rales will be defined as 0, 1, 2, 3 for its 4 categories; 
jugular venous pulse will be defined as 0, 1, 2 for its 3 categories).  Change from baseline will 
be computed as the baseline value subtracted from the post-baseline value. Treatment groups 
will be compared with respect to change from baseline at each time point using Wilcoxon 
rank sum tests. 
2.2.7.3 
Change from baseline in selected biomarkers from baseline through 
Day 14 in a subset of randomized subjects 
A biomarker substudy as measured by a core laboratory will be conducted to enroll at least 
1600 subjects.   
Change from baseline through Day 14 will be performed on the key biomarkers high 
sensitivity troponin T, cystatin C and NT-proBNP using a repeated measurement model. It is 
anticipated that the assumption of normally distributed residuals for biomarkers may not hold. 
Therefore, the model will be performed on log-transformed biomarker. Treatment group, visit 
(Day 2, Day 5 and Day 14) and region will be fitted as factors and log-baseline biomarker will 


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be fitted as a continuous covariate. Treatment group by visit and visit by log baseline will be 
included as interaction terms in the model. 
The analysis will be presented by treatment group and visit (Day 2, Day 5 and Day 14). The 
detailed analysis of changes in biomarkers and analyses of associations of baseline biomarker 
levels with clinical outputs are described in the separate biomarker statistical analysis plan.  
Of note the discharge visit for biomarkers will be mapped to Day 2, Day 5 (within +/- 1 day 
window) or Day 14 (within +/- 3 days window) if Day 2, Day 5 or Day 14 visits are missing.  


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2.2.9 
Handling of missing values/censoring/discontinuations in efficacy 
analyses 
The detailed censoring for time-to-event is mentioned in previous sections.  
 
Missing date 
It is assumed that the day and month of all event dates will be known.  If the date’s day of the 
month is missing such that a determination of whether the event occurred within the reporting 
window cannot be made, the day will be imputed following an attempt to get an approximate 
date from the family or other records: 
a) if only the month of the event is known, then the 15th day of this month will be 
imputed for a missing day in case the month and year are after the month and year 
of double blind treatment start. If the month and year are equal to the double blind 
treatment start then the event date will be imputed by the treatment start date. 
b) if only the year of the event is known, then the 1st July will be imputed for a 
missing day and month in case the 1st July is after double-blind treatment start 
(otherwise treatment start date will be used), or 
c) for events occurring between two visits after randomization, without other 
information available, the date in the middle of these visits will be used. 
An adjudicated death with unknown cause will be classified as a CV death. Similarly, 
investigator suspected deaths of unknown cause will be classified as CV deaths. 
 
Missing time 
For efficacy variables require date and time in calculation, if time is missing or incomplete, 
the following will be applied: 
a) if hour and minute are both missing, then the 12:00pm (24hr clock) of the day will 
be imputed in case the hour and minute are after double blind treatment start 
(otherwise, treatment start hour and minute will be used).  


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b) if only minute is missing, 30th minute of the hour will be imputed in case the 
minute is after double blind treatment start (otherwise, treatment start minute will 
be used). 
2.3 
Safety evaluation 
Safety will be assessed by comparing the study drug to the placebo group with regard to the 
frequency of AEs, changes in clinical laboratory test results (chemistry and hematology), 
confirmed blood pressure decreases and vital signs. All safety analyses will be presented for 
the SAF.  
The treatment group will be based on the actual treatment received for each subject.  
2.3.1 
Adverse events 
The incidence of AEs and non-serious AEs recorded through Day 5 and the incidence of 
SAEs recorded through Day 14 will be presented for the Safety population.  
For presentation, AE verbatim text will be coded into a MedDRA (Medical Dictionary for 
Regulatory Activities) term and classified by MedDRA System Organ Class (SOC) and 
Preferred Term (PT). The incidence of all reported AEs will be summarized by SOC and PT.  
A subject reporting the same event more than once will be counted once when reporting the 
number of subjects with that particular event. Percentages will be based on the number of 
subjects in SAF. 
SAEs will be summarized by time period of onset: from study drug initiation through Day 5 
and from Day 6 through Day 14 separately. All AEs through Day 14 will also be provided. 
Additionally, a summary of AEs by PT and severity, using the worst reported severity grade 
for each event for the subject, will be provided.  
All study-drug-related AEs, AEs leading to discontinuation of study drug, and study-drug-
related SAEs, SAEs with an outcome of death, and SAEs leading to study drug 
discontinuation will be summarized by the number and percentage of subjects reporting 
particular events. For analysis purposes, if the relationship to study drug is unknown or 
missing, the AE will be considered to be drug-related. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables 
summarizing treatment emergent adverse events which are not serious adverse events with an 
incidence greater than 0.5% and summarizing treatment emergent serious adverse events and 
SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the Safety population. 
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 


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For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.  
Detailed AE listings will also be provided.  
In addition, AEs representing identified and potential safety risk in addition to events of 
interest will be grouped.  The incidence (absolute and relative frequency) of each potential 
risk will be summarized by treatment group.  Odds ratios and associated 95% confidence 
intervals comparing serelaxin with placebo will be presented using the Mantel-Haenszel test. 
In addition, subjects experiencing each of these risks will be listed.  Such safety risks and 
events of interest are displayed in below table.   
Table 2-7  
Safety risk and event of interest search specification 
 
Type of Risk 
Specification 
Safety risk 
 
Hypotension 
    Search terms include the following PTs: 
    Blood pressure ambulatory decreased 
    Blood pressure decreased 
    Blood pressure diastolic decreased 
    Blood pressure immeasurable 
    Blood pressure orthostatic decreased 
    Blood pressure systolic decreased 
    CT hypotension complex 
    Diastolic hypotension 
    Dizziness postural 
    Hypotension 
    Mean arterial pressure decreased 
    Neonatal hypotension 
    Orthostatic hypotension 
    Procedural hypotension 
    Altered state of consciousness 
    Blood pressure abnormal 
    Blood pressure ambulatory abnormal 
    Blood pressure diastolic abnormal 
    Blood pressure fluctuation 
    Blood pressure inadequately controlled 
    Blood pressure orthostatic abnormal 
    Blood pressure systolic abnormal 
    Blood pressure systolic inspiratory decreased 
    Consciousness fluctuating 
    Depressed level of consciousness 
    Dizziness 
    Dizziness exertional 
    Labile blood pressure 
    Loss of consciousness 
    Presyncope 


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Type of Risk 
Specification 
    Schellong test 
    Syncope 
    Tilt table test positive 
Hemoglobin/ hematocrit transient 
decrease 
SMQ ‘Haemorrhages’ (Broad) 
HLGT ‘Anaemias nonhaemolytic and marrow 
depression’ 
SMQ ‘Haematopoietic erythropenia’ (Broad) 
Fetotoxicity and Teratogenicity 
SMQ ‘Pregnancy and neonatal topics’ (Broad)  
Event of interest  
 
Hypokalemia 
    Search terms include the following PTs: 
    Alkalosis hypokalaemic 
 
 
    Blood potassium abnormal 
 
    Blood potassium decreased 
 
 
    Hypokalaemia 
 
 
    Hypokalaemic syndrome  
 
    Hyperkaliuria 
 
 
    Transtubular potassium gradient 
 
 
    Urine potassium abnormal  
 
    Urine potassium decreased 
 
 
    Urine potassium increased 
 
Menorrhagia/Metrorrhagia 
HLGT ‘Menstrual cycle and uterine bleeding disorders’ 
Potential promotion of cancers 
SMQ ‘Malignancies’ (Broad) 
Immunogenicity/Hypersensitivity 
SMQ ‘Hypersensitivity’ (Broad) 
SMQ ‘Angioedema’(Broad) 
SMQ ‘Anaphylactic reaction’(Broad) 
SOC ‘Immune system disorders’ 
HLGT ‘Immunology and allergy investigations’ 
HLGT ‘Administration site reactions’ 
SMQ ‘Severe cutaneous adverse reactions’(Broad) 
Cardiac failure 
SMQ ’Cardiac  failure’ (Broad) 
 
QT prolongation 
SMQ ‘Torsade de pointes/QT prolongation’ (Broad) 
SMQ ‘Cardiac arrhythmias’ (Broad) 
Thromboembolic events 
SMQ ‘Embolic and thrombotic events’ 
Renal impairment 
SMQ ‘Acute renal failure’ (Broad) 
Respiratory failure 
SMQ ‘Respiratory failure’ (Broad) 
Hepatotoxicity 
SMQ ‘Drug related hepatic disorders – comprehensive 
search’ (Broad) 
AEs with an onset between informed consent and study drug initiation will be listed.  
For each AE listed, the verbatim term and PT, the corresponding severity, relationship to 
study drug, seriousness (yes/no), and start and stop date and time of the event will be specified 
and displayed by treatment group and subject number.  


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2.3.2 
Laboratory data 
2.3.2.1 
Hematology and chemistry 
In addition to local laboratory evaluations for all randomized subject, a laboratory substudy 
will be conducted at a subset of selected sites to enroll at least 1600 subjects. Subjects without 
written informed consent for the laboratory substudy before any study-specific assessment is 
performed will be excluded from the population. 
Descriptive summaries of actual and change from baseline will be presented for all continuous 
clinical laboratory values by treatment and time point. 
Clinical shift tables showing the pattern of change from baseline versus each post-baseline 
time point will be presented based on the cross-classification of the number of subjects with 
clinical laboratory values below (low), within (normal), or above (high) normal ranges for 
each laboratory test.  
All laboratory data will be listed for each subject.  Laboratory values that are outside the 
normal ranges will be flagged high (H) or low (L).   
The number and percentage of subjects with clinically notable laboratory results, including 
categorical analysis on laboratory parameters of interest after baseline will be presented. 
Clinically notable laboratory values are defined in protocol Appendix 1. The notable 
laboratory values related to liver function are detailed in Section 2.3.7.  
The data from local and central laboratory will be presented separately.  
2.3.2.2 
Creatinine and eGFR changes 
eGFR will be calculated according to simplified Modification of Diet in Renal Disease 
(sMDRD). 
The proportion of subjects with > 0.3 mg/dL increase, >0.5 mg/dL increase, > 1.0 mg/dL 
increase and >50% increase from baseline in serum creatinine levels at each time point, and at 
any time point, will be presented.   
The proportion of subjects with decreases from baseline GFR of >25%, >40%, >50%, 
and >30 mL/min/1.73 m2 at each time point, and at any time point, will be presented. 
The data from local and central laboratory will be presented separately.  
2.3.3 
Vital signs 
Descriptive statistics will be provided for values and change from baseline at each assessment 
time point for systolic blood pressure, diastolic blood pressure, pulse, respiratory rate, body 
temperature, and weight. 
Blood pressure and pulse during 48 hours drug infusion and 48 hours post infusion will also 
be listed.  


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2.3.4 
Electrocardiogram (ECG) 
An ECG substudy will be conducted at a subset of selected sites to enroll at least 500 subjects. 
Subjects without written informed consent for the ECG substudy before any study-specific 
assessment is performed will be excluded from the population.  
The analyses will be performed based on subjects who have at least one ECG at baseline 
(ECG recordings taken before the infusion starts will be considered) and one ECG post 
baseline (48 hour time point) which is recorded within 60 minutes after study drug infusion 
ends.  
The following quantitative variables will be summarized: RR interval, PR interval, QRS 
duration, QT interval, and corrected QT interval (QTc).   
The number and percentage of subjects with the following criterion will be presented. 
• QT > 500 msec  
• QT > 480 msec  
• QT > 450 msec 
• QT > 450 msec, male only 
• QT > 460 msec, female only 
• QT increases from baseline > 30 msec 
• QT increases from baseline > 60 msec 
• PR > 200 
• PR > 220 msec 
• PR increases from baseline > 25% 
• QRS > 110 msec and increase from baseline >=25% 
• QRS > 120 msec and increase from baseline >=25% 
• Heart rate >100 beats per minute and increase from baseline >=25% 
• Heart rate < 50 beats per minute and decrease from baseline >=25% 
QT data will be analyzed for both the Fridericia (primary) and Bazzett’s (secondary) 
corrections. 
 
Newly occurring abnormalities in ECG morphology will be summarized by treatment 
group and overall. Newly occurring is defined as no occurrence on any of the baseline 
ECGs with the presence of the finding on any single ECG post baseline. 
A listing of all abnormalities will be provided, as well as a by-subject listing of all 
quantitative ECG parameters.   
2.3.5 
Confirmed blood pressure decreases (CBPD) 
The number and percentage of subjects who experience a confirmed blood pressure decrease 
requiring a study drug dose adjustment during study drug administration will be provided. 
Among subjects who experience a confirmed blood pressure decrease event, the events will be 
further characterized with respect to impact on study drug administration (dose decreased or 


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study drug discontinued or both), the timing of event onset relative to study drug initiation, 
the magnitude of the blood pressure decrease at its onset and the trough blood pressure 
recorded, the blood pressure measurements after study drug discontinuation, outcome, 
treatment(s) required, and whether considered symptomatic, i.e. an AE. In addition, these 
summaries will be provided separately for those confirmed events that resulted in study drug 
dose reduction, and those that resulted in study drug discontinuation. 
Course of blood pressure after the occurrence of first CBPD up to Day 5 will be presented.  
To further investigate the impact of CBPD, the following analyses will be performed.  
• Baseline characteristics by CBPD subgroup (yes/no). 
• Concomitant medications by CBPD subgroup (yes/no). 
• CV death through Day 180, WHF through Day 5 and CV death or rehospitalization 
due to heart failure or renal failure through Day 180 by CBPD impact on study drug 
administration (dose decreased or study drug discontinued or both). 
• AEs associated with the occurrence of the CBPD. 
2.3.6 
Pregnancy test results  
Any pregnancies reported will be listed. 
2.3.7 
Liver toxicity function and liver events 
2.3.7.1 
Liver toxicity function 
The liver toxicity (LFT abnormality) will be identified with the SMQ ‘Drug related hepatic 
disorders – comprehensive search’ (Broad) and the laboratory parameters mainly AST 
(aspartate aminotransferase; also known as SGOT), ALT (alanine aminotransferase; also 
known as SGPT), ALP (alkaline phosphatase) and TBL (total bilirubin; conjugated (direct) 
and unconjugated (indirect) bilirubin). 
The standard SMQ-PT table and odds ratio will be used to provide the number and percentage 
of subjects with hepatic disorders as mentioned in Section 2.3.1 (hepatotoxicity, SMQ ‘Drug 
related hepatic disorders – comprehensive search’)  
The liver function related parameters will be shown in the laboratory standard tables (see 
Section 2.3.2). 
In addition, summary tables will be provided on the number and percentage of subjects having 
the following criteria: 
Table 2-8 
Criteria for evaluating liver toxicity 
Parameter 
Criterion 
ALT or AST 
ALT or AST > 3xULN 
 
ALT or AST > 5xULN 
 
ALT or AST > 8xULN 
 
ALT or AST > 10xULN 
 
 


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Parameter 
Criterion 
ALT/AST & TBL 
ALT or AST >3x ULN and TBL >1.5x ULN 
 
ALT or AST >3x ULN and TBL >2x ULN 
 
ALT or AST >5x ULN and TBL >2x ULN 
 
ALT or AST >8x ULN and TBL >2x ULN 
 
ALT or AST >10x ULN and TBL >2x ULN 
 
ALT or AST >3x ULN and TBL >2x ULN and ALP <2x ULN 
 
 
TBL & ALP 
TBL >1.5x ULN and ALP >2x ULN 
 
TBL >2x ULN and ALP >2x ULN 
 
 
Isolated TBL 
TBL >1.5x ULN & ALT and AST <=3x ULN and ALP <=2x ULN 
 
TBL >2x ULN & ALT and AST <=3x ULN and ALP <=2x ULN 
 
TBL >3x ULN & ALT and AST <=3x ULN and ALP <=2x ULN 
 
 
Isolated ALP 
ALP >1.5x ULN &  ALT and AST <=3x ULN and TBL <=1.5x ULN 
 
ALP >2x ULN & ALT and AST <=3x ULN and TBL <=1.5x ULN 
 
ALP >3x ULN & ALT and AST <=3x ULN and TBL <=1.5x ULN 
 
ALP >5x ULN & ALT and AST <=3x ULN and TBL <=1.5x ULN 
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total 
bilirubin; ULN: upper limit of normal. 
Plots showing the relationship between TBL and ALT or AST (eDish plot) will also be 
provided.  
 
2.3.7.2 
Liver events 
Detailed information of liver event is collected only if subjects report liver event.  
The following eCRF pages will be collected and details are listed for the reported liver event. 
• Medical history possibly contributing to liver dysfunction. 
• Liver event overview: details of clinical signs and symptoms, event related to study 
drug, other alternative diagnoses etc.  
• History of alcohol use 
• Drugs of abuse history 
• Imaging 
• Pathology 
• Autoimmune 
• Viral serology 
• Local laboratory liver function test 
• Concomitant medication Acetaminophen/Paracetamol 


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2.4 
Interim analyses 
It is planned to establish an external and Independent Data Monitoring Committee (DMC) to 
monitor subject safety data on a regular basis during the course of the study. For this study, it 
is planned that the DMC will review safety data on a regular frequency, e.g., every six 
months. DMC may request additional safety data review.  Such safety analyses do not inflate 
the type I error for the primary efficacy hypothesis testing and thus require no multiplicity 
adjustments. 
It is planned to have one formal interim efficacy analyses. The cut-off for this interim analysis 
is planned when the information fraction (number of confirmed CV deaths relative to the 
targeted total number of confirmed CV death at the study completion) of 60% is achieved 
(corresponding to 329 CV deaths). Some adjustment to the time of interim analysis may be 
made to coincide with the regular DMC meetings. One-sided tests will be performed and 
appropriate statistical adjustments for the interim analysis actually performed will be made to 
ensure the overall one-sided type I error of 0.02 (Lan-DeMets spending function to match an 
O’Brien-Fleming stopping boundary). For the interim analysis, the analysis dataset will 
comprise all subjects who were randomized before the cut-off date.  
The trial may be concluded early for efficacy, if a significant difference between two 
treatment arms for the number of CV deaths is achieved by crossing the pre-specified 
boundary at interim analysis. Interim analysis will be performed by an external independent 
statistician at an external data analysis center, who will not be involved in the study conduct. 
The results will be reviewed by the independent DMC. Investigators and others who are 
involved in the conduct of the trial and in the analysis of the final trial results, or who have 
contact with study centers, will remain blinded to the treatment codes and interim analysis 
results until all monitoring decisions have been made and the database has been locked for 
final analysis.  
If the DMC recommends stopping the study due to overwhelming efficacy of CV deaths, i.e., 
crossing the pre-specified boundary and favorable risk and benefit ratio, the multiple testing 
procedure in Figure 2-1 will be applied and updated as Figure 2-2 below. The significance 
levels for WHF, LOS and CVDR are 0.6α, 0.2α and 0.2α. 
The Lan-DeMets spending function of the O’Brien-Fleming stopping boundary will then be 
applied to determine the nominal significance level at the interim analysis based on the one-
sided alpha of 0.025.  
The information fraction at the interim analysis for the three efficacy variables will be 
calculated as follows: 
• WHF: number of randomized subjects at the interim analysis divided by 6800 
It is expected that all randomized subjects will have complete WHF information 
through Day 5, as all patients will be followed up at least 14 days.   
• LOS and CVDR: number of randomized subjects at the interim analysis divided by 
6800 times 0.9 
This assumes that 10% of the efficacy data will be missing at the interim analysis 
cutoff date.    


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Figure 2-2 
Sequentially rejective multiple testing procedure if DMC recommends 
stopping of the study due to overwhelming efficacy in CV death 
 
Applying the Lan-DeMets spending function of the O’Brien-Fleming stopping boundary if the 
DMC recommends stopping the study, assuming 70% of the randomized subjects are accrued 
at the interim analysis, the nominal one-sided alpha for the three efficacy variables are 
calculated as shown in the Table 2-9.  
 
Table 2-9 
Nominal one-sided alpha at 70% randomized subjects accrued if CVD 
is rejected 
Efficacy variable 
Updated alpha if 
CVD rejected  
Information 
fraction 
Nominal 1-sided alpha  
at interim analysis 
WHF 
0.6x0.025=0.015 
0.7 
0.0036 
LOS 
0.2x0.025=0.005 
0.7x0.9=0.63 
0.0004 
CVDR 
0.2x0.025=0.005 
0.7x0.9=0.63 
0.0004 
Note if the boundary is crossed for any of the remaining hypotheses, the multiple testing 
procedure will reject the hypothesis and update the graph. The nominal one-sided significance 
level will be re-calculated. The process continues until no hypothesis can be rejected. 
 
For subjects not discharged by interim analysis cutoff date, the LOS will be imputed as the 
maximum of 


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(1) mean value for subjects with actual LOS, including censoring at Day 60 and die in 
hospital 
(2) LOS at the cutoff date 
All cause death will be tested at alpha of 0.025 (one-sided). 
 
2.5 
Sample size and power considerations 
The alpha (α) level of 5% is split to CV death at 4% and to WHF at 1%. The sample size 
calculation is based on the CV death endpoint. This is an event-driven trial with fixed 
maximum duration of 180 day follow-up period for each patient. In the sample size 
calculation, the 180-day CV death rate is assumed to be 9.0% in the placebo group, which is 
about 80% of 11.3% of all cause death observed in the placebo group in the RELAX-AHF 
study. 
 
 
 
 
 
The interim analysis will be performed when 329 CV deaths are accrued. At the interim 
analysis, if Z-score of 2.786 (one-sided nominal p = 0.0027) is observed, which corresponds 
to HR of 0.735 (at least 26.5% RRR), the DMC may recommend to stop the study due to 
crossing the boundary. If there is no stopping at the formal efficacy interim analysis, the final 
analysis will need to have a Z-score of 2.072 (one-sided nominal p = 0.0192), which 
corresponds to HR of 0.838 (at least 16.2% RRR), to declare a significant study. (East ® 
5.4.2, Cytel Inc., Cambridge MA, 2010). 
 
 
 
If the observed overall event rate of the CV death endpoint during the course of the trial is 
much lower than expected based on the design assumptions (assessed on a blinded basis), 
adjustments may be made to the number of patients to be randomized in order to achieve the 
required number of events in the pre-planned timeframe (180 days) and thus to preserve the 
target study power. 
For the sample size of 6,800, the unconditional power for the WHF endpoint and all three key 
secondary endpoints under various HRs (mean difference for Length of Stay) are summarized 
in the tables below: 


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Table 2-10 
Assumed effect sizes for worsening heart failure and the key 
secondary efficacy variables on power calculation  
 
Assumed HR or mean 
difference 
Worsening Heart Failure (placebo rate: 
12.2%) 
0.70 
0.80 
All cause death (placebo rate: 11.3%) 
0.80 
0.816 
0.83 
Length of Stay (mean ±SD between placebo 
and serelaxin: 0.9 ±9.6 day) 
0.9 day 
0.7 day 
CV death or HF/RF rehospitalization (placebo 
rate: 34.1%) 
0.85 
0.88 
Note: Assumed placebo rates for all cause death and WHF and mean difference (mean + SD) in LOS between 
serelaxin and placebo were based on RELAX AHF study; placebo event rate of CV death or HF/RF 
rehospitalization was estimated to be 34.1% by assuming an exponential distribution with the same hazard as that 
observed through Day 60 in RELAX AHF study.   
Table 2-11 
Powers (unconditional) of primary and key secondary variables on 
selected scenarios 
A) All cause death 
Scenarios of effect sizes 
All cause 
death Day 
180* 
All-cause death (HR=0.80); WHF (HR=0.70) 
83 
All-cause death (HR=0.816); WHF (HR=0.70) 
77 
All-cause death (HR=0.82); WHF (HR=0.70) 
70 
All-cause death (HR=0.80); WHF (HR=0.80) 
82 
All-cause death (HR=0.816); WHF (HR=0.80) 
76 
All-cause death (HR=0.82); WHF (HR=0.80) 
70 
Note: The true HR for CV death is assumed to be 0.78 in all scenarios. 
          *Power if one or both of the two primary variables are significant.   
 
 


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Note: The true HR for CV death is assumed to be 0.78 in all scenarios. 
Note: The power for the WHF endpoint is approximated based on logrank test, but the analysis will be based on 
Gehan-Wilcoxon test. 
3 
References 
1. Bretz F, Maurer W, Brannath W, and Posch M (2009) A graphical approach to
sequentially rejective multiple test procedures. Statistics in Medicine 28, 586-604
2. Levey AS, Coresh J, Balk E, et al (2003) National Kidney Foundation Practice Guidelines
for Chronic Kidney Disease:  Evaluation, Classification, and Stratification. Ann Intern
Med; 139:137-147.
3. Metra M, Ponikowski P, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH,
Hua TA, Severin T, Unemori E, Voors AA, Teerlink JR (2013). Effects of serelaxin in
subgroups of patients with acute heart failure: results from RELAX-AHF. European Heart
Journal; 34:3128-3136.
B) CVD, WHF, LOS and CVDR
Scenarios of effect sizes 
CV 
death 
Day 180 
WHF 
Day 5 
LOS 
CV 
death or 
HF/RF 
hosp. 
Reject All 
WHF (HR=0.7) – LOS (0.9 days) – 
CVD/rehosp (HR=0.85)  
82 
99 
93 
93 
77 
WHF (HR=0.7) – LOS (0.9 days) – 
CVD/rehosp (HR=0.88)  
82 
99 
92 
79 
68 
WHF (HR=0.7) – LOS (0.7 days) – 
CVD/rehosp (HR=0.85) 
82 
99 
78 
93 
69 
WHF (HR=0.7) – LOS (0.7 days) – 
CVD/rehosp (HR=0.88) 
82 
99 
77 
77 
60 
WHF (HR=0.8) – LOS (0.9 days) – 
CVD/rehosp (HR=0.85) 
82 
82 
87 
87 
68 
WHF (HR=0.8) – LOS (0.9 days) – 
CVD/rehosp (HR=0.88) 
82 
82 
86 
73 
59 
WHF (HR=0.8) – LOS (0.7 days) – 
CVD/rehosp (HR=0.85) 
82 
81 
73 
86 
60 
WHF (HR=0.8) – LOS (0.7 days) – 
CVD/rehosp (HR=0.88) 
81 
81 
72 
72 
53